Thèses : « Familial cancer genetics »

1

Agenbag, Gloudi. « Molecular genetic analysis of familial breast cancer in South Africa ». Thesis, Link to the online version, 2005. http://hdl.handle.net/10019/953.

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2

Henry, Marie-Louise. « Non-thyroid malignancies in familial non-medullary thyroid cancer ». The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555088063551251.

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3

Rattenberry, Eleanor Clare. « Identification and assessment of variants of uncertain significance in familial cancer syndromes ». Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6742/.

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The identification of the causative mutation(s) in individuals with familial cancer syndromes informs their clinical management and allows cascade testing of family members, which informs their clinical management in turn. The advent of next generation sequencing (NGS) has revolutionised diagnostic genetic analysis, demonstrated by this thesis. Three novel NGS assays have been developed. The first two assays allowed more comprehensive analysis of two genetically heterogeneous tumours, phaeochromocytoma/parganglioma and renal cell carcinoma, by creation of NGS-based gene panel tests. These assays allowed increased detection of germline mutations at a lower cost per gene and reduced processing time compared to previous methods of analysis. The third assay also uses NGS but, instead, to more thoroughly analyse a single gene. The full gene region for VHL was examined at mosaic detection level, with a clinically actionable mutation identified in 18% of patients with von Hippel-Lindau disease in whom a mutation could not be identified by conventional analysis. The difficulty of providing more comprehensive genetic analysis is the concurrent increase in identification of variants of uncertain significance (VUSs). In depth variant analysis was conducted for all VUSs identified during this research. The reassignment of 17% of these VUSs as pathogenic or benign was enabled.

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4

Naicker, Sundresan. « Evaluating Familial History as a Phenotypic Screening Tool for Colorectal Cancer in the Australian General Practice Population ». Thesis, University of Sydney, 2016. http://hdl.handle.net/2123/16868.

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Colorectal cancer (CRC) is the second most common cancer among males and third among females across the world. In Australia it is the second most prevalent and the second leading cause of cancer-related mortality with the number of CRC incidences doubling over the last decade. While there has been a reduction of the incidence-adjusted mortality of CRC, a significant number of CRC detections are made at either the intermediate or later stages of the disease progression despite the roll out of a population based screening program for individuals aged 50 and over. Data shows that ‘one size fits all’ nature of the program despite recommendations from the NHMRC to screen according to the familial risk of an individual and inappropriate colonoscopy referrals, may have led to over screening those at average risk while potentially under-screening and missing those at an increased risk. Furthermore this program may have missed individuals under the age of 50 that have a high familial lifetime risk of developing CRC and require earlier CRC screening with a colonoscopy. It was hypothesised that implementing an online familial risk tool that notified both patients (aged 25-74) and their GPs of their familial CRC lifetime risk would increase the uptake of risk-appropriate screening among the study population relative to controls that receive usual care, during the 12 month study period. In doing so, this thesis used a complex intervention aimed at improving the rate of risk-appropriate screening for colorectal cancer (CRC) among an Australian General Practice population. This intervention utilised an online evidenced -based familial history algorithm, that stratified participants into three Australian National Health and Medical Research Council (NHMRC) recommended relative risk groups for screening CRC. These categories are based on a strong body of evidence showing that familial phenotype as measured by family history is a significant and non-modifiable risk factor for an increased lifetime risk of CRC. The algorithm used in the online tool was adapted from the NHMRC guidelines but were also updated by utilising the most recent evidence-base in addition to consulting with a group of experts. This algorithm was then programmed into an online website called “Which test is best?”. This website notified participants of their familial risk in addition to faxing or emailing this information to their consulting General Practitioner (GP). The website was piloted among members of a cancer consumer group (n=26), before being amended to improve clarity and the website interface. It was then implemented in a clustered RCT to evaluate its effect on risk-appropriate CRC screening. The intervention was implemented at both the cluster (GP practice) (Intervention n=27, Control n=28) and participant (eligible patients aged 25-74 with no personal history of CRC and/or inflammatory bowel diseases) level (Intervention, n=836, Control n=726). Those in the intervention arm were given access to the online website with risk tool and their family history information. In addition to their familial risk category with NHMRC recommended screening guidelines were forwarded to their consulting GP, while the control group had usual care. Both groups were followed up 12 months later to obtain their self-reported CRC screening information using the online survey. Thereafter, the control group was immediately given access to the online website with risk tool so that their family history information could be recorded and the level of risk-appropriate screening could be calculated for both groups. The results from this study showed ,that there was no significant difference in risk-appropriate screening rates amongst participants allocated to the intervention group compared to the control group as there was no main effect of allocation when included as a predictor within a binomial logistic regression when modelled to the GEE. However, participants allocated to the intervention group that were designated as belonging to the potentially high-risk category did engage in significantly higher levels of risk-appropriate screening when compared to the control group at 12 month follow-up. This was observed by a significant interaction effect of both family history and allocation in predicting risk-appropriate screening the final GEE model. Specifically, potentially high-risk individuals that were allocated to the intervention group had higher odds (about five times) of engaging in risk-appropriate screening when compared to those at population level risk that were assigned to either control or intervention, when controlling for other variables. This suggests that the online familial risk tool was effective in changing the behaviour of participants from the intervention group that were categorised as having a family history consistent with a potentially high risk (defined as having lifetime relative risk three times or greater of the general population) of developing CRC in their lifetimes. GPs from participating clusters were followed up by a survey (n=66) to assess their attitudes, knowledge and perceived barriers on utilising family history to risk-appropriately screen their average risk patients. Three important findings emerged from this survey. Firstly it shows that the majority of GPs in this study regard family history as the most important factor in screening their asymptomatic patients for CRC. It also shows that these GPs in principle strongly support the NHMRC guidelines, continuing education and peer-reviewed evidence as the most important knowledge factors in evaluating their CRC screening recommendations for asymptomatic patients, while being somewhat less influenced by government policy and their patients’ personal perceptions about the efficacy of a particular CRC screening test. However GPs appear very sensitive to their patients’ fears and anxiety over CRC screening, assessing this factor as the most important barrier to screening for CRC followed by their subjective lack of experience with CRC screening and time constraints imposed during the consultation. Findings also showed a substantial level of dissonance between what GPs believe to be appropriate CRC screening for their asymptotic patients and what they may be likely to recommend with 77% GPs self-reporting that they still refer up to 10 average risk asymptomatic patients to a colonoscopy during a typical month. Taken together the findings from this thesis show that that an intervention which aims to include both the patient and GP improves the uptake CRC risk-appropriate screening for individuals with potentially high-risk. It shows that a tailored risk tool, that supports GP triage may be sufficient to improve uptake of CRC screening modalities across all risk groups but may not be sufficient to encourage risk-appropriate screening of those from average and moderate risk. This is mainly due to persistent over-screening in the average-risk group within our study sample. Future studies may need to examine and differentiate between under screeners and over-screeners in order to target and tailor interventions to those groups separately.

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5

Naicker, Sundresan. « Evaluating Familial History as a Phenotypic Screening Tool for Colorectal Cancer in the Australian General Practice Population ». Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16868.

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Colorectal cancer (CRC) is the second most common cancer among males and third among females across the world. In Australia it is the second most prevalent and the second leading cause of cancer-related mortality with the number of CRC incidences doubling over the last decade. While there has been a reduction of the incidence-adjusted mortality of CRC, a significant number of CRC detections are made at either the intermediate or later stages of the disease progression despite the roll out of a population based screening program for individuals aged 50 and over. Data shows that ‘one size fits all’ nature of the program despite recommendations from the NHMRC to screen according to the familial risk of an individual and inappropriate colonoscopy referrals, may have led to over screening those at average risk while potentially under-screening and missing those at an increased risk. Furthermore this program may have missed individuals under the age of 50 that have a high familial lifetime risk of developing CRC and require earlier CRC screening with a colonoscopy. It was hypothesised that implementing an online familial risk tool that notified both patients (aged 25-74) and their GPs of their familial CRC lifetime risk would increase the uptake of risk-appropriate screening among the study population relative to controls that receive usual care, during the 12 month study period. In doing so, this thesis used a complex intervention aimed at improving the rate of risk-appropriate screening for colorectal cancer (CRC) among an Australian General Practice population. This intervention utilised an online evidenced -based familial history algorithm, that stratified participants into three Australian National Health and Medical Research Council (NHMRC) recommended relative risk groups for screening CRC. These categories are based on a strong body of evidence showing that familial phenotype as measured by family history is a significant and non-modifiable risk factor for an increased lifetime risk of CRC. The algorithm used in the online tool was adapted from the NHMRC guidelines but were also updated by utilising the most recent evidence-base in addition to consulting with a group of experts. This algorithm was then programmed into an online website called “Which test is best?”. This website notified participants of their familial risk in addition to faxing or emailing this information to their consulting General Practitioner (GP). The website was piloted among members of a cancer consumer group (n=26), before being amended to improve clarity and the website interface. It was then implemented in a clustered RCT to evaluate its effect on risk-appropriate CRC screening. The intervention was implemented at both the cluster (GP practice) (Intervention n=27, Control n=28) and participant (eligible patients aged 25-74 with no personal history of CRC and/or inflammatory bowel diseases) level (Intervention, n=836, Control n=726). Those in the intervention arm were given access to the online website with risk tool and their family history information. In addition to their familial risk category with NHMRC recommended screening guidelines were forwarded to their consulting GP, while the control group had usual care. Both groups were followed up 12 months later to obtain their self-reported CRC screening information using the online survey. Thereafter, the control group was immediately given access to the online website with risk tool so that their family history information could be recorded and the level of risk-appropriate screening could be calculated for both groups. The results from this study showed ,that there was no significant difference in risk-appropriate screening rates amongst participants allocated to the intervention group compared to the control group as there was no main effect of allocation when included as a predictor within a binomial logistic regression when modelled to the GEE. However, participants allocated to the intervention group that were designated as belonging to the potentially high-risk category did engage in significantly higher levels of risk-appropriate screening when compared to the control group at 12 month follow-up. This was observed by a significant interaction effect of both family history and allocation in predicting risk-appropriate screening the final GEE model. Specifically, potentially high-risk individuals that were allocated to the intervention group had higher odds (about five times) of engaging in risk-appropriate screening when compared to those at population level risk that were assigned to either control or intervention, when controlling for other variables. This suggests that the online familial risk tool was effective in changing the behaviour of participants from the intervention group that were categorised as having a family history consistent with a potentially high risk (defined as having lifetime relative risk three times or greater of the general population) of developing CRC in their lifetimes. GPs from participating clusters were followed up by a survey (n=66) to assess their attitudes, knowledge and perceived barriers on utilising family history to risk-appropriately screen their average risk patients. Three important findings emerged from this survey. Firstly it shows that the majority of GPs in this study regard family history as the most important factor in screening their asymptomatic patients for CRC. It also shows that these GPs in principle strongly support the NHMRC guidelines, continuing education and peer-reviewed evidence as the most important knowledge factors in evaluating their CRC screening recommendations for asymptomatic patients, while being somewhat less influenced by government policy and their patients’ personal perceptions about the efficacy of a particular CRC screening test. However GPs appear very sensitive to their patients’ fears and anxiety over CRC screening, assessing this factor as the most important barrier to screening for CRC followed by their subjective lack of experience with CRC screening and time constraints imposed during the consultation. Findings also showed a substantial level of dissonance between what GPs believe to be appropriate CRC screening for their asymptotic patients and what they may be likely to recommend with 77% GPs self-reporting that they still refer up to 10 average risk asymptomatic patients to a colonoscopy during a typical month. Taken together the findings from this thesis show that that an intervention which aims to include both the patient and GP improves the uptake CRC risk-appropriate screening for individuals with potentially high-risk. It shows that a tailored risk tool, that supports GP triage may be sufficient to improve uptake of CRC screening modalities across all risk groups but may not be sufficient to encourage risk-appropriate screening of those from average and moderate risk. This is mainly due to persistent over-screening in the average-risk group within our study sample. Future studies may need to examine and differentiate between under screeners and over-screeners in order to target and tailor interventions to those groups separately.

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6

Kechik, Joy E. « Comparing Family Sharing Behaviors in BRCA Carriers with PALB2 Carriers ». Scholar Commons, 2019. https://scholarcommons.usf.edu/etd/7825.

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Identifying individuals with hereditary cancer predisposition can improve health outcomes for patients and their family members through early cancer detection and prevention strategies. Prior research about family sharing of genetic test results among those with hereditary breast cancer has overwhelmingly been limited to the BRCA1 and BRCA2 genes. The present study sought to compare family sharing behaviors in women with pathogenic BRCA variants to women with pathogenic variants in the more recently identified and characterized PALB2 gene. A total of 18 BRCA carriers and 13 PALB2 carriers were interviewed about family sharing practices using a semi-structured guide based on the Integrated Behavioral Model. Barriers and facilitators to family sharing were similar for both BRCA and PALB2 carriers, with logistical difficulties and emotional struggles related to anticipated negative reactions from relatives being the most salient barriers. The most important facilitators were: attitude that sharing enables health protection, provider recommendation, strong family relationships, confidence in sharing basic information, knowledge of what to share and how to share, and belief that sharing is highly important. Given similar attitudes, norms, and control beliefs related to family sharing, similar, but tailored interventions may be effective at increasing family disclosures among both groups. Such interventions should involve a discussion of patients’ attitudes towards sharing with healthcare providers to strengthen motivations and address barriers and provision of informational resources to increase confidence and knowledge. Family sharing resources should clearly specify which relatives need to be informed, why sharing is important, and how at-risk relatives may benefit.

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7

de, Zwaan Sally Elizabeth. « The Genetics of Basal Cell Carcinoma of the Skin ». Thesis, The University of Sydney, 2008. http://hdl.handle.net/2123/3878.

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BCC is the commonest cancer in European-derived populations and Australia has the highest recorded incidence in the world, creating enormous individual and societal cost in management of this disease. The incidence of this cancer has been increasing internationally, with evidence of a 1 to 2% rise in incidence in Australia per year over the last two decades. The main four epidemiological risk factors for the development of BCC are ultraviolet radiation (UVR) exposure, increasing age, male sex, and inability to tan. The pattern and timing of UVR exposure is important to BCC risk, with childhood and intermittent UVR exposure both associated with an increased risk. The complex of inherited characteristics making up an individual’s ‘sun sensitivity’ is also important in determining BCC risk. Very little is known about population genetic susceptibility to BCC outside of the rare genodermatosis Gorlin syndrome. Mutations in the tumour suppressor gene patched (PTCH) are responsible for this BCC predisposition syndrome and the molecular pathway and target genes of this highly conserved pathway are well described. Derangments in this pathway occur in sporadic BCC development, and the PTCH gene is an obvious candidate to contribute to non-syndromic susceptibility to BCC. The melanocortin 1 receptor (MC1R) locus is known to be involved in pigmentary traits and the cutaneous response to UVR, and variants have been associated with skin cancer risk. Many other genes have been considered with respect to population BCC risk and include p53, HPV, GSTs, and HLAs. There is preliminary evidence for specific familial aggregation of BCC, but very little known about the causes. 56 individuals who developed BCC under the age of 40 in the year 2000 were recruited from the Skin and Cancer Foundation of Australia’s database. This represents the youngest 7 – 8% of Australians with BCC from a database that captures approximately 10% of Sydney’s BCCs. 212 of their first degree relatives were also recruited, including 89 parents and 123 siblings of these 56 probands. All subjects were interviewed with respect to their cancer history and all reports of cancer verified with histopathological reports where possible. The oldest unaffected sibling for each proband (where available) was designated as an intra-family control. All cases and control siblings filled out a questionnaire regarding their pigmentary and sun sensitivity factors and underwent a skin examination by a trained examiner. Peripheral blood was collected from these cases and controls for genotyping of PTCH. All the exons of PTCH for which mutations have been documented in Gorlin patients were amplified using PCR. PCR products were screened for mutations using dHPLC, and all detectable variants sequenced. Prevalence of BCC and SCC for the Australian population was estimated from incidence data using a novel statistical approach. Familial aggregation of BCC, SCC and MM occurred within the 56 families studied here. The majority of families with aggregation of skin cancer had a combination of SCC and BCC, however nearly one fifth of families in this study had aggregation of BCC to the exclusion of SCC or MM, suggesting that BCCspecific risk factors are also likely to be at work. Skin cancer risks for first-degree relatives of people with early onset BCC were calculated: sisters and mothers of people with early-onset BCC had a 2-fold increased risk of BCC; brothers had a 5-fold increased risk of BCC; and sisters and fathers of people with early-onset BCC had over four times the prevalence of SCC than that expected. For melanoma, the increased risk was significant for male relatives only, with a 10-fold increased risk for brothers of people with early-onset BCC and 3-fold for fathers. On skin examination of cases and controls, several phenotypic factors were significantly associated with BCC risk. These included increasing risk of BCC with having fair, easyburning skin (ie decreasing skin phototype), and with having signs of cumulative sun damage to the skin in the form of actinic keratoses. Signs reflecting the combination of pigmentary characteristics and sun exposure - in the form of arm freckling and solar lentigines - also gave subjects a significantly increased risk BCC. Constitutive red-green reflectance of the skin was associated with decreased risk of BCC, as measured by spectrophotometery. Other non-significant trends were seen that may become significant in larger studies including associations of BCC with propensity to burn, moderate tanning ability and an inability to tan. No convincing trend for risk of BCC was seen with the pigmentary variables of hair or eye colour, and a non-significant reduced risk of BCC was associated with increasing numbers of seborrhoeic keratoses. Twenty PTCH exons (exons 2, 3, 5 to 18, and 20 to 23) were screened, accounting for 97% of the coding regions with published mutations in PTCH. Nine of these 20 exons were found to harbour single nucleotide polymorphisms (SNPs), seen on dHPLC as variant melting curves and confirmed on direct sequencing. SNPs frequencies were not significantly different to published population frequencies, or to Australian general population frequencies where SNP database population data was unavailable. Assuming a Poisson distribution, and having observed no mutations in a sample of 56, we can be 97.5% confident that if there are any PTCH mutations contributing to early-onset BCC in the Australian population, then their prevalence is less than 5.1%. Overall, this study provides evidence that familial aggregation of BCC is occurring, that first-degree relatives are at increased risk of all three types of skin cancer, and that a combination of environmental and genetic risk factors are likely to be responsible. The PTCH gene is excluded as a major cause of this increased susceptibility to BCC in particular and skin cancer in general. The weaknesses of the study design are explored, the possible clinical relevance of the data is examined, and future directions for research into the genetics of basal cell carcinoma are discussed.

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8

de, Zwaan Sally Elizabeth. « The Genetics of Basal Cell Carcinoma of the Skin ». University of Sydney, 2008. http://hdl.handle.net/2123/3878.

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Doctor of Philosophy(PhD)
BCC is the commonest cancer in European-derived populations and Australia has the highest recorded incidence in the world, creating enormous individual and societal cost in management of this disease. The incidence of this cancer has been increasing internationally, with evidence of a 1 to 2% rise in incidence in Australia per year over the last two decades. The main four epidemiological risk factors for the development of BCC are ultraviolet radiation (UVR) exposure, increasing age, male sex, and inability to tan. The pattern and timing of UVR exposure is important to BCC risk, with childhood and intermittent UVR exposure both associated with an increased risk. The complex of inherited characteristics making up an individual’s ‘sun sensitivity’ is also important in determining BCC risk. Very little is known about population genetic susceptibility to BCC outside of the rare genodermatosis Gorlin syndrome. Mutations in the tumour suppressor gene patched (PTCH) are responsible for this BCC predisposition syndrome and the molecular pathway and target genes of this highly conserved pathway are well described. Derangments in this pathway occur in sporadic BCC development, and the PTCH gene is an obvious candidate to contribute to non-syndromic susceptibility to BCC. The melanocortin 1 receptor (MC1R) locus is known to be involved in pigmentary traits and the cutaneous response to UVR, and variants have been associated with skin cancer risk. Many other genes have been considered with respect to population BCC risk and include p53, HPV, GSTs, and HLAs. There is preliminary evidence for specific familial aggregation of BCC, but very little known about the causes. 56 individuals who developed BCC under the age of 40 in the year 2000 were recruited from the Skin and Cancer Foundation of Australia’s database. This represents the youngest 7 – 8% of Australians with BCC from a database that captures approximately 10% of Sydney’s BCCs. 212 of their first degree relatives were also recruited, including 89 parents and 123 siblings of these 56 probands. All subjects were interviewed with respect to their cancer history and all reports of cancer verified with histopathological reports where possible. The oldest unaffected sibling for each proband (where available) was designated as an intra-family control. All cases and control siblings filled out a questionnaire regarding their pigmentary and sun sensitivity factors and underwent a skin examination by a trained examiner. Peripheral blood was collected from these cases and controls for genotyping of PTCH. All the exons of PTCH for which mutations have been documented in Gorlin patients were amplified using PCR. PCR products were screened for mutations using dHPLC, and all detectable variants sequenced. Prevalence of BCC and SCC for the Australian population was estimated from incidence data using a novel statistical approach. Familial aggregation of BCC, SCC and MM occurred within the 56 families studied here. The majority of families with aggregation of skin cancer had a combination of SCC and BCC, however nearly one fifth of families in this study had aggregation of BCC to the exclusion of SCC or MM, suggesting that BCCspecific risk factors are also likely to be at work. Skin cancer risks for first-degree relatives of people with early onset BCC were calculated: sisters and mothers of people with early-onset BCC had a 2-fold increased risk of BCC; brothers had a 5-fold increased risk of BCC; and sisters and fathers of people with early-onset BCC had over four times the prevalence of SCC than that expected. For melanoma, the increased risk was significant for male relatives only, with a 10-fold increased risk for brothers of people with early-onset BCC and 3-fold for fathers. On skin examination of cases and controls, several phenotypic factors were significantly associated with BCC risk. These included increasing risk of BCC with having fair, easyburning skin (ie decreasing skin phototype), and with having signs of cumulative sun damage to the skin in the form of actinic keratoses. Signs reflecting the combination of pigmentary characteristics and sun exposure - in the form of arm freckling and solar lentigines - also gave subjects a significantly increased risk BCC. Constitutive red-green reflectance of the skin was associated with decreased risk of BCC, as measured by spectrophotometery. Other non-significant trends were seen that may become significant in larger studies including associations of BCC with propensity to burn, moderate tanning ability and an inability to tan. No convincing trend for risk of BCC was seen with the pigmentary variables of hair or eye colour, and a non-significant reduced risk of BCC was associated with increasing numbers of seborrhoeic keratoses. Twenty PTCH exons (exons 2, 3, 5 to 18, and 20 to 23) were screened, accounting for 97% of the coding regions with published mutations in PTCH. Nine of these 20 exons were found to harbour single nucleotide polymorphisms (SNPs), seen on dHPLC as variant melting curves and confirmed on direct sequencing. SNPs frequencies were not significantly different to published population frequencies, or to Australian general population frequencies where SNP database population data was unavailable. Assuming a Poisson distribution, and having observed no mutations in a sample of 56, we can be 97.5% confident that if there are any PTCH mutations contributing to early-onset BCC in the Australian population, then their prevalence is less than 5.1%. Overall, this study provides evidence that familial aggregation of BCC is occurring, that first-degree relatives are at increased risk of all three types of skin cancer, and that a combination of environmental and genetic risk factors are likely to be responsible. The PTCH gene is excluded as a major cause of this increased susceptibility to BCC in particular and skin cancer in general. The weaknesses of the study design are explored, the possible clinical relevance of the data is examined, and future directions for research into the genetics of basal cell carcinoma are discussed.

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9

Díaz, Gay Marcos. « Identification of new candidate genes for germline predisposition to familial colorectal cancer using somatic mutational profiling ». Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668900.

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Colorectal cancer (CRC) is one of the malignant neoplasms with higher incidence and mortality in Spain, Europe and worldwide. As a complex disease, both environmental and genetic factors influence CRC predisposition. Up to 35% of CRC patients present familial aggregation for the disease, whereas only around 2-8% of cases are linked to a well-known hereditary syndrome associated to pathogenic germline alterations in specific genes, namely APC, MUTYH, POLE, POLD1 or the DNA mismatch repair genes. During last years, next generation sequencing (NGS) techniques such as whole exome sequencing (WES) have been used to address this gap of missing heritability. Characterization of somatic mutational profiles, performed by the application of NGS to both germline and tumor DNA, has also been recently established as a powerful tool to identify novel genes linked to CRC predisposition. However, although some bioinformatic packages have been developed to address this analysis, it remains inaccessible for a substantial proportion of the scientific community. Accordingly, the main purpose of this doctoral thesis was to identify new genes involved in germline predisposition to familial CRC, by using an integrated germline-tumor WES analysis and somatic mutational profiling, as well as facilitating the application of these genomic analyses to the scientific community. As a first step, a bioinformatic tool to deal with somatic mutational profiling was developed. Shiny framework was used to build MuSiCa, a user-friendly web application freely accessible and potentially useful for non-specialized researchers. Tumor mutational burden calculation and mutational signature refitting analysis according to the information present in COSMIC database is available, as well as different options for sample classification through clustering and principal component analysis. Subsequently, an integrated germline-tumor analysis was implemented in a cohort of 18 familial CRC unrelated patients. WES data of both germline and tumor DNA was available, allowing the identification of new potential tumor suppressor genes according to Knudson’s two-hit hypothesis. Benefitting from the development of MuSiCa application, somatic mutational profiling was also analyzed, uncovering five hypermutated samples. An enrichment of DNA repair-associated genes was found, as well as some genes previously linked to predisposition syndromes to other cancer types. BRCA2, BLM, ERCC2, RECQL, REV3L and RIF1 were found as the most promising candidate genes for germline CRC predisposition. Interestingly, a germline mutation was found in the DNA repair gene RECQL in a patient with one of the hypermutated tumors, reinforcing the putative role of this gene in hereditary CRC. These findings could be helpful in clinical practice improving genetic counseling in the affected families.
El cáncer colorrectal (CCR) es una de las neoplasias con mayor incidencia y mortalidad en España y el mundo. Aunque un 35% de los pacientes presentan agregación familiar, sólo un 2-8% se asocia con un síndrome hereditario conocido, causado por mutaciones germinales en genes como APC, MUTYH, POLE, POLD1 o los genes del sistema de reparación del ADN por mal apareamiento de bases. En los últimos años, las técnicas de secuenciación de nueva generación (SNG), como la secuenciación del exoma completo (SEC), han sido utilizadas para el descubrimiento de nuevos genes implicados en la predisposición al CCR. La caracterización de los perfiles mutacionales somáticos, aplicando SNG al ADN germinal y tumoral, también se ha utilizado recientemente en este proceso. Sin embargo, aunque se han desarrollado algunos paquetes bioinformáticos para su análisis, todavía permanece inaccesible para una gran parte de la comunidad científica. En consecuencia, el objetivo principal de esta tesis doctoral ha sido el de identificar nuevos genes implicados en la predisposición germinal al CCR familiar, utilizando un análisis de SEC germinal-tumoral y caracterización mutacional somática, así como facilitar la aplicación de estos análisis genómicos a la comunidad científica. En primer lugar, se llevó a cabo el desarrollo de una herramienta bioinformática denominada Mutational Signatures in Cancer (MuSiCa), una aplicación web de manejo sencillo y acceso libre desarrollada a través de la plataforma Shiny, que permite el cálculo de la carga mutacional tumoral y la caracterización de las firmas mutacionales según la información disponible en la base de datos COSMIC. Posteriormente, se implementó un análisis integrado de SEC germinal-tumoral en una cohorte de 18 pacientes de CCR familiar, complementado con una caracterización mutacional somática, gracias al desarrollo de MuSiCa. Se detectaron cinco tumores hipermutados, así como un enriquecimiento de mutaciones germinales en genes involucrados previamente en síndromes de predisposición a otros tipos de cáncer y a la reparación del ADN. Los genes BRCA2, BLM, ERCC2, RECQL, REV3L y RIF1 fueron priorizados como los más prometedores de cara a la predisposición al CCR. Estos descubrimientos podrían ser de utilidad en la práctica clínica, mejorando el consejo genético en las familias afectadas.

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10

Sun, Sophie. « CDKN2Ap16 and familial cancer ». Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=24375.

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CDKN2A/p16 is a cell cycle inhibitor which blocks abnormal cell growth and proliferation. The CDKN2A gene is frequently mutated or deleted in a wide variety of tumour types. Germline mutations have also been identified in familial atypical multiple mole melanoma (FAMMM) pedigrees. However, the role of CDKN2A in hereditary cancer is uncertain. To explore the relationship between CDKN2A germline mutations and risk of cancer, 75 families with cancers at multiple sites were analysed for germline mutations in the CDKN2A gene. A Met53Ile mutation was found in a non-FAMMM kindred with multiple cancers, including one case of melanoma. The Met53Ile mutation has been previously reported in three Australian FAMMM kindreds. A known Ala148Thr polymorphism was also detected in 5 individuals. No other families were found to have CDKN2A alterations. There were no reported CDKN2A mutations in families without cases of melanoma. Analysis of microsatellite markers adjacent to CDKN2A on chromosome 9p21 revealed that this family shares a common haplotype with one other family with this mutation, suggesting that Met53Ile is a founder mutation. These results suggest that while CDKN2A mutations are not restricted to FAMMM pedigrees, they are very rare or absent in families with individuals without melanoma.

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11

Mohammed, Shehla Nilofer. « Familial breast cancer : a clinicopathological and genetic study ». Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299826.

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12

Luo, Liping. « A genetic study on familial breast cancer predisposing genes / ». Stockholm, 2002. http://diss.kib.ki.se/2002/91-628-5184-5.

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Ng, Wai-tong, et 吳偉棠. « Early detection and screening of familial nasopharyngeal carcinoma ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290720.

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Gauerke, Jennifer Leigh. « Genetic Evaluation of Patients and Families with Concern for Hereditary Tumor Syndromes within the OSU James Multidisciplinary Neuroendocrine/Thyroid Cancer ». The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555086532080802.

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Viana, Danilo Vilela 1975. « Historia familial de cancer nos pacientes com diagnostico de cancer de colon e reto no Hospital de Clinicas da Unicamp ». [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309743.

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Orientador: Iscia Teresinha Lopes-Cendes, Carmen Passos Lima
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-06T07:38:24Z (GMT). No. of bitstreams: 1 Viana_DaniloVilela_M.pdf: 17449794 bytes, checksum: 5628cf41f1e3b3dae3d2ad85bb64f5d4 (MD5) Previous issue date: 2006
Resumo: O câncer de cólon e reto é a quinta causa de mortalidade por câncer no Brasil. Sua taxa de mortalidade vem apresentando um aumento contínuo desde 1979. Entre os fatores de risco mais importantes para essa doença está a história familial de câncer de cólon e reto ou de pólipos adenomatosos. O propósito do presente estudo foi investigar a qualidade das histórias familiais (HF) registradas nos prontuários médicos e estimar a freqüência dos agregados familiais e das síndromes hereditárias de câncer nos pacientes com diagnóstico de câncer de cólon e reto atendidos no Hospital de Clínicas da UNICAMP. Um estudo retrospectivo foi delineado para avaliar os prontuários dos pacientes que tinham confirmação histopatológica do diagnóstico de adenocarcinoma de cólon ou reto. Inicialmente, 415 prontuários que apresentavam codificação para a doença foram selecionados a partir do livro de cirurgias e de uma lista de pacientes atendidos nos ambulatórios de oncologia clínica, radioterapia e proctologia. Foram excluídos 104, sendo realizada a revisão de 311 prontuários. Numa segunda fase do estudo todos esses pacientes foram convocados para um entrevista com médico geneticista para obtenção de nova história familial, e comparação subseqüente dos dados, na qual a história familial previamente registrada foi classificada como completa ou incompleta. Dentre os 311 prontuários revisados, 193 (62%) tinham HF de câncer registrada. No total, 95 pacientes compareceram à entrevista, dos quais 66 tinha HF registrada no seu prontuário para que fosse feita comparação. Dessas 66 HF, 21 (32%) puderam ser consideradas completas e 45 (68%) incompletas. Pelo menos um critério clínico para câncer hereditário foi preenchido por 39 pacientes. Agregação familiar de CCR foi encontrada em 19% dos indivíduos entrevistados. Estes achados demonstram que a coleta e o correto preenchimento das histórias familiais nos prontuários dos pacientes com câncer são freqüentemente negligenciados, o que poderia influenciar negativamente na qualidade da assistência médica a eles prestada. As formas hereditárias de câncer hereditário, em especial a síndrome de Lynch (câncer colorretal hereditário sem polipose - HNPCC), são subdiagnosticadas, impossibilitando que medidas preventivas e diagnóstico precoce sejam oferecidos às suas famílias.
Abstract: Colorectal cancer is the 5th mortality cause by cancer in Brazil, and has been showing a continuous increase in mortality since 1979. Among the most important risk factors for this disease is family history of CRC or adenomatous polyps. The purpose of the present study was to investigate family histories (FH) recorded in medical charts for completeness and accuracy and to estimate the frequency of cancer aggregates and cancer syndromes in colorectal cancer patients treated in a general hospital. A retrospective study was assembled to evaluate archived charts of patients with pathological diagnosis of colorectal adenocarcinoma. Four hundred and fifteen medical records with ICD-10 coding of colorectal cancer were selected from the list of pacients who had had consultation in the clinical oncology, radiation oncology or proctology clinics, from which 104 were excluded because of misclassification or unconfirmed diagnosis. 311 charts were fully reviewed, and these patients invited for a personal interview by a medical geneticist. FH obtained from chart reviews were compared to data obtained from personal interviews and subsequently classified as complete or incomplete. Among the 311 charts, 193 (62%) had FH of cancer recorded. Overall, 95 patients attended the interviews, 66 of whom had a FH recorded in their hospital charts allowing accuracy comparisons. Of these, 21/66 (32%) FH could be considered complete and 45/66 (68%) incomplete. Thirty-nine patients met at least one criterion for hereditary cancer. Familial aggregates of colorectal cancer were found in 18 families (19%). In conclusion, the data in this study showed that FH in medical charts were often flawed or carried important omissions, which could influence negatively medical attention delivered to patients, and that hereditary forms of cancer, especially hereditary non-polyposis colorectal cancer, were underdiagnosed, making it impossible to extend the benefits of early diagnosis and preventive measures to at risk family members.
Mestrado
Genetica Medica
Mestre em Ciências Médicas

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Morr, Lindsey. « Cascade testing communication within Lynch syndrome families : An examination of communication privacy management theory ». The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1525765585195444.

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Davis, Sarah Harmon. « Does Family Communication Matter ? Exploring Knowledge of Breast Cancer Genetics in Cancer Families ». BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/7246.

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Purpose: Knowledge of breast cancer genetics is critical for those at increased risk whomust make decisions about breast cancer screening options. The purpose of this study was toexplore cognitive and emotional variables that might influence knowledge of breast cancergenetics.Methods: This descriptive, exploratory study analyzed theory-based relationships amongvariables related to knowledge of breast cancer genetics in cancer families. Participants includedfirst-degree relatives of women with breast cancer who had received genetic counseling andtesting; participants themselves did not have breast cancer and had not received geneticcounseling or testing. Data were collected by telephone interview and survey. Variables analyzedinclude numeracy, health literacy, cancer-related distress, age, education, and the reportedamount of information shared by the participants<'> family members about genetic counseling.Results: The multiple regression model explained 13.9% of variance in knowledge of breastcancer genetics (p = 0.03). Best fit of the multiple regression model included all variables excepteducation. Reported amount of information shared was the only independently significantpredictor variable (p = 0.01).Conclusion: Participants who reported higher levels of information shared by a familymember about genetic counseling also demonstrated increased knowledge about breast cancergenetics.

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Maguire, Paula. « Investigation of the genetic basis of familial non-BRCA1/2 breast cancer / ». Stockholm, 2005. http://diss.kib.ki.se/2006/91-7140-602-6/.

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Hansford, Samantha. « Genetic basis of familial gastric cancer : beyond the e-cadherin (CDH1) locus ». Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46420.

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Importance. Familial aggregation occurs in approximately 10% of gastric cancers, which are generally sub-classified histologically as intestinal-type and diffuse gastric cancers. Though the genetic basis of familial intestinal-type gastric cancers is not known, in <50% of families clinically defined as hereditary diffuse gastric cancer, germline mutations in the E-cadherin gene, CDH1, are detected. This has lead to management guidelines and prevention strategies for mutation carriers. Objectives. To determine whether pathogenic germline mutations in genes alternative to CDH1 can be found in hereditary gastric cancer families using a multiplex panel sequencing approach. Design, Setting and Participants. One hundred fifteen probands from families who met the International Gastric Cancer Linkage Consortium clinical criteria for hereditary diffuse gastric cancer (n=106) or familial intestinal-type gastric cancer (n=9) were included. All diffuse gastric cancer probands tested negative for CDH1-mutations. Germline DNA was screened against a custom panel of 55 genes, including 14 prospective gastric cancer susceptibility genes, using a multiplexed amplicon-based next generation sequencing assay. Candidate mutations were validated via Sanger sequencing. Tumours from pathogenic mutation-positive probands were evaluated by immunohistochemistry. Results. Of 115 probands, four clearly pathogenic truncating mutations were identified in unrelated families, including two different mutations in CTNNA1 (alpha-catenin) and two different mutations in BRCA2. Previously described, functionally pathogenic missense mutations in SDHB (2 families) and STK11 (2 families) were also seen. Additional truncating mutations of likely lower penetrance were identified in ATM (4 families), MSR1 (2 families) and PALB2 (1 family). Cancers from carriers of CTNNA1 truncating variants had prominent loss of protein expression, further supporting their pathogenicity. Conclusion and Relevance. Using a multi-gene panel, families with hereditary gastric cancer were found to carry pathogenic mutations in genes commonly associated with other cancer susceptibility syndromes. In addition, this data suggests that familial gastric cancers, specifically hereditary diffuse gastric cancer syndrome, may benefit from a genetic, rather than clinical, classification. The genetic basis of the remaining families is likely attributable to mutations in genes yet to be implicated in hereditary gastric cancer or, in the diffuse gastric cancer families, atypical aberrations in the non-coding regions of CDH1.

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Antebi, Yael Jennifer. « Genetic predisposition to ovarian cancer in Ashkenazi Jewish families ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0009/MQ40766.pdf.

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Godino, Lea. « Presymptomatic testing for familial cancer syndromes in young adults : considerations, decision making and impact ». Thesis, University of Plymouth, 2017. http://hdl.handle.net/10026.1/8643.

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Background: Presymptomatic genetic testing should always involve a considered choice. Young adults are at a key life stage as they may be developing a career, forming partnerships and potentially becoming parents. Presymptomatic testing may therefore affect the future lives of consultands significantly when testing is undertaken in early adulthood. Aim: To explore presymptomatic testing for hereditary cancer in consultands aged 18-30 years with particular reference to psychosocial impact, the decision-making process and the consequent counselling needs. Methods: A mixed-methods sequential exploratory design was used, comprising a systematic review, a qualitative study and a quantitative study. Results of all phases were used to build a theoretical model regarding the process of presymptomatic testing in young adults. Findings: The systematic review indicated that many participants grew-up with little or no information concerning their genetic risk. The experience of genetic counselling was either reported as an opportunity for discussing problems or associated with feelings of disempowerment. Parents appeared to have exerted pressure on their children during the decision-making process. However, as a result of the qualitative study, the influence of other people and the decision-making process prior to counselling were identified as key factors. Further results from the quantitative phase underlined that parents felt they had control over the decisions their children made, while the majority of the young adults reported the request for the genetic test as their own decision. A new theoretical model of decision making and impact on young adults was built to synthesise the overarching experience of participants in this research project. Conclusion: Counselling approaches to this population may require modification both for young adults and their parents. Young adults may benefit from a multi-step approach to presymptomatic testing. Parents need to be more informed that genetic counselling is a forum where information can be obtained and young adults can talk about the testing decision, regardless of whether they want to be tested or not. The traditional ‘wait until they come to us’ approach by health services may be failing to meet the educational and emotional needs of this population.

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Ford, Deborah. « Genetic epidemiology of breast and ovarian cancer ». Thesis, Institute of Cancer Research (University Of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367527.

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Vaittinen, Pauli. « Risk characterization of familial cancer using the Swedish Family-Cancer database with a special reference to breast cancer / ». Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-723-1/.

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Izatt, Louise Patricia. « Ataxia telangiectasia : mutation detection in ataxia telangiectasia families and early-onset breast cancer cases ». Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343596.

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Catucci, Irene. « Identification of low-penetrance alleles, genetic modifiers and mutation analysis in familial breast cancer cases ». Thesis, Open University, 2013. http://oro.open.ac.uk/54681/.

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To date, germline mutations in known high-penetrance genes, mainly BRCAI and BRCA2, and in moderate- and low-penetrance genes are responsible for approximately 30- 35% of breast cancer familial clustering, leaving the majority of them unexplained. In addition, the variability of the risk conferred by BRCAI and BRCA2 mutations suggests the presence of genetic modifiers of this risk. Therefore, the identification and characterization of as many as possible of genetic factors is crucial for risk prediction in members of breast cancer families. In this context, the aim of this thesis was firstly to investigate the role of the two Fanconi Anemia (FA) genes PALB2 and SLX4 as breast cancer predisposing loci. In the PALB2 screening, I observed a frequency of deleterious mutation of 2.1 % in familial cases recruited in cancer centers in Milan. Interestingly, I also identified the recurrent mutation c. l 027C > T, detected with 10-fold increased frequency in cases from Bergamo with respect to those ascertained in Milan, suggesting a founder effect. On the contrary. the SLX 4 analysis failed to identify any clearly deleterious mutation, excluding a major role of this gene in breast cancer susceptibility in the Italian population. In addition, I genotyped the candidate low-risk rs895819 polymorphism, located in the gene coding for miR-27a, to evaluate its role in reducing breast cancer risk, previously reported in the German population. No such an association was observed in our sample set. Finally, I investigated the role of the CASPS rs3834129 ins/del polymorphism as a genetic modifier in Italian BRCA1 and BRCA2 mutation carries and I observed an association of this SNP with increased breast cancer risk only in individuals carrying BRC1 mutations. In conclusion, our investigation contributed to assess the role of candidate predisposing loci and genetic modifiers of breast cancer risk, providing further knowledge on the susceptibility to this disease.

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Elliott, Diana. « The impact of genetic counselling for familial breast cancer on women's psychological distress, risk perception and understanding of BRCA testing ». University of Western Australia. School of Population Health, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0190.

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[Truncated abstract] Background: A review of the literature indicated there was a need for more long-term randomised controlled studies on the effects of BRCA counselling/testing on high risk women, including improved strategies for risk communication. Reviews have also shown women are confused about the significance of inconclusive or non informative results with a need for more research in this area. Aims: The general aim of this study was to evaluate the impact of breast cancer genetic counselling on psychological distress levels, perception of risk, genetic knowledge and understanding of BRCA testing/test results in a cohort of 207 women from high risk breast cancer families who were referred for genetic counselling in Perth during the period 1997 to 2001. Short- and long-term impact of BRCA genetic counselling/testing was determined in women with and without cancer in a randomised controlled trial as part of which women were randomised to either receive immediate versus delayed genetic counselling. This included family communication patterns before BRCA testing, anticipated outcomes of testing on oneself and family including intentions for result disclosure. Comprehension of index and predictive BRCA testing with possible results was assessed both in the short- and the long-term and understanding of individual or family BRCA test results was evaluated at long-term. The effect of genetic counselling on breast cancer risk perception in unaffected women was evaluated. This study considered a theoretical framework of educational learning theories to provide a basis for risk communication with possible relevance for future research. ... Only 25% of the original study population (52/207) reported BRCA results and women's understanding of results is concerning. Key findings were: 1. The majority of affected women received an inconclusive result. 2. Out of twelve unaffected women who reported results, seven were inconclusive which are not congruent with predictive testing. This implies that these women did not understand their test result. 3. A minority of untested relatives did not know whether a family mutation had or had not been found in their tested family member or what their actual test result was. This implies either a lack of disclosure or that woman did not understand the rationale for and significance of testing for a family mutation. 4. Three relatives did not understand a positive result was a mutation. Conclusion: The implication of this research for breast cancer counselling and testing services is that women who wait for counselling are no worse off in terms of short- or long-term general psychological distress than women who receive the intervention early. There is a suggestion that unaffected women without the disease found counselling more advantageous than affected women. The meaning of BRCA results as reported by women is concerning particularly women's understanding of negative and inconclusive results and further research is needed in this area. Too much information presented at counselling may affect women's comprehension of risk, BRCA testing and future test results and further research is required to evaluate the effects of information overload.

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Erkko, H. (Hannele). « TOPBP1, CLSPN and PALB2 genes in familial breast cancer susceptibility ». Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289682.

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Abstract The currently known susceptibility genes account for approximately 25% of familial breast cancer predisposition. Additional factors contributing to the pathogenesis of breast cancer are, therefore, likely to be discovered. Most of the known genes affecting breast cancer predisposition function in the DNA damage response pathway. In this study three genes, TOPBP1, CLSPN and PALB2, involved in this complex process were investigated to reveal potentially pathogenic mutations associated with breast cancer susceptibility. In the analysis of the TOPBP1 gene, one novel putative pathogenic alteration was observed. The Arg309Cys variant was found at an elevated frequency among familial cases (19/125) vs. controls (49/697) (p = 0.002; OR 2.4; 95% CI 1.3–4.2). In addition, altogether 18 other germline alterations were observed in this gene, but they all appeared to be harmless polymorphisms. Investigation of CLSPN alterations among familial breast cancer families revealed altogether seven different changes. No clearly pathogenic alterations were observed. However, a potential modifier effect was discovered for the 1195delGlu change. The obtained results suggest that CLSPN alterations are unlikely to be significant breast cancer susceptibility alleles. In the PALB2 gene, a pathogenic mutation c.1592delT was identified at an elevated frequency among breast cancer patients (0.9%) compared to controls (0.2%) (p = 0.003, OR 3.94, 95% CI 1.5–12.1). Among familial cases the frequency of c.1592delT was even higher (2.7%). This mutation was also functionally deficient. It had a markedly decreased BRCA2-binding affinity and was unable to support homologous recombination or to restore cross link repair in PALB2 knock-down cells. Additionally, this mutation was discovered in a familial prostate cancer family and was found to segregate with the disease, suggesting some association also with prostate cancer. The penetrance and hazard ratio associated with PALB2 c.1592delT were determined in unselected breast cancer families. A substantially increased risk of breast cancer (HR 6.1; 95% CI 2.2–17.2; p = 0.01) was discovered resulting in an estimated 40% (95% CI 17–77) breast cancer risk by age 70 years, comparable to that for carriers of BRCA2 mutations. This markedly increased cancer risk suggests that genetic counselling for carriers is needed and screening for this mutation should be considered.

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Karppinen, S. M. (Sanna-Maria). « The role of BACH1, BARD1 and TOPBP1 genes in familial breast cancer ». Doctoral thesis, University of Oulu, 2009. http://urn.fi/urn:isbn:9789514291593.

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Abstract Approximately 5–10% of all breast cancer cases are estimated to result from a hereditary predisposition to the disease. Currently no more than 25–30% of these familial cases can be explained by mutations in the known susceptibility genes, BRCA1 and BRCA2 being the major ones. Additional predisposing genes are therefore likely to be discovered. This study evaluates whether germline alterations in three BRCA1-associated genes, BACH1 (i.e. BRIP1/FANCJ), BARD1 and TOPBP1, contribute to familial breast cancer. Altogether 214 Finnish patients having breast and/or ovarian cancer were analysed for germline mutations in the BACH1 gene. Nine alterations were observed, four of which located in the protein-encoding region. The previously unidentified Pro1034Leu was considered a possible cancer-associated alteration as it appeared with two-fold higher frequency among cancer cases compared to controls. All the other observed alterations were classified as harmless polymorphisms. Mutation analysis of the BARD1 gene among 126 Finnish patients having family history of breast and/or ovarian cancer revealed seven alterations in the protein-encoding region. The Cys557Ser alteration was seen at an elevated frequency among familial cancer cases compared to controls (p = 0.005, odds ratio [OR] 4.2, 95% confidence interval [CI] 1.7–10.7). The other alterations appeared to be harmless polymorphisms. To evaluate further the possible effect of Cys557Ser on cancer risk, a large case-control study was performed, consisting of 3,956 cancer patients from the Nordic countries. The highest prevalence of Cys557Ser was found among breast and ovarian cancer patients from BRCA1/BRCA2 mutation-negative families (p < 0.001, OR 2.6, 95% CI 1.7–4.0). In contrast, no significant association with male breast cancer, ovarian, colorectal or prostate cancer was observed. The current study is the first evaluating the role of TOPBP1 mutations in familial cancer predisposition. The analysis of 125 Finnish patients having breast and/or ovarian cancer revealed one putative pathogenic alteration. The commonly occurring Arg309Cys allele was observed at a significantly higher frequency among familial cancer cases compared to controls (p = 0.002, OR 2.4, 95% CI 1.3–4.2). The other 18 alterations observed were classified as harmless polymorphisms.

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Aissaoui, Souria. « Elaboration d'un outil pour l'évaluation et l'amélioration de la qualité de la prise de décision lors du Comité d'Onco-Génétique multidisciplinaire dans le cadre de prédisposition héréditaire au cancer colorectal. : une expérience française ». Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5020.

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Les maladies les plus fréquentes prédisposant au cancer colorectal sont le Syndrome de Lynch et la Polypose Adénomateuse Familiale. Les gènes du système MMR, le gène APC et le gène MUTYH sont respectivement responsables. Le conseil génétique est primordial pour une prise en charge optimale des patients et des familles. Les Comités d'Oncogénétique aident les professionnels de santé à décider d'une indication d'analyse génétique et au suivi des familles. Nous souhaitons évaluer et améliorer a qualité décision prise pour une famille à risque. Des décisions très disparates d'un cas familial à un autre équivalent ont été suspectées. A Lyon, nous avons créé une base de données pour analyser et contribuer cela. Résultat : 100% (33/33) des centres français de consultations principales d'oncogénétique ont décrit l'organisation de leurs COG: 76% développent un COG spécifique, 24% utilisent une concertation standard. Environ 3.75 spécialités médicales sont rassemblées par COG, dont des oncogénéticiens (100%), gastro-entérologues (76%), conseillers en génétiques (84%), chirurgiens (32%), et biologistes/anatomopathologistes (36%). Vingt pourcent des centres ayant une COG spécifique discutent tous leurs cas familiaux, 80% sélectionnent leurs dossiers. Dans notre région, un outil informatique a été élaboré et sera largement diffusé. Notre but étant de standardiser nos décisions et, catégoriser des groupes de patients/familles, pour standardiser la surveillance proposée chez les familles équivalentes. Une meilleure rationalisation de la prise en charge, du suivi des familles, et de la prévention est ici ciblée
The most common diseases that predispose for colorectal cancers are Lynch Syndrome and Familial Adenomatous Polyposis. The genes of MMR system, the APC gene and the MUTYH gene are respectively responsible. Genetic counselling is imperative for an optimal care making for patients and at-risk families. Multidisciplinary committees (MDC) are organized so as to help healthcare professionals for gene analysis decision and families' follow-up. Our aim is evaluation and improvement of quality decision-making for at-risk families. A disparate distribution of decisions from one familial case to another equivalent one has been suspected and observed. In Lyon region we created a database to analyse that and contribute to harmonize the different participants' work in MDC. Results: the 33 French oncogenetic main consultation centers described the organization of their MDC. Answering rate reached 100%. Among these centers, 76% developed a specific MDC, whereas 24% used standard consultation. About 3.75 different medical specialities are gathered by MDC. Among them, there are oncogeneticists (100%), gastroenterologists (76%), genetic counsellors (84%), surgeons (32%), and biologists (36%). Twenty percent of centers having a specific MDC evaluate all their patient cases, whereas 80% select them. In Lyon region, a computerized tool has been elaborated and will be widely disseminated to every collaborating partners of our MDC. It will enable us to standardize our decision-making and, by comparing decisions through quality criteria, to differentiate and categorize some patients/families groups. A better rationalization of care management, families' follow-up and prevention is targeted

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Batalha, Ana Rita Coelho. « O papel do farmacêutico na implementação de estudos de farmacogenómica : interação com a medicina familiar ». Master's thesis, [s.n.], 2013. http://hdl.handle.net/10284/3957.

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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
Nos dias de hoje existe uma preocupação acrescida de aumentar a segurança, efetividade e racionalização dos fármacos, pretendendo com isto otimizar as terapêuticas. Muitas vezes utiliza-se erradamente a Farmacogenómica como sinónimo de Farmacogenética. A Farmacogenómica é uma ciência promissora e em expansão, tendo como objetivo a terapêutica individualizada, diminuindo o risco das RAMs e da ineficácia do tratamento. Devido à sua formação, o papel do farmacêutico poderá ser uma mais-valia para esta área da terapia personalizada, prestando o seu conhecimento em fármacos. Esta dissertação divide-se em parte teórica e parte prática. Esta última consiste num estudo realizado através de um inquérito via-online, cujo objetivo é apurar o conhecimento de estudantes universitários sobre a Farmacogenómica. Nowadays there is a heightened concern of increasing safety, effectiveness and rationalization of drugs, intending to optimize this therapeutic. Often it is used incorrectly as a synonym for the Pharmacogenomics Pharmacogenetics. The Pharmacogenomics is a science promising and expanding, aiming to individualized therapy, reducing the risk of ADRs and treatment failure. Because of their training, the role of the pharmacist can be an asset to this area of personalized therapy, paying their knowledge in pharmaceuticals. This thesis is divided into theoretical and practical part. The latter consists of a study conducted through a survey via online-whose goal is to determine the knowledge of university students on Pharmacogenomics.

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Esteban, Jurado Clara. « Identificación y caracterización de nuevos genes de predisposición al cáncer colorrectal familiar ». Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/401896.

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INTRODUCCIÓN El cáncer colorrectal (CCR) representa una de las neoplasias más frecuentes a nivel mundial. Los casos de CCR se pueden clasificar en formas esporádicas, hereditarias y familiares en base a la agregación familiar. Las formas hereditarias están causadas por mutaciones germinales de alta penetrancia en genes conocidos que se transmiten en la familia, provocando una fuerte agregación y aparición temprana de la enfermedad. El CCR familiar se caracteriza por la presencia de cierta agregación y causas genéticas de predisposición desconocidas, siendo en algunos casos la agregación familiar tan fuerte como en las formas hereditarias. Estos casos son sugestivos de estar causados por variantes de alta penetrancia en genes aún por identificar. Para detectar la causa germinal de predisposición en las familias con agregación para CCR existen distintas estrategias, siendo la secuenciación de nueva generación una manera de analizar grandes cantidades de datos de forma rápida y económica. La secuenciación del exoma, consistente en secuenciar toda la región codificante del genoma, es una aproximación útil para detectar variantes de alta penetrancia causantes de enfermedades con herencia mendeliana. OBJETIVOS 1) Identificación de nuevos genes candidatos implicados en cáncer colorrectal familiar mediante secuenciación completa del exoma. 2) Implementación de una metodología automática de filtrado y priorización de variantes genéticas a partir de los datos de secuenciación del exoma. 3) Búsqueda de nuevas vías de señalización relacionadas con la aparición de cáncer colorrectal familiar. 4) Cribado de los genes POLE y POLD1 en pacientes con múltiples pólipos o CCR de aparición temprana. ARTÍCULOS (METODOLOGÍA Y RESULTADOS) La metodología y resultados de esta tesis se recogen en tres artículos, siendo los dos primeros estudios de secuenciación del exoma en familias con fuerte agregación para CCR y sin alteraciones germinales en los genes hereditarios APC, MUTYH o los genes de Lynch (Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer. Genetics in Medicine 2015;17:131-42; The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer). European Journal of Human Genetics 2016 May 11 doi: 10.1038/ejhg.2016.44). Por otro lado, el tercer estudio se basa en la búsqueda de mutaciones en el dominio exonucleasa de los nuevos genes hereditarios POLE y POLD1 en 155 casos con múltiples pólipos o CCR de aparición temprana mediante secuenciación convencional Sanger (POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Scientific reports, en revisión). DISCUSIÓN Los dos primeros estudios, al tener una metodología similar debido a que las técnicas realizadas son las mismas con pequeñas modificaciones en el análisis de datos, se comentan juntos. Se argumenta la adecuación de la tecnología utilizada, la selección de pacientes, la implementación de la metodología de anotación y filtrado de variantes, los genes candidatos de predisposición identificados mediante estos estudios y por último qué estudios adicionales se podrían realizar para reforzar la evidencia de estos descubrimientos. La discusión del tercer artículo incluye la tecnología utilizada, las características de los pacientes secuenciados y las variantes detectadas en nuestro estudio (incluyendo una variante de cambio aminoacídico para la cual se realizan múltiples experimentos para comprobar su patogenicidad).
Colorectal cancer (CRC) is one of the most common tumours and an important cause of mortality in the developed world. It is caused by environmental and genetic factors, with 35% of the variation in CRC susceptibility probably explained by inherited causes. The best known examples of inherited CRC predisposition are Mendelian forms such as Lynch syndrome and familial adenomatous polyposis. They account for ~5% of all cases, and are due to germline mutations in APC, MUTYH and the mismatch repair (MMR) genes, which confer a high risk of developing this disease. However, there is still a considerable number of cases with strong familial CRC aggregation and early disease onset with an unknown inherited genetic basis. Next generation sequencing is a good strategy to identify the germline predisposition cause in these cases, being exome sequencing a cost-efective approximation, useful for detecting high penetrance variants. This thesis is focused on the identification of new CRC predisposition genes through whole-exome sequencing in families with a strong aggregation for CRC and no alterations in the genes responsible for the classical hereditary forms. This strategy led to the publication of two papers: * Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cáncer. Genetics in Medicine 2015;17:131-42 * The Fanconi anemia DNA damage repair pathway in the spotlight for germline predisposition to colorectal cancer. European Journal of Human Genetics 2016 May 11 doi: 10.1038/ejhg.2016.44 On the other hand, another study was conducted with the aim to find pathogenic variants in the exonuclease domain of the recently discovered hereditary genes POLE and POLD1, in a cohort of 155 Spanish patients, using conventional Sanger sequencing. A paper including the results of this study has been submitted * POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cáncer. Scientific Reports (under revision)

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Destro, Maria Fernanda de Sousa Setubal. « Analise dos niveis de expressão dos membros da familia HOX de genes homeobox localizados nos loci B e C em mucosa oral normal e carcinoma espinocelular oral ». [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/288726.

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Orientador: Ricardo Della Coletta
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
Made available in DSpace on 2018-08-11T04:25:53Z (GMT). No. of bitstreams: 1 Destro_MariaFernandadeSousaSetubal_M.pdf: 4049997 bytes, checksum: c65b11d1e2e17169065f897077fbfb75 (MD5) Previous issue date: 2008
Resumo: Genes homeobox transcrevem fatores de transcrição com participação importante na organogênese através do controle da proliferação e diferenciação celular. Dentre estes genes destacam-se os membros da família HOX de genes homeobox, os quais estão envolvidos em processos celulares cruciais como controle do ciclo celular, diferenciação e apoptose. Os genes HOX estão relacionados com o surgimento de diferentes tipos de neoplasias, incluindo cânceres de mama, ovário, próstata, rins, pulmão, pele e leucemias. Na cavidade oral a participação destes genes é desconhecida. O objetivo deste estudo foi comparar os níveis de expressão dos membros da família HOX de genes homeobox dos loci B e C entre amostras orais de mucosa normal e carcinoma espinocelular (CEC). Para a realização deste trabalho, amostras de mucosa oral normal de pacientes não expostos aos principais fatores de risco para o câncer oral (hábito de fumar e consumir bebidas alcoólicas) e amostras orais de mucosa normal e CEC provenientes do mesmo paciente foram submetidos a ensaios semi-quantitativos de transcriptase reversa-reação em cadeia da polimerase (RT-PCR) ¿duplex¿, utilizando-se primers para o gene controle GAPDH e primers específicos para cada um dos membros dos loci B e C. Em adição, os níveis de expressão destes genes foram analisados em uma linhagem de queratinócito normal (HaCAT) e em 4 linhagens celulares derivadas de CEC oral. As linhagens celulares de CEC oral expressaram todos os membros do loci C, sendo que os genes HOXC4, HOXC5 e HOXC6 apresentaram maiores níveis de expressão quando comparado com a linhagem HaCAT. HOXB13 foi expresso por todas as linhagens celulares de CEC oral. Os genes HOXB1, HOXB3, HOXB5, HOXB8 e HOXC12 não foram expressos por nenhuma das amostras de mucosa oral normal, independente da origem, e de CEC oral. O padrão de expressão dos genes HOX foi muito similar entre os dois grupos de mucosa oral normal. As expressões dos membros HOXB7, HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXC10 e HOXC11 foram significantemente maiores nas amostras de CEC oral comparado com amostras de mucosa oral normal. Os níveis de expressão dos membros HOXB2 e HOXC13 foram significantemente maiores nas amostras de CEC oral quando comparado com os níveis de expressão encontrados nas amostras de mucosa normal de pacientes livres de fatores de risco. Estes resultados sugerem que a expressão alterada de alguns membros da família HOX de genes homeobox pode estar associada com o desenvolvimento e/ou progressão do CEC oral
Abstract: Homeobox genes encode transcription factors with an important role during normal development by controlling cellular proliferation and differentiation. Among those genes, the HOX family is involved in crucial biological processes such as the control of the cell cycle, differentiation and apoptosis. HOX genes are related to many cancers, including those of the breast, ovary, prostate, kidney, lung, skin and leukemias. In the oral cavity, the role of those genes is unclear. The aim of this study was to compare the expression levels of HOX genes from loci B and C between normal oral mucosa and oral squamous cell carcinoma (SCC). Samples of normal oral mucosa and oral SCC obtained from the same patient, and samples of normal oral mucosa from patients without history of exposition to risk factors related to oral SCC (smoking habit and alcohol consumption) were analyzed by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) duplex method with specific primers for the control gene GAPDH and for each of the HOXB and HOXC members. Additionally, we analyzed the expression profile of those genes in a normal keratinocyte cell line (HaCAT) and 4 oral SCC cell lines. Oral SCC cell lines expressed all members of the locus C, and the expression of HOXC4, HOXC5 and HOXC6 was higher in those cell lines compared with HaCAT. Only HOXB13 was expressed for all oral SCC cell lines. None of the normal oral mucosa and oral SCC samples expressed HOXB1, HOXB3, HOXB5, HOXB8 and HOXC12. The HOX expression profile of the 2 groups of normal oral mucosa was quite similar. Regardless of the oral normal mucosa source, the expression of HOXB7, HOXC4, HOXC5, HOXC6, HOXC8, HOXC9, HOXC10 and HOXC11 was statistically higher in oral SCC samples. HOXB2 and HOXC13 were significantly overexpressed in oral SCC when compared with normal oral mucosa from patients without risk factors related to oral SCC. These results suggest that a dysregulated expression of HOX genes from clusters B and C may be related to the tumorigenesis and/or tumor progression of oral SCCs
Mestrado
Patologia
Mestre em Estomatopatologia

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Drouet, Youenn. « Modélisation de la susceptibilité génétique non observée d’un individu à partir de son histoire familiale de cancer : application aux études d'identification pangénomiques et à l'estimation du risque de cancer dans le syndrome de Lynch ». Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10178/document.

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Le syndrome de Lynch est responsable d’environ 5% des cas de cancer colorectaux (CCR). Il correspond à la transmission d’une mutation,variation génétique rare, qui confère un haut risque de CCR. Une telle mutationn’est cependant identifiée que dans une famille sur deux. Dans lesfamilles sans mutation identifiée, dites négatives, le risque de CCR est malconnu en particulier les estimations individuelles du risque. Cette thèse comportedeux objectifs principaux. Obj. 1- étudier les stratégies capables de réduireles tailles d’échantillon dans les études visant à identifier de nouveauxgènes de susceptibilité ; et Obj. 2- définir un cadre théorique permettantd’estimer des risques individualisés de CCR dans les familles négatives, enutilisant l’histoire familiale et personnelle de CCR de l’individu. Notre travails’appuie sur la théorie des modèles mendéliens et la simulation de donnéesfamiliales, à partir desquelles il est possible d’étudier la puissance d’étudesd’identification, et d’évaluer in silico les qualités prédictives de méthodesd’estimation du risque. Les résultats obtenus apportent des connaissancesnouvelles pour la planification d’études futures. D’autre part, la cadre méthodologiqueque nous proposons permet une estimation plus précise durisque individuel, permettant d’envisager une surveillance plus individualisée
Lynch syndrome is responsible of about 5% of cases of colorectal cancer (CRC). It corresponds to the transmission of a mutation, which is arare genetic variant, that confers a high risk of CRC. Such a mutation isidentified, however, in only one family of two. In families without identifiedmutation, called negative, the risk of CRC is largely unknown in particularthere is a lack of individualized risk estimates. This thesis has two main objectives.Obj. 1 - to explore strategies that could reduce the required samplesizes of identification studies, and Obj. 2 - to define a theoretical frameworkfor estimating individualized risk of CRC in negative families, using personaland family history of CRC of the individuals. Our work is based on thetheory of Mendelian models and the simulation of family data, from whichit is possible to study the power of identification studies as well as to assessand compare in silico the predictive ability of risk estimation methods. Theresults provide new knowledge for designing future studies, and the methodologicalframework we propose allows a more precise estimate of risk, thatmight lead to a more individualized cancer follow-up

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Maubec, Eve. « Prédisposition génétique au mélanome : de la génétique à la recherche clinique ». Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T034.

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Ce travail avait deux objectifs: 1) définir des groupes de patients (pts) susceptibles de bénéficier d’un conseil génétique par l’identification de facteurs prédictifs de l’existence d’une mutation du gène CDKN2A, un des gènes majeurs de prédisposition au mélanome, dans les familles ne comportant que deux cas (Fam_2 cas). 2) la caractérisation épidémiologique et clinique d’entités particulières du mélanome dans l’objectif secondaire de contribuer à l’identification de gènes de prédisposition à ces entités. Les 2 entités étudiées étaient le mélanome cutané (MC) associé au cancer du rein (CR) et les mélanomes muqueux de la sphère ano-génitale (MMAG).Les populations d’étude sont une collection de 293 pts atteints de MC recrutés de façon consécutive sans connaissance à priori de l'histoire familiale et la collection française MELARISK qui comprend ≥ 3000 sujets prélevés appartenant à des familles à cas multiples de mélanomes ou ayant un MC survenant dans un contexte particulier (association à un autre cancer, topographie rare, survenue avant l’âge de 20 ans, MC multiples sporadiques). Nous avons étudié l'effet de 3 facteurs prédictifs potentiels sur la présence d’une mutation de CDKN2A dans une famille en fonction du nombre de pts atteints dans une famille (2 pts versus ≥3 pts). L’étude a été menée dans 483 familles françaises comprenant 387 Fam_2 cas, et 96 familles avec ≥3 pts atteints de mélanome (Fam_3+ cas). Les facteurs étudiés dans la famille un à un puis conjointement étaient : l’âge médian <50 ans au diagnostic de MC, la survenue de ≥1 cas de MC primitifs multiples (MPM) et la survenue de ≥1 cas de cancer du pancréas (CPCP). La fréquence des mutations était plus élevée dans les Fam_3+ cas (32%) que dans les Fam_2 cas (13%). Alors qu’un âge jeune au diagnostic et la survenue de ≥ 1 MPM étaient associés à la présence de mutations de CDKN2A dans les Fam_2 cas, un âge jeune au diagnostic ainsi que la présence de ≥1 cas de CP était associé significativement aux mutations de CDKN2A dans les Fam_3+ cas. L’étude a montré que les caractéristiques cliniques associées aux mutations de CDKN2A varient, en France, pays de faible incidence de mélanome, en fonction du degré d’agrégation familiale. L’identification de facteurs prédictifs de mutations de CDKN2A dans les Fam_2 cas a contribué à définir des sous-groupes de familles (âge jeune au diagnostic, survenue de MPM) dans lesquels la fréquence des mutations de CDKN2A est supérieure à 20% et auxquels il est légitime de proposer un test génétique. L’analyse des deux séries de pts MM+CR et MMAG a permis d’identifier, en les comparant à la série de MC recrutés de manière consécutive, leurs caractéristiques cliniques et histologiques. Dans ces deux séries, nos résultats ont mis en évidence un contexte de prédisposition héréditaire en partie indépendant de CDKN2A. L’étude de l’association MC et CR chez un même patient a eu deux conséquences pratiques: pour les cliniciens ces résultats suggèrent l’intérêt d’un examen dermatologique en cas de CR et l’intérêt de l’échographie abdominale dans le bilan initial d’un MC pour le dépistage du CR; pour la recherche en génétique, cette série a contribué à l’identification d’une mutation germinale dans le gène MITF qui augmente le risque de développer un MC, un CR ou l’association des deux cancers et qui a des propriétés biologiques intéressantes. L’étude des MMAG a montré que ces mélanomes pouvaient être associés à des MC chez un même malade et/ou survenir dans un contexte familial de mélanome. Le corollaire clinique de ces résultats est que l’examen dermatologique de dépistage ou de surveillance doit être à la fois cutané et muqueux dans un contexte familial de mélanome et qu’en cas de MMAG un examen dermatologique des apparentés doit être proposé comme c’est la règle dans les MC. L’absence de mutation de CDKN2A dans ces localisations muqueuses incite à entreprendre des études génétiques pour identifier les gènes impliqués
This thesis had two main objectives: 1) To define groups of patients which may benefit from genetic counseling by identifying predictors of mutations of the CDKN2A gene, a major gene predisposing to cutaneous melanoma (CM) in families with only two cases. 2) Epidemiological and clinical characterization of specific entities of melanoma with the secondary objective of contributing to the identification of susceptibility genes for these entities. Coexistence of CM with renal cell carcinoma and mucosal anogenital melanomas were studied.The study populations are a collection of 293 melanoma patients that were ascertained systematically and the French collection MELARISK which is a collection including over 3000 subjects drawn from families with multiple cases of melanoma or melanoma occurring in a particular context (association with another cancer, rare locations, occurrence before the age of 20, multiple sporadic melanomas).We investigated association of three clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 versus ≥3 CM patients among first-degree relatives in a family).The study was conducted in 483 French families including 387 families with two melanoma patients, and 96 families with three or more patients with melanoma. The factors examined individually and in a joint analysis in a family were: median age at diagnosis <50 years, ≥1 patient in a family with multiple primary melanomas (MPM) or with pancreatic cancer. The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). While early age at melanoma diagnosis and occurrence of MPM in ≥1 patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. Thus this study showed that clinical features associated with CDKN2A mutations vary, in France, a country of low incidence of melanoma, according to the degree of familial clustering. Identifying predictors of CDKN2A mutations in families with two melanoma cases has helped to define subgroups of families (early age at CM diagnosis, and/or ≥1 MPM patient) in which the frequency of CDKN2A mutations is above 20% such that these subgroups of F2 families should be offered genetic testing.The analysis of two series of patients, either patients with melanoma coexisting with renal cell carcinoma or patients with anogenital mucosal melanoma identified their clinical and histological features by comparing them to a series of melanomas that were ascertained systematically. In both series, our results suggested a genetic predisposition at least partly independent of CDKN2A. The study of the c renal cell carcinoma; coexistence of CM and renal cancer in the same patient had two practical consequences for clinicians: it suggests the interest of a dermatologic screening visit in patients with renal cell carcinoma and that abdominal ultrasonography or computed tomography scanning performed at the initial workup and during the follow-up of patients with CM may be of value for the early detection of renal cancer. Regarding genetic research, this series has contributed to the identification of a germline mutation in the MITF gene that increases the risk of developing melanoma, renal cancer or both cancers and has interesting biological properties. The study of anogenital melanoma has shown that these melanomas could be associated with cutaneous melanoma in the same patient and it has also shown a high frequency of family history of melanoma associating mucosal and CM suggesting a shared genetic predisposition. Consequently dermatological screening or monitoring must include examination of both skin and mucosa in families with multiple cases of CM; and in case of a mucosal melanoma, a dermatological examination should be offered to relatives. The genetic mechanism has to be identified

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Clark, Cammi. « When Bad Genes Ruin a Perfectly Good Outlook : Psychological Implications of Hereditary Breast and Ovarian Cancer via Narrative Inquiry Methodology ». Antioch University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=antioch1565254126257837.

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FitzGerald, Liesel Maria. « The genetics of familial prostate cancer in Tasmania ». Thesis, 2007. https://eprints.utas.edu.au/19839/1/whole_FitzGeraldLieselMaria2007_thesis.pdf.

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Prostate cancer is the most frequently diagnosed non-cutaneous cancer in Australia and the second largest cause of male cancer deaths after lung cancer. One of the strongest risk factors for prostate cancer is family history and investigators have undertaken to identify susceptibility genes through linkage analysis of high-risk families. A number of putative prostate cancer susceptibility genes and candidate loci have been identified, however little consensus has been reached as to their contribution to disease. The objective of this study was to identify susceptibility genes and loci that contribute to familial prostate cancer in the population of Tasmania, Australia. The research takes advantage of 43 Tasmanian prostate cancer pedigrees and a second case control dataset comprising sporadic cases and age-matched controls. The familial dataset includes nine extended pedigrees, comprising at least 11 affected men. The first aim of the study was to evaluate the effects of previously reported putative prostate cancer susceptibility genes in the Tasmanian population. This was achieved by screening selected risk variants from ELAC2, MSR1, RNASEL, and AMACR in familial and sporadic Tasmanian prostate cancer cases and in controls. In addition, the families were used to perform linkage analysis in the vicinity of the above mentioned genes, as well as at BRCA1, BRCA2, and at chromosomal regions 16q23 and 20q13. Analyses did not provide evidence that any of these genes or chromosomal regions play a significant role in prostate cancer susceptibility in Tasmania. However, a BRCA2 mutation was found to partially segregate with disease in one large prostate cancer pedigree (p=0.035). A high-density 10K SNP genome-wide scan was performed on individuals from one large pedigree comprising 25 cases (PcTas9). A novel linkage analysis method was used for analysis of this family. Suggestive evidence for linkage to chromosome 5p13- q12 was obtained. This locus has been suggested previously as a candidate susceptibility region for prostate cancer. Follow up microsatellite analysis of an expanded number of cases from this family, including samples derived from pathology specimens, identified a shared haplotype in 8 cases (p=0.0017; Simwalk2 non-parametric B Statistic of 2.42, p=0.0038). The contribution of this putative susceptibility locus was investigated in the remaining large pedigrees, however no evidence of linkage was observed. A 10K SNP genome-wide scan was also performed on a second large pedigree (PcTas72). Because a smaller number of individuals were genotyped in this pedigree, it was analysed in a standard fashion using Merlin. Analysis revealed suggestive evidence for linkage to 10p14-15 (NPL=5.77, p=0.0009). KLF6, a previously proposed prostate cancer susceptibility gene, is located within this region. Screening of this gene did not reveal any mutations segregating with disease. A second approach to identifying genes that may be important in prostate cancer development and/or progression involved examining tumour samples for regional DNA sequence copy number abnormalities. The tumours of 20 cases in PcTas9 and PcTas72 were laser-dissected and studied using BAC array comparative genomic hybridisation (aCGH). To our knowledge, this is the first known aCGH analysis of multiple tumours from the same family. All tumours displayed multiple regions of loss and gain, and three common alterations were identified: seven cases displayed loss at 7p21, 5 cases displayed loss at 19p13.3, and 4 cases displayed gain at 17p13.3. This study has exploited a rare resource - a number of Tasmanian multiplex prostate cancer families - to examine the contribution of previously identified prostate cancer susceptibility genes in this population, and to identify novel putative loci. While two suggestive linkage loci and three regions of common chromosomal alterations were identified, the study has also highlighted the heterogeneous nature of prostate cancer even in large extended pedigrees from a genetically homogeneous island population.

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McKay, James Dowling. « The molecular genetics of familial non-medullary thyroid cancer ». Thesis, 2002. https://eprints.utas.edu.au/20538/1/whole_McKayJamesDowling2002_thesis.pdf.

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Familial non-medullary thyroid cancer (fNMTC) has been recognised as a clinical entity. However, the susceptibility gene, or genes, that predispose patients to this form of cancer have yet to be identified. The initial genetic analysis of a large Tasmanian family (Tas 1) with eight patients affected with NMTC allowed the exclusion of the three fNMTC susceptibility loci that have been identified, MNG1,TCO and PRN1 on chromosomes 14, 19 and 1, respectively. Similarly, the candidate genes RET, NTRK1, APC, PTEN and MET were excluded using linkage analysis. As the susceptibility gene in Tasl appeared to be novel, a genome-wide search was performed. On 2q21, 7 of the 8 PTC cases in the Tas 1 family shared a haplotype. The significance of the 2q21 locus was tested in an independent set of 80 fNMTC pedigrees. Targeted linkage analysis using 13 markers positioned across this locus yielded a LOD score of 3.07 and an NPL score of 3.19 (p=0.001) with 42% of families estimated to be linked. Stratification by the phenotype over-represented in Tas 1 , fvPTC, revealed 17 families, and linkage analysis using this subgroup yielded a maximum HLOD score of 4.07, NPL=4.99 (p=0.00002) with 80% of families estimated to be linked. This data indicated the likelihood of a susceptibility locus for fNMTC at 2q21 and it was named NMTC1. Families with oxyphilia, which has been associated with the TCO locus, were stratified from the fNMTC family set. One large oxyphilic family, 103, showed suggestive evidence for linkage to TCO, LOD score of 2.0 at D19S391, and additionally at NMTC1, LOD score of 1.9 at marker D2S2215, suggesting interaction between these loci in conferring susceptibility to this trait. Four of the remaining smaller families with oxyphilia showed evidence for linkage to both loci. Under a two loci linkage analysis using a multiplicative risk model, the 103 family gave a LOD score of 3.2 and the smaller families also provided evidence for linkage, indicating the possibility of a multigenic inheritance pattern in fNMTC. Finally, recombinants in the families used in this study limited the candidate region containing the NMTCI susceptibility gene limited to approximately 200 000 bases, making its identification a realistic possibility in the near future.

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O'Doherty, Kieran Christian. « Risk communication in familial cancer : the discursive management of uncertainty in genetic counselling ». 2005. http://hdl.handle.net/2440/37766.

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This thesis deals with the communication of cancer risk in genetic counselling sessions. There are two primary foci that form threads throughout both the theoretical and empirical chapters of the dissertation. The first concerns the meaning of risk as it manifests in familial cancer. In particular, there is a lack of a sound theoretical grounding for the probabilistic aspect of risk that is evident in many forms of risk communication. The thesis aims to illustrate the problem constituted by this lack of theoretical clarity. As most decisions faced by clients arise from attending genetic counselling, it is concluded that clients ' agency is highly constrained when genetic counselling is understood as a process of assisting decision - making. However, genetic counselling can be seen to enable agency when it is conceptualised as a process aimed at making available new medical technologies for the purpose of addressing clients ' own concerns.
Thesis (Ph.D.)--Faculty of Health Sciences, Dept. of Psychology, 2005.

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Seto, Kelly Kai Yin. « Identification of Genes and Pathways Involved in Familial Ovarian Cancer ». Thesis, 2011. http://hdl.handle.net/1807/29862.

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One of the most important risk factors in ovarian cancer is family history, and two well-studied tumour suppressor genes BRCA1 and BRCA2 have already been identified in “high-risk” families. However, alterations of other genes may also be important for ovarian cancer pathogenesis in individuals with family history of breast/ovarian cancer. In this thesis, I compared the gene expression profiles of tumours from patients with strong and weak family history of breast and/or ovarian cancer to identify genes that may be significant in the subset of patients with ovarian cancer predisposition. Based on this comparison, two genes of interest were selected for further investigations: hCDC4/FBXW7 (F-box and WD repeat domain containing 7) and PRKCZ (protein kinase C zeta). Through mutational analyses I identified one nucleotide alteration within exon 7 of hCDC4; however, overall I found that hCDC4 mutation is a rare event in ovarian tumours. Additional epigenetics analyses revealed that promoter methylation is not a significant mechanism responsible for repression of hCDC4 expression in ovarian cancer. Nevertheless, the variable expression of hCDC4 proteins observed in ovarian tumour tissues by immunohistochemical staining of tissue microarrays suggests that hCDC4 deregulation may potentially be important in a subset of ovarian cancers. Additionally, I observed that expression levels of PRKCZ are higher in ovarian tumours from patients with strong family history compared to patients with weak family history. PRKCZ has previously been shown to be involved in a variety of cellular processes; however its role in ovarian cancer remained elusive. To further understand the role of PRKCZ in ovarian tumourigenesis, including cell viability, cell migration, as well as relevant downstream signaling pathways, I performed functional assays using an in vitro ovarian cancer model. I observed that PRKCZ increases proliferation of the SKOV3 ovarian cancer cell line and participates in EGF-induced chemotaxis. Furthermore, I identified IGF1R (insulin-like growth factor 1 receptor) and ITGB3 (integrin beta 3) as downstream effectors of PRKCZ as expression of these genes is significantly altered when PRKCZ is over-expressed. Given their previously identified associations with familial ovarian cancer, the IGF1 and ITGB3 signaling pathways may therefore represent a possible link between PRKCZ and this disease.

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Chong, Chan Eng. « Genetics and functional characterization of GATA2 : a novel cancer gene in familial leukaemia ». Thesis, 2013. http://hdl.handle.net/2440/85983.

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We first report GATA2 mutations (heterozygous) in 4 families that are susceptible to MDS/AML (3 large families) and MDS (1 small family). Molecular analysis revealed a germline transmission of a GATA2 missense mutation (T354M) in MDS/AML families and a GATA2 deletion mutation (T355del) in MDS family. Neither germline RUNX1 nor CEBPA mutations were found in these families, in 695 non-leukemic ethnically matched controls and 268 sporadic AML samples. The mutations resided within the GATA2 zinc finger 2 domain, a critical region for DNA-binding and protein-protein interactions, but not for nuclear localization. T354M reduced DNA binding ability of GATA2; whereas, T355del bound very little, if any, to the consensus WGATAR DNA motif. T354M and T355del also significantly reduced the transactivation of GATA2 in known GATA2 responsive sequences. Moreover, co-transfection of T354M or T355del with WT reduced WT transactivation ability, suggesting that these mutants act in a dominant negative fashion. Regulatable stable promyelocytic HL- 60 cells expressing WT and mutants were generated. Forced expression of WT and T354M inhibited HL-60 cell differentiation when induced with all trans retinoic acid. However, when compared to WT, T354M enabled cell proliferation/survival while simultaneously reducing apoptosis. In contrast, T355del was a complete loss-of-function mutant. Microarray studies elucidated that both T354M and T355del significantly decreased the expression of downstream target genes. Together, our data suggest that both T354M and T355del are loss-of- function mutations with some dominant negative attributes. Recently, we and others have described GATA2 genetic lesions in other diseases. We further investigated in vitro functions of an alllelic series of GATA2 mutants representing the major disease phenotypes: MDS/AML (T354M), MDS (T355del), CML-BC (L359V), Emberger syndrome (R361L and C373R), AML-M5 and biallellic CEBPA AML (R362Q), and immunodeficiency syndrome (R398W). We showed that these GATA2 mutants (except L359V) are loss-of-function that reduce DNA binding affinity and transactivation of target genes. Nevertheless, they maintain the ability to bind to known protein binding partners. Intriguingly, T354M and C373R have an enhanced affinity for PU.1, highlighting that these mutants can influence both DNA-binding and protein-protein interaction. Preliminary transduction of Gata2 WT or mutant expression constructs into mouse whole bone marrow cells demonstrated that GATA2 mutants did not confer self-renewal capacity, but allowed specific myeloid progenitor differentiation. We further demonstrated that Gata2 is expressed in lymphatic endothelial cells and that it can bind to and transactivate a Prox1 promoter/enhancer element (PEE) region. Prox1 is required for lymphatic development and maintenance, and hence Gata2 may contribute to lymphoedema throught its action on Prox1. Intriguingly, Gata2 mutants displayed differential binding affinity to two GATA binding sites and reduced transactivation of the PEE region. Furthermore, an enhancer region 11.3kb upstream of Prox1 is activated by GATA2, FOXC2 and SOX18, but repressed by PROX1 itself suggesting that these key lymphatic TFs may cooperate to regulate Prox1 expression. In conclusion, I present the experimental work for the landmark discovery of a new MDS/AML predisposition gene. I have also characterized the molecular landscape of GATA2 mutations where each of the mutations confers specific and major effects on GATA2 function, but where there are also subtle differences between the mutants in the contexts of DNA binding and transactivation.
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2013

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Raspin, K. « Using families to understand the impact of genetic variation on prostate cancer ». Thesis, 2020. https://eprints.utas.edu.au/35249/1/Raspin_whole_thesis.pdf.

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Prostate cancer (PCa) is the most common, non-cutaneous malignancy in men in the developed world. It is highly heritable, with twin studies suggesting that as much as 58% of disease risk can be explained by genetics. While more than 170 common genetic risk variants have been identified, these variants still only explain a minor portion of heritability, are largely of low to moderate effect size, and for many their function remains unclear. There has recently been significant success in the discovery of rare genetic variants contributing to complex disease through next-generation sequencing studies of large families. Mancuso and colleagues (2016) have estimated that as much as 42% of PCa risk is due to rare variants, but to date only 6% of this risk has been elucidated. With two-thirds of PCa heritability still unexplained, including the contribution of rare variants, we hypothesise that the utilisation of PCa families will aid in the identification of these rare variants. Germline risk variants and somatic tumour alterations have traditionally been regarded as unrelated events in cancer. However, there is now increasing evidence to suggest that specific germline variants may predispose some somatic tumour events, including copy number changes and gene fusions. Of particular interest in PCa, is the fact that germline variants have been reported to be significantly associated with the TMPRSS2:ERG fusion. Given the high frequency of these fusion events and accumulating evidence from previous studies, we also hypothesise that there are inherited determinants of somatic tumour variation, and this will be the second focus of this thesis. Family studies are proving highly valuable in the study of complex disease and here I will explore these hypotheses using the Tasmanian Familial Prostate Cancer Study cohorts, comprising genetic material from large families with multiple PCa cases and their relatives (Tasmanian Familial Prostate Cancer Cohort), as well as the Tasmanian Prostate Cancer Case-Control Study. To address the first hypothesis, whole-genome sequencing (WGS) was undertaken in five large Tasmanian PCa pedigrees to identify rare genetic variants contributing to disease risk. Variants were prioritised on a per-family basis by minor allele frequency, segregation with disease, mutation type and predicted functional consequence. Of the 20 prioritised rare variants, four were determined to be significantly associated with PCa risk in the Tasmanian population. This included rare variants in the genes RND1, WNT1, EZH2 and the known G84E HOXB13 variant. Both RND1 and WNT1 have been found to promote the growth and migration of cancer cells and, notably, in our study the variants appeared to be co-inherited. The EZH2 variant is a rare, intronic variant (rs78589034) present within a 3’ splice consensus sequence. EZH2 encodes the histone methyltransferase enzyme and is constitutively overexpressed in a range of cancers, including PCa. EZH2 is a highly variable gene and multiple transcripts have been identified. In fact, Chen et al (2017) observed that alternative splicing involving the inclusion of exon 14 plays a major role in the tumourigenesis of renal cancer. While this variant was significantly associated with PCa risk in the Tasmanian population (OR=3.27, p=0.001), functional assays were unable to determine the potential impact of this variant on the splicing mechanisms of EZH2. The G84E HOXB13 variant (rs138213197) was initially observed in the WGS data and followup genotyping found a significant association with PCa risk in the larger Tasmanian Familial Prostate Cancer Study cohorts (OR=6.59, p=4.22x10\(^{-5}\)). Although multiple studies have demonstrated an association of the G84E variant with PCa risk, no study has assessed the functional impact of the variant on HOXB13 gene and protein expression. Here, no difference in HOXB13 gene or protein expression was observed between prostate tumours from G84E carriers and non-carriers, but interestingly, the variant allele was rarely transcribed in carriers. The unbalanced allele transcription did not appear to be caused by methylation differences and, thus, other mechanisms, such as DNA copy number variation at the HOXB13 site or rapid targeted degradation of the variant mRNA transcript, may underpin the observed allelic imbalance. Hence, questions remain regarding how this variant influences tumour development. Given the rarity of the G84E variant, achieving a sufficient sample size for analyses is challenging, therefore, through collaboration with members of the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium, we aim to further explore the function of this variant. To address the second hypothesis, germline and tumour samples from PCa cases were utilised to explore inherited determinants of somatic tumour variation. Tumours from 14 PcTas9 cases were analysed using the TruSight RNA Fusion Panel (Illumina), identifying seven tumours as TMPRSS2:ERG fusion positive. Subsequently, analysis of the entire Tasmanian Prostate Tissue Pathology Resource showed that 31.5% of tumours were fusion positive. This event was more frequent in tumours from two families, PcTas2 and PcTas9 and, interestingly, was not identified in any of the eight sporadic tumours examined. These results suggest that there may be an underlying inherited genetic variant(s) predisposing to this fusion event. Subsequent work is focusing on screening for germline risk variants previously found to be associated with fusion positive tumours, including rare variants in POLI and ESCO1. Somatic copy number changes, including amplifications and deletions, are also common events in tumours, leading to the suggestion that they may also arise due to germline genetic variation. To explore this hypothesis, array comparative genomic hybridisation was applied to 12 PcTas9 prostate tumours to determine shared altered chromosomal regions. The most consistent alteration involved amplification of the EEF2 gene, which is a novel finding. EEF2 is highly expressed in human carcinoma tissue and has been suggested as a potential PCa biomarker. Immunohistochemistry of the Tasmanian Prostate Tissue Pathology Resource found that the EEF2 protein was overexpressed in 49% of malignant compared to matched benign tissue, but no difference was observed between tumours from PcTas9 cases and non-PcTas9 cases. However, gene expression assays found malignant cells from PcTas9 tumours had significantly higher EEF2 5’UTR/exon 2 expression compared to malignant cells isolated from non-PcTas9 tumours. Thus, these results suggest that the EEF2 amplification may be specific to PcTas9 and due to an inherited predisposition variant(s). To test this hypothesis, recent WGS data generated for this family will be utilised in linkage analysis based on EEF2 amplification status. Establishing rare variants as disease-causing requires analysis of large cohorts and secondly, comprehensive functional analyses. This study has identified four rare germline variants significantly associated with PCa risk in the Tasmanian population. Variant screening in larger cohorts of PCa cases and controls is required to determine their contribution to other populations. Moreover, the functional impact of the EZH2 and HOXB13 variants on gene and protein expression remains unclear and requires more comprehensive functional analyses. This study also identified recurrent somatic variations in the tumour genomes of Tasmanian PCa cases. The TMPRSS2:ERG fusion and amplification of the EEF2 gene is more apparent in tumours from the PcTas9 family, suggesting that these somatic tumour events could be underpinned by inherited predisposition. There is currently a strong push to implement polygenic risk scores based on common variants in the clinical setting, yet with only one-third of genetic predisposition explained, clinical implementation may be premature. Studies such as the one described here, aim to directly explore genetic contribution to PCa. Rare germline variants and somatic tumour variation are of great interest as potential screening biomarkers and therapeutic targets, and if we are to understand the genetic determinants of PCa development, a strong focus on fully characterising these factors is essential.

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Duarte, Teresa Patrícia da Silva Gil. « Candidate Germline Genetic Variants for Familial Colorectal Cancer Type X ». Master's thesis, 2017. http://hdl.handle.net/10362/27103.

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Familial colorectal cancer type X (FCCTX) defines families that fulfill the Amsterdam criteria without evidence of defects in the DNA mismatch repair (MMR) genes and whose tumors do not present microsatellite instability. However, its genetic etiology remains unknown, therefore this study aimed to identify and evaluate novel variants and candidate genes that may play a role in FCCTX susceptibility. Based on a previous whole exome sequencing (WES) study in a FCCTX family, a bioinformatic analysis and a subsequent in silico and segregation studies were conducted to identify candidate genes and/or specific variants that may predispose for this syndrome. Since this analysis was already started, variants in 6 genes have already been identified to segregate with the disease. Therefore, the aim of this project was to continue this work by completing the selection of candidate variants and to characterize and try to clarify the role of these variants for FCCTX susceptibility. In order to elucidate the possible contribution of the corresponding genes for FCCTX, a mutational analysis was performed to search for germline mutations in index patients from FCCTX and FCCTX-like families. In addition, using the WES data, a copy number variation (CNV) analysis was also performed for the family subjected to WES, followed by a bioinformatic and in silico analysis to reveal amplicon deletions that may segregate with disease. It was also evaluated the involvement of the TPP2 gene, previously identified as a possible candidate gene for FCCTX in another family, in healthy and affected FCCTX patients, by mutational/splicing analysis, relative quantification by quantitative PCR and protein truncation test to assess resulting truncating proteins. The bioinformatic followed by in silico and segregation analysis of the variants obtained from WES, revealed 1 variant in the CACNA1S gene that segregated with the disease. Adding this variant to the already obtained, a total of 7 variants in different genes were found as possible contributors to FCCTX in this family. The segregation analysis also revealed the segregation of the previously identified MTMR3 and TAS1R1 variants in a patient from an older generation of the family. The CNV analysis revealed, after selective criteria, 22 amplicons of interest with a deletion scenario, for further segregation studies. The germline mutational analysis in a set of FCCTX and FCCTX-like families uncovered 2 and 3 potentially pathogenic variants for the MTMR3 and TAS1R1 genes, respectively. One of the variants found in MTMR3 was the same found in the WES analysis. Thus far no relevant variants were observed for LGR6 and DUSP12, however this analysis is not completed. The TPP2 study revealed the presence of non-described splicing isoforms. One of these isoforms exhibited a differential expression between healthy and affected individuals and the protein truncation test revealed that this alternative transcript gives rise to a truncated protein. In conclusion, the identification of more than one genetic variant appears to agree with the suggestion that FCCTX is a heterogeneous entity and the discovery of potentially pathogenic variants in MTMR3 and TAS1R1 reinforce their possible involvement in FCCTX. The alternative TPP2 transcript appears to be involved in the earlier stages of colorectal carcinogenesis
O cancro do cólon e reto familiar do tipo X (FCCTX) define as famílias que preenchem os critérios de Amesterdão nas quais não é identificada mutação germinal nos genes de reparação de erros de DNA do tipo mismatch (MMR) e cujos tumores não apresentam instabilidade de microssatélites. Sendo a sua causa molecular desconhecida. Assim, o presente estudo teve como objetivo identificar e avaliar novas variantes e genes candidatos que possam estar envolvidos na suscetibilidade para o FCCTX. Com base num estudo prévio de whole exome sequencing (WES), realizado numa família FCCTX, foi efetuada uma análise bioinformática e in silico e um subsequente estudo de segregação, de modo a identificar genes candidatos e/ou variantes específicas que possam predispor para esta condição hereditária. Uma vez que esta análise já tinha sido iniciada, 6 variantes em diferentes genes, que segregaram com a doença, já tinham sido identificadas. Assim, o objetivo deste trabalho consistiu na continuação deste estudo, completando a seleção das variantes candidatas, e na caracterização e clarificação destas variantes para a suscetibilidade para o FCCTX. De modo a elucidar a possível contribuição destes genes para o FCCTX, foi realizada uma análise mutacional em indivíduos index de famílias FCCTX e potenciais famílias FCCTX. Adicionalmente, utilizando os resultados da WES, foi também realizada uma análise de copy number variantion (CNV) para a família integrada na análise de WES, seguida de uma análise bioinformática e estudos in silico de modo a avaliar a presença de deleções de amplicons que pudessem segregar com a doença. O envolvimento de transcritos alternativos do gene TPP2, previamente identificado como um possível gene candidato para o FCCTX noutra família, foi também avaliado em indivíduos saudáveis e afetados por análise mutacional/splicing, quantificação relativa por PCR quantitativo e teste da proteína truncada, para avaliar a existência de proteínas truncantes. A análise bioinformática seguida pela análise in silico e segregação das variantes obtidas por WES revelou a segregação com a doença de uma variante no gene CACNA1S. Tendo em conta as variantes já obtidas, foram identificadas 7 variantes em diferentes genes como possíveis intervenientes na suscetibilidade para o FCCTX nesta família. A análise de segregação revelou ainda a segregação das variantes dos genes MTMR3 e TAS1R1 num individuo proveniente de uma geração anterior. A análise de CNV revelou, após a introdução de critérios seletivos, 22 amplicons de interesse com um cenário de deleção, para estudos de segregação adicionais. A análise de mutações germinais num conjunto de famílias FCCTX e potenciais famílias FCCTX revelou 2 e 3 variantes potencialmente patogênicas para os genes MTMR3 e TAS1R1, respetivamente. Uma das variantes encontradas no gene MTMR3 correspondeu à variante encontrada no estudo de WES. Não foram observadas até ao momento variantes relevantes para os genes LGR6 e DUSP12, porém esta análise não está completa. O estudo do gene TPP2 revelou a presença de isoformas não descritas. Uma destas isoformas apresentou uma expressão diferencial entre o transcrito normal e o alternativo em indivíduos saudáveis e afetados e, o teste da proteína truncada revelou que este transcrito alternativo dá origem a uma proteína truncada. Em conclusão, a identificação de mais de uma variante genética parece concordar com a sugestão de que o FCCTX é uma entidade heterogénea, e a descoberta de variantes potencialmente patogénicas nos genes MTMR3 e TAS1R1 reforçam seu possível envolvimento no FCCTX. O transcrito alternativo do gene TPP2 parece estar envolvido numa fase inicial da carcinogénese colorretal.

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Blackburn, NB. « Identifying genetic susceptibilities underlying familial haematological malignancies in a Tasmanian family resource ». Thesis, 2015. https://eprints.utas.edu.au/22967/1/Blackburn_whole_thesis.pdf.

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Haematological malignancies (cancers of the haematopoietic and lymphoid tissues) are collectively one of the most frequently diagnosed cancers in Australia. Family history is one of the strongest risk factors for disease. Evidence for this derives from large population-based studies that have identified an increased risk of haematological malignancies in first degree relatives of cases, as well as studies of individual families where analyses have identified genes where family specific germline mutations predispose to these malignancies. Despite intensive research into the genetic predisposition to these cancers, the known genes account for only a small portion of the overall inherited component of haematological malignancies, leaving a significant gap in our understanding of the genetic basis of disease. Earlier studies used candidate gene approaches or sparse sets of genome wide markers to identify predisposition genes. Such approaches have a limited capacity for disease gene identification. Now, application of innovative technologies, such as next generation sequencing, to familial datasets with multiple cases of haematological malignancies presents an ideal opportunity to identify new predisposing germline mutations and other genetic factors contributing to disease development. The aim of this study was to identify the genetic architecture of disease susceptibility in large families affected by multiple subtypes of haematological malignancies. This study takes advantage of a collection of extended Tasmanian haematological malignancy pedigrees comprising 48 families, as well as 84 additional Tasmanian haematological malignancy cases with no known family history of disease. This resource is particularly valuable due to the recognised stability and relative genetic homogeneity of the island population of Tasmania. Next generation sequencing approaches were employed to identify novel, rare and shared predisposing mutations in affected family members. This was achieved through a combination of whole exome and whole genome sequencing in five prioritised families. Genome and exome alignment and variant calling were conducted using BWA and SAMtools. High-quality single nucleotide and small insertion / deletion variants identified were then annotated with information from public data sources using ANNOVAR. Variants were filtered to focus in on rare variants (with population frequency estimates of 1% or less) using frequencies in Caucasian population data from the 1000 Genomes Project and the UK10K consortia dataset. A large number of rare shared genetic mutations were identified between related haematological malignancy cases in these families. A tiered prioritisation strategy was developed and employed to identify the top preferred candidates for further followup. This strategy incorporated variant-based prioritisation, using in silico predictions of variant effect, and gene-based prioritisation using known gene biology. For genebased prioritisation a literature curated network analysis tool (Ingenuity Pathway Analysis) and an ontology-based tool (Phevor) as well as publically available tissue expression profiles of the mutated genes were used. Genes prioritised for further follow-up include examples such as TNFSF9, TDP2, MMP8, and NOTCH1. These genes have not been previously implicated in the familial risk for haematological malignancies, although some have previously established roles in malignancy. For example, TNFSF9 is a gene with clear connections to both T-cell and B-cell biology and there is evidence from a mouse knockout model that disruption to this gene can contribute to malignancy development. A subsequent aim of this study was to explore the role of telomere biology in familial haematological malignancies. Telomere biology has a well-characterised role in cancer development. Disruption of key telomere biology genes has been shown to lead to a spectrum of syndromes of which haematological malignancies are a feature such as dyskeratosis congentia and aplastic anaemia. To examine whether disrupted telomere biology was detectable in haematological malignancies, an analysis of telomere length was conducted using a PCR-based assay measuring across the familial resource, non-familial cases and population controls. Telomere length was analysed as a quantitative trait using variance components modelling, adjusting for age, sex and importantly kinship. The key finding from this analysis was that telomere length was highly heritable at 62.5% (P=4.7×10-5) indicating a strong genetic effect driving variation in telomere length and that both familial and non-familial haematological malignancy cases had shorter telomeres (P=2.2×10-4 and 2.2×10-5 respectively). These results indicate that telomere length contributes broadly to haematological malignancies. Genetic variation in some of the known telomere biology genes was examined, however the underlying genetic contribution to the observed shortened telomere length remains to be determined. This thesis describes the genetic analysis of a rare resource, providing evidence for several novel genes with possible roles in the development of haematological malignancies. As expected next generation sequencing of these families has further highlighted the multigenic contribution to risk in this complex disease.

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Pedro, Ana Rita Serra. « Genome editing to be applied in functional characterization of genetic variants in familial breast cancer patients ». Master's thesis, 2021. http://hdl.handle.net/10362/114625.

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RESUMO: O cancro da mama (CM) familiar representa 15% de todos os casos de CM, estando principalmente relacionado a variantes hereditárias nos genes BRCA. Vários genes ligados ao CM estão sobretudo relacionados com a Recombinação Homóloga (RH), a principal via de reparação de quebras de cadeia-dupla de DNA. A presença de variantes genéticas nestes genes, como o BRCA1 e BRCA2, pode comprometer a RH e consequentemente o desenvolvimento da doença. No cancro da mama familiar, o aconselhamento genético e a triagem através de testes genéticos têm se tornado padrão, aumentando a deteção de variantes de significado desconhecido (VUS). O efeito biológico atribuído às VUS é pouco claro, sendo necessários ensaios funcionais para caracterizar o seu significado clínico. Num estudo anterior, uma VUS foi identificada no gene BRCA1 em pacientes saudáveis, mas com histórico familiar de cancro relevante. Para estudar a sua relevância funcional, implementamos um modelo in vitro com linhas celulares de mama (MCF10-A e MCF-7) para introduzir a VUS de interesse com uma ferramenta de edição genómica, CRISPR-Cas9 e avaliar a resposta celular através de um desafio genotóxico com doxorrubicina (DOX). Introduzimos com sucesso a VUS como clone heterozigoto nas MCF10-A. Várias metodologias foram selecionadas para avaliar e comparar a resposta celular às lesões genéticas: ensaios do Cometa, ɣ-H2AX e Anexina V. Adicionalmente, avaliamos a expressão relativa da proteína através de Western Blot. Os resultados do ensaio do cometa mostram uma diminuição da sensibilidade à DOX no MCF10-A VUS, porém, no ensaio ɣ-H2AX, observamos um maior % de quebras e cadeia-dupla. Na Anexina V, o MCF10- A VUS apresentou menor % de células em necrose. Por último, a expressão da proteína BRCA1 encontra-se diminuída nas MCF10-A VUS. No geral, os resultados mostram uma diminuição da suscetibilidade à DOX para a linha celular com a VUS, sugerindo um efeito benigno. No entanto, são necessários mais ensaios funcionais para entender o seu papel no risco de cancro.
ABSTRACT: Familial breast cancer (BC) is responsible for 15% of all BC cases being mainly linked to inherited variants in BRCA genes. Several genes associated with BC are mostly related to Homologous Recombination (HR), the main pathway to repair DNA double-strand breaks. The occurrence of genetic variants in these genes, such as BRCA1 and BRCA2, might compromise the HR, thus the development of disease. In familial breast cancer the genetic counselling and the screening through genetic testing has been widespread increasing detection of variants of unknown significance (VUS). The biologic effect attributed to those VUS is mostly unclear, so functional assays need to be performed to characterize their mutational status. In a previous study a VUS was identified in the BRCA1 gene in healthy patients but with a relevant familial history of cancer. To study its functional relevance, we implemented an in vitro model using breast cell lines (MCF10-A and MCF-7). to introduce the VUS of interest with a genome editing tool, CRISPR-Cas9 and assess the cellular response through a genotoxic challenge with doxorubicin (DOX). We successfully established MCF10-A heterozygous clone for the VUS. Several methodologies were selected to evaluate and compare the cellular response to genetic lesions: Comet, ɣ-H2AX and Annexin V assays. Also, we assessed the protein relative expression using Western Blot. The comet assay results showed a decreased sensitivity to DOX in MCF10-A VUS, yet, in ɣ-H2AX assay, we observed a higher % DSB. In Annexin V, MCF10-A VUS showed lower % of cells in necrosis. Lastly, the expression of BRCA1 protein was decreased in MCF10-A VUS. Overall, the results show a decreased susceptibility to DOX for the VUS cell line, suggesting a benign behaviour. Nonetheless more functional assays need to be performed to understand their role on cancer risk.

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Van, der Westhuizen Andre. « The development of a genetic counselling program to identify, test and manage families at risk for inherited colorectal cancer ». Thesis, 2011. http://hdl.handle.net/10539/10343.

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Yu-ChingTsai et 蔡郁清. « Analysis of host pathologic features and genetic factors predisposing to advanced pre-cancerous changes after Helicobacter pylori infection in gastric cancer families ». Thesis, 2015. http://ndltd.ncl.edu.tw/handle/91245218607093286556.

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博士
國立成功大學
臨床醫學研究所
103
Background: To eradicate H. pylori before the occurrence of pre-cancerous changes is important to prevent gastric cancer (GCA). GCA exhibits familial clustering, and GCA families tend to present with corpus-predominant gastritis and precancerous lesions as spasmolytic polypeptide-expressing metaplasia (SPEM) or intestinal metaplasia (IM) after H. pylori infection. This study aimed to validate whether corpus-predominant gastritis index (CGI) and host genomic single nucleotide polymorphisms (SNPs) predisposed to gastric carcinogenesis processes in children of GCA patients (GCF) could offer early markers to screen high GCA risk subjects for early H. pylori eradication. Methods: Totally 389 family relatives of 193 non-cardiac GCA patients and 173 duodenal ulcer (DU) patients as control were included initially. Blood samples for DNA extraction were collected to identify SNPs. The participants with positive urea breath test (UBT) were invited to receive panendoscope. Topographic histology was assessed according to updated Sydney’s system, and translated into the operative link on gastritis assessment (OLGA), operative link on gastric intestinal metaplasia assessment (OLGIM) stages, and the presence of CGI. SPEM identified by immunostaining of trefoil factor 2 (TFF2) and α5β1 integrin expression were assessed and correlated to the genotype of SNPs within the GCF and verified in GCA patients. Results: Both GCA patients and their 1st-degree relatives (1st-degree GCF) had 3-3.4 folds higher prevalence of CGI than the DU controls (p〈 0.05). Of the 1st-degree GCF, the presence of CGI increased 5.5 folds risk of SPEM and 5.7 folds of advanced SPEM (p〈 0.05). CGI also correlated to corpus shift of bacterial densities and integrin α5β1 apical distribution. The combined genotypes ITGA5-1160T/ITGB1-1949A/ITGB1+31804C and COX-2-1195G/IL-10-592AA was more frequent seen in the GCF than in the DU patients (p〈 1x10-4), and predisposed to a 5.3-fold risk of SPEM in the H. pylori-infected GCF (p= 0.016). Such risk of getting SPEM increased to 112 folds, if combined with either or both of RUNX3+492A and TFF2-308CC (p= 1x10-4). The prevalence of CGI tended to decrease in the GCA patients in descending order from no precancerous lesion, SPEM only, with both IM and SPEM (82%), and IM only (p〈 0.05). GCA patients without precancerous lesion and with SPEM only had high prevalence of CGI and tended to have younger age, female predominant, tumor more frequently located at the corpus than the antrum, more advanced in stage and poorer differentiation (p〈 0.05). Within these GCA patients, the presence patterns of IM and/or SPEM were closely correlated between the tumor part and non-tumor parts (p〈 0.001). The GCF with integrin α5β1 apical distribution at corpus had 8.8 folds-increase risk of advanced SPEM and 29 folds-increase frequency of ITGB1-685-/C/ITGB1-1660AATTT/AATTT/ITGB1+32492G than those without (p= 0.007). This study also found the non-CGI GCA patients with IM only were more frequent to have combinations of SNPs ITGA5-1160GG/TFF2+4649GG, and COX-2+8473TT or MMP-9-1562CC than the DU controls (p〈 0.05). Conclusions: CGI can be early marker to identify H. pylori-infected subjects with high GCA risks. The combined SNPs of ITGA5-1160T/ITGB1-1949A/ITGB1+31804C and COX-2-1195G/IL-10-592AA predisposed to GCA and may serve as markers to identify high-risk subjects for early H. pylori eradication. Moreover, addition of RUNX3+492A or TFF2-308CC this combined SNPs would greatly facilitate SPEM development. In those without CGI, combined SNPs ITGA5-1160GG/TFF2+4649GG and COX-2+8473TT or MMP-9-1562CC may offer potential rescue markers worth further investigation.

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Matějů, Martin. « Klinicko-genetické aspekty familiárního výskytu karcinomu prsuFrekvence rekurentních mutací v genech BRCA1 a BRCA2 v České republice ». Doctoral thesis, 2014. http://www.nusl.cz/ntk/nusl-332552.

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Summary: Background: An increased risk for development of hereditary breast cancer is associated with germline mutations in BRCA1/2 and the influence of NBN mutations is also supposed. The aim of this study is to specify the frequency of recurrent mutations in BRCA1/2 in unselected breast cancer patients and the frequency of most common pathogenic mutations in NBN in Czech republic, to assess current criteria for genetic testing and to consider the addition of NBN to the tested genes. Methods: Screening for recurrent mutations 5382insC and 300T>G in BRCA1 was performed by RFLP, screening for mutations in exon 11 of BRCA1 was performed by PTT, screening for mutations in a selected region of exon 11 of BRCA2 by DHPLC, and screening for mutations in exon 6 of NBN by HRMA. All the mutations were confirmed by direct sequencing. Results: In 679 unselected breast cancer patients 7 carriers of 5382insC, 3 of 300T>G, and 4 of other mutations in BRCA1 were identified. 2 locally prevalent mutations were found in BRCA2. In 730 controls only one 5382insC BRCA1 mutation was identified. Out of 5 NBN mutations found in 600 high-risk patients two were 657del5 and one R215W. A total of 8 NBN mutation carriers were identified among 703 breast cancer patients, 2 of them 657del5 carriers and three R215W carriers. In 915...

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Thèses sur le sujet « Familial cancer genetics »

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