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Дисертації з теми "Genetic of cancer"
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1
Michael, Agnieszka. "Genetic immunotherapy for cancer." Thesis, St George's, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437318.
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2
Singh, Rashmi. "Genetic predisposition to prostate cancer." Thesis, Institute of Cancer Research (University Of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416575.
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3
Skoglund, Johanna. "Genetic studies of colorectal cancer /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-098-5/.
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4
Wiklund, Fredrik. "Genetic epidemiology of prostate cancer." Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-281.
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5
Lutke, Holzik Martijn Frederik. "Genetic predisposition to testicular cancer." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2007. http://irs.ub.rug.nl/ppn/304254797.
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6
González-Zuloeta, Ladd Angela Maria. "Genetic determinants of breast cancer." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10525.
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7
黎子韻 and Tsz-wan Kristi Lai. "Genetic polymorphisms in ovarian cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31970618.
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8
Cheung, Chin-ling, and 張展寧. "Genetic analysis of nasopharyngeal cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B44659866.
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9
Cheng, Timothy. "Genetic susceptibility to endometrial cancer." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:3a559ae0-156f-48a2-a64e-b03a13c562df.
Повний текст джерелаАнотація:
Endometrial cancer (EC) is the fourth most common cancer affecting women in the UK. Those with a family history of EC have an increased risk compared with the general population. Highly penetrant germline mutations in mismatch repair (MMR) genes and DNA polymerases account for only a small proportion of the familial aggregation. The aim of this thesis is to investigate the genetic susceptibility to EC in the general population using cases and controls of European ancestry. A GWAS meta-analysis totalling 7,737 EC cases and 37,144 controls yielded five novel EC risk loci of genome-wide significance (P < 5x10−8). In decreasing order of significance, these were at chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). A second independent EC signal was found in the 8q24 locus. The association found in a previous EC GWAS at HNF1B on chromosome 17 was replicated at a higher significance, with the most significant SNP being rs11263763. CYP19A1 SNPs have previously been associated with EC and higher circulating levels of oestrogen from candidate studies, but I confirmed this locus to be genome-wide significant for the first time. Functional annotation and in vitro studies for the EC risk loci at the intergenic region of chromosome 13q22 suggested that the functional SNP sits within a transcriptional repressor for KLF5, with the higher-risk allele reducing repressor activity. The propensity for germline MMR and DNA polymerase muations to cause both EC and colorectal cancer (CRC) prompted me to search for common variants associated with both cancer phenotypes. An EC CRC GWAS meta-analysis showed little evidence of shared susceptibility loci. However, this meta-analysis revealed a novel genome-wide significant risk locus: rs3184504, a missense SH2B3 SNP that has not previously been associated with either EC or CRC. This thesis has enhanced the understanding of genetic susceptibility to sporadic EC and increased the number of genome-wide EC-associated variants to seven.
10
Lai, Tsz-wan Kristi. "Genetic polymorphisms in ovarian cancer." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25176493.
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11
Kho, Pik Fang. "Genetic epidemiology of endometrial cancer." Thesis, Queensland University of Technology, 2021. https://eprints.qut.edu.au/211383/1/Pik%20Fang_Kho_Thesis.pdf.
Повний текст джерелаАнотація:
Endometrial cancer is the fifth most common cancer diagnosed in women in developed countries. This research used genetics to assess relationships between endometrial cancer and, previously identified and novel, risk factors. This work brings new insights by providing evidence that HDL and LDL cholesterol levels are linked to endometrial cancer risk. Further, I have shown that two gynaecological diseases, which are comorbid with endometrial cancer, also share genetic risk architecture with endometrial cancer. This work also advances the understanding of biological mechanisms of endometrial cancer by identifying candidate susceptibility genes.
12
Sotheran, Wendy. "Genetic predisposition to breast cancer in selected individuals in Guernsey." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264721.
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13
Tai, Lai-shan, and 戴麗珊. "Molecular genetic characterizations of human non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B31375315.
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14
Marsh, Howard Piers. "Genetic polymorphisms in bladder cancer angiogenesis." Thesis, University of Bristol, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428513.
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15
Quan, Xiaojiang. "Genetic study of mammary cancer development." Doctoral thesis, Universite Libre de Bruxelles, 2001. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211503.
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16
Zhou, ZiaoLei. "Molecular genetic studies of colorectal cancer /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-489-9/.
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17
Hasmats, Johanna. "Analysis of genetic variations in cancer." Doctoral thesis, KTH, Genteknologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-104438.
Повний текст джерелаАнотація:
The aim of this thesis is to apply recently developed technologies for genomic variation analyses, and to ensure quality of the generated information for use in preclinical cancer research. Faster access to a patients’ full genomic sequence for a lower cost makes it possible for end users such as clinicians and physicians to gain a more complete understanding of the disease status of a patient and adjust treatment accordingly. Correct biological interpretation is important in this context, and can only be provided through fast and simple access to relevant high quality data. Therefore, we here propose and validate new bioinformatic strategies for biomarker selection for prediction of response to cancer therapy. We initially explored the use of bioinformatic tools to select interesting targets for toxicity in carboplatin and paclitaxel on a smaller scale. From our findings we then further extended the analysis to the entire exome to look for biomarkers as targets for adverse effects from carboplatin and gemcitabine. To investigate any bias introduced by the methods used for targeting the exome, we analyzed the mutation profiles in cancer patients by comparing whole genome amplified DNA to unamplified DNA. In addition, we applied RNA-seq to the same patients to further validate the variations obtained by sequencing of DNA. The understanding of the human cancer genome is growing rapidly, thanks to methodological development of analysis tools. The next step is to implement these tools as a part of a chain from diagnosis of patients to genomic research to personalized treatment.QC 20121105
18
Ilyas, Mohammad. "The genetic basis of colorectal cancer." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301849.
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19
Lubbe, Steven John. "The genetic epidemiology of colorectal cancer." Thesis, Institute of Cancer Research (University Of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538696.
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20
Lancaster, Johnathan Mark. "Molecular genetic etiology of ovarian cancer." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55576/.
Повний текст джерелаАнотація:
Ovarian cancer is the fifth leading cause of cancer death among women in Western Europe and the United States and has the highest mortality rate of all gynecologic cancers. Approximately 75% of cases of epithelial ovarian carcinoma are diagnosed at advanced-stage (III/IV) with disseminated intra-peritoneal metastases, such that the majority of patients succumb to the disease within 5 years. Mortality from the disease has changed little over the last several decades. Despite such dismal statistics, our understanding of the molecular etiology that underlies ovarian cancer development, progression and response to therapy remains incomplete. The recent development of DNA microarrays enables the simultaneous measurement of expression of thousands of genes in a single sample, providing a molecular phenotyping not evident by traditional clinical, molecular or histopathologic methods. This thesis outlines the characterization of genome-wide expression patterns that underlie ovarian cancer development and metastasis, as well as clinical behavior relating to likelihood of optimal surgical resection, response to chemotherapy, and ultimate survival. Individual genes that contribute to the expression profiles are analysed further to delineate their specific role in ovarian cancer development and progression. Additionally, the contribution of a low penetrance polymorphic allele in the progesterone receptor gene as a risk factor for the development of the disease is examined in a large population-based case-control trial. Our data suggest that microarray analysis can facilitate the characterization of the molecular basis to ovarian cancer development, metastasis, and response therapy. Specific genes identified in this analysis represent not only potential biomarkers for the presence and clinical behavior of ovarian cancers, but appealing therapeutic targets. Our findings suggest that gene-expression profiles can be developed that can be applied in the clinic to not only provide prognostic information, but predict response to specific chemotherapeutic agents, enabling treatments to be tailored to individual patients with ovarian cancer.
21
Reles, Angela. "Molecular genetic alterations in ovarian cancer." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2001. http://dx.doi.org/10.18452/13801.
Повний текст джерелаАнотація:
Einleitung: Das p53 Tumorsuppressorgen spielt eine zentrale Rolle für Regulation des Zellzyklus und die Induktion der Apoptose. MDM2, das Protein des mdm2 Gens, bindet an p53, hemmt seine Funktion als Transkriptionsfaktor und bewirkt den raschen Abbau des Proteins. Methode: Gefriergewebe von 178 primären Ovarialkarzinomen wurde mittels PCR, SSCP Single Strand Conformation Polymorphism), DNA-Sequenzierung und Immunhistochemie auf p53 Mutationen (exon 2-11) und p53 Proteinüberexpression untersucht. Das mdm2-Gen wurde an 92 Ovarialkarzinomen, neun Borderline-Tumoren, sechs Cystadenomen und 20 normalen Ovargeweben mittels reverse Transkriptase PCR der Gesamt-RNA und Sequenzierung der mdm2-cDNA auf alternatives RNA-splicing untersucht. Ergebnisse: p53 Mutationen waren in 56% (99/178) und eine p53 Proteinüberexpression in 62% (110/178) der Ovarialkarzinome nachweisbar. Bei p53 Mutationen war die rezidivfreie und Gesamtüberlebenszeit der Patientinnen signifikant kürzer als bei p53 Wildtyp (p=0,029 und p=0,014). Patientinnen mit p53 Überexpression (p=0,001) oder p53 missense Mutationen (p=0,008) waren signifikant häufiger resistent oder refraktär gegen eine Chemotherapie mit Cis- oder Carboplatin und Cyclophosphamid als Patientinnen mit normalem p53. mdm2 alternatives oder aberrantes RNA splicing war in 66/92 (72%) der Ovarialkarzinome, 7/9 (78%) der Borderline-Tumore, 5/6 (83%) der Cystadenome und 11/20 (55%) der normalen Ovargewebe nachweisbar. Eine Gesamtzahl von 30 verschiedenen Splice-Varianten-Sequenzen wurde identifiziert, von denen 22 einen partiellen oder vollständigen Verlust der p53 Bindungsstelle aufwiesen. Bei 28/30 der Sequenzen fand das splicing nicht an Exon/Intron-Grenzen statt, so daß diese als aberrantes Splicing klassifiziert wurden. Eine splice-Variante von 654 bp (mdm2b) wurde in 41% der Ovarialkarzinome, aber nur 11% (1/9) der Borderline-Tumore und 5% (1/20) der normalen Ovargewebe exprimiert. Die Expression von mdm2b in Ovarialkarzinomen korrelierte signifikant mit schlechtem Differenzierungsgrad (p=0,004), Resttumor nach Operation (p=0,004), hoher S-phase-Fraktion (p=0,016) und p53 Proteinüberexpression (p=0,018). Eine kürzere Splice-Variante von 221 bp war in nur 16% der Ovarialkarzinome, 56% der Borderline-Tumore und 40% der normalen Ovargewebe nachweisbar und korrelierte mit frühem Stadium (p=0,017) und längerem Gesamtüberleben (p=0,048) bei Ovarialkarzinom. Zusammenfassung: p53 Alterationen korrelieren in der univariaten Analyse signifikant mit einer Resistenz gegen eine platinhaltige Chemotherapie, frühem Rezidiv und kürzerem Gesamtüberleben bei Ovarialkarzinom. In der multivariablen Analyse ist p53 jedoch kein unabhängiger Prognosefaktor. mdm2 alternatives und aberrantes Splicing sind in Ovarialkarzinomen häufig, kommen aber auch in normalem Ovargewebe vor. Während die Expression der mdm2b Splice-Variante mit histologisch aggressiveren Tumoren assoziiert war, kamen kürzere Splice-Varianten typischerweise in frühen Ovarialkarzinomen und benignen Geweben vor. mdm2 Alterationen stabilisieren möglicherweise das p53 Protein und führen ohne Vorhandensein einer p53 Mutation zu einer Proteinakkumulation in Ovarialkarzinomen.Objective: The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. MDM2, the protein of the mdm2 gene, binds to p53, inhibits its transcriptional activity and promotes nuclear export and rapid degradation of the p53 protein. Methods: Frozen tissue of 178 ovarian carcinomas was analyzed for mutations of the p53 gene (exons 2-11) and p53 overexpression by SSCP (Single Strand Conformation Polymorphism), DNA-sequencing and immunohistochemistry. 92 cases of ovarian cancer, nine borderline ovarian tumors, six cystadenomas and 20 normal ovarian tissues were analyzed for mdm2 alternative RNA splicing by reverse transcription of total RNA, nested PCR amplification of mdm2 cDNAs and DNA sequencing of RT-PCR products. Results: p53 mutations were found in 56% (99/178) and p53 protein overexpression in 62% (110/178) of the tumors. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared to wildtype p53 (p=0.029 and p=0.014). Resistance to adjuvant Cis- or Carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (p=0.001) or p53 missense mutations (p=0.008) than patients with normal p53. mdm2 RNA splicing was seen in 66/92 (72%) of the ovarian carcinomas, 7/9 (78%) of borderline tumors, 5/6 (83%) of benign cystadenomas and 11/20 (55%) of the normal ovarian tissues. A total of 30 splice variant sequences were identified, out of which 22 had a partial or complete loss of the p53 binding site. 28/30 do not splice at exon/intron boundaries and were therefore considered aberrant splice variants. The mdm2b splice variant of 654 bp, which splices out most of the p53 binding domain, was expressed in 41% of ovarian carcinomas, but only in 1/9 (11%) LMP tumors, and 1/20 (5%) of the normal ovaries. Expression of mdm2b in ovarian carcinomas was significantly correlated with poor grade of differentiation (p=0.004), residual tumor after surgery (p=0.004), high S-phase fraction (p=0.016) and p53 protein overexpression (p=0.018). A small splice variant of only 221 bp was present in only 16% of the ovarian carcinomas, but 56% of borderline tumors, and 40% of normal ovarian tissues and was correlated with early stage of ovarian cancer (p=0.017) and longer overall survival (p=0.048). Conclusion: p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor. mdm2 alternative and aberrant splicing was found frequently in ovarian tumors but also in normal ovarian tissue. While expression of the mdm2b splice variant was associated with histologically more aggressive ovarian carcinomas, smaller size variants were typically seen in early stage ovarian carcinomas and benign tissues. mdm2 alterations may stabilize p53 protein and cause p53 accumulation in the absence of p53 mutation in ovarian tumors.
22
Hayat, Roshanai Afsaneh. "Psychological and Behavioral Aspects of Receiving Genetic Counseling for Hereditary Cancer." Doctoral thesis, Uppsala universitet, Vårdvetenskap, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-128870.
Повний текст джерелаАнотація:
The overall aims of this thesis were to investigate psychological and behavioral effects of receiving cancer genetic counseling for breast, ovarian and colorectal cancer and/or with a family history of these cancer types and to determine whether counselees’ informational needs were met. Study I was performed 3-7 years post-counseling. Participants (n=214) reported a relatively high level of anxiety but a low level of depression compared to cancer patients in general. However, there was no indication that the distress experienced was due to the counseling. Moderate changes in life and family relations, high level of adherence to recommended controls and satisfaction was reported. Study II was a randomized control trial (RCT) intervention study which involved 147 counselees. An increase in the level of knowledge and correct estimation of personal risk was reported in both the intervention and control groups, although this increase declined at later follow-up. Enhanced information led to significantly greater satisfaction with the given information, and the way of informing relatives. Most counselees had shared information with their at-risk relatives. Study III focused on sharing information with at-risk relatives among participants in study II and their relatives (n=81). Counselees were interviewed and answered a questionnaire, whilst their relatives only answered the questionnaire. Counselees reported positive/neutral feelings about communicating genetic information and mostly interpreted their relatives’ reactions as positive/ neutral. Also, approximately 50% of relatives reported positive/neutral reactions and were generally satisfied with the received information. Study IV was conducted in Sweden and Norway based on 235 counselees. Counselees expected counselors to be skillful and thoughtful, take them seriously and provide risk estimations and medical information. Most important issues to counselees were satisfactorily addressed by the counselors. Analyzing importance rankings resulted in five categories of needs: a need for facts, caring communication and medical information, need for understanding and support in sharing genetic information, practical care and medical/practical information. In conclusion, no adverse psychological or behavioral effect on counselees was observed. Apparently, genetic counseling is managed properly and counselors successfully address counselees’ needs. Providing extended information does not seem necessary, however, tailoring information to individual counselees needs may create a more effective counseling.
23
Chen, Lina. "Genetic epidemiology of Prostate Cancer : a genetic approach to identifying casual modifiable risk factors for prostate cancer." Thesis, University of Bristol, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627980.
Повний текст джерелаАнотація:
Prostate cancer is now the second most common cancer among men in many developed countries. A Western diet which is high in dairy products and low in vegetables is thought to increase risk of the disease. However, despite hundreds of observational epidemiological studies, the evidence for a causal relationship between many nutrients and prostate cancer risk remains inconclusive. Mendelian Randomization is a method which uses genetic variants that are robustly associated with modifiable exposures (i.e. the association is demonstrated and replicated in several independent datasets) to determine whether these exposures are truly causally related to disease outcomes. The aim of this project was to investigate the causal effect of several dietary factors (specifically calcium, selenium, vitamin C, vitamin D, milk/dairy consumption and cruciferous vegetable intake) and body mass index (BMI), on prostate cancer risk and aggressiveness at diagnosis, via Mendelian Randomization approach. Participants in this project were drawn from the ProtecT (The Prostate Testing for Cancer and Treatment) study and included 1566 screen-detected prostate cancer cases, 1824 age and general practice matched controls with unrestricted prostate specific antigen (PSA) values and 1183 low-PSA controls (PSA :5 0.5 ng/ml). Mendelian Randomization analyses provided limited evidence that high calcium concentrations in blood increased prostate cancer risk, whilst high vitamin D levels were protective against prostate cancer. In addition, BMI showed a weak inverse association with low grade prostate cancer. However, there was uncertainty in these results and others presented in the thesis due to lack of power. These findings suggest that nutrients and BMI could influence prostate cancer risk, but the results require independent replication, preferably in larger populations with more prostate cancer cases and using multiple genetic variants as instruments.
24
Upstill-Goddard, Rosanna. "Genetic dissection of early-onset breast cancer and other genetic diseases." Thesis, University of Southampton, 2015. https://eprints.soton.ac.uk/386938/.
Повний текст джерелаАнотація:
Genetic variation in the genome of an individual plays a key role in susceptibility to many human diseases. Analysis of the genetic variants harboured by individuals presenting with disease phenotypes is crucial for unravelling the genetic landscape of human disease. The methods that are now available for the characterisation of genetic variants, including single nucleotide polymorphism (SNP) microarrays and next generation sequencing, make it possible to explore all genetic variants harboured within an individual with a specific disease phenotype, allowing for tailoring of treatments. This thesis focuses on the genetic dissection of early-onset breast cancer, syndromic and nonsyndromic forms of cleft lip with or without palate (CLP), and an oculopharyngeal muscular dystrophy-like (OPMD-like) phenotype through the analysis of SNP and exome data. Novel analysis approaches were used to explore the breast cancer genome-wide SNP data; a variety of machine learning algorithms were used to identify potential interactions and pathways influencing disease that cannot be uncovered using conventional analysis techniques. Such approaches are necessary because in many cases disease aetiology is likely to be complex with many genetic factors and interactions influencing disease susceptibility. Further characterisation of the genetic landscape of early-onset breast cancer, as well as the genetics of CLP and OPMD-like disease phenotypes, was possible through the use of whole exome sequencing technology. Exome sequencing identified many potentially important variants in the breast cancer samples and nonsyndromic CLP cases. Particular success was observed in the disease that were Mendelian in nature, namely syndromic CLP and the OPMD-like family; in all cases the likely causative mutation was successfully identified. Genetic studies of human disease using sequencing technologies and novel methods to analyse data are vital as personalised medicine becomes a real possibility in healthcare.
25
陳安安 and On-on Annie Chan. "Methylation in colorectal cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B25256312.
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26
Djureinovic, Tatjana. "Investigation of genetic factors involved in colorectal cancer predisposition /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-864-9/.
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27
Young, Alison Luk. "Next generation communication about hereditary cancer." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/20973.
Повний текст джерелаАнотація:
Individuals with a BRCA1 or BRCA2 pathogenic variant have an increased risk of developing breast, ovarian and prostate cancer. Offspring have a 50% chance of inheriting the pathogenic variant. At-risk young adults informed of their risk are often contemplating family planning and risk management choices. Few studies have explored communication processes regarding disclosure of genetic status from parents to young adults from the perspectives of all family members. This thesis includes: 1) a systematic review of young adults’ family communication experiences, risk perception, and cancer knowledge; 2) semi-structured interviews with young adults’ about their need for genetic information; 3) family interviews exploring the collective family experience with communicating genetic risk; and 4) focus groups and semi-structured interviews with genetic health professionals (GHPs) about the perceived needs of at-risk young adults, the challenges the GHPs experienced in supporting families during disclosure of genetic results, including strategies and training needed to support this process. In brief, young adults were not satisfied with the resources offered and although genetic information was accessible, the collective family’s experience with cancer influenced perceptions towards hereditary cancer information. Six key themes were identified exploring responsibility, gender, family culture, adversarial growth, key events, and GHPs role in supporting families. A lack of understanding of the importance to inform others and wider family systemic issues were challenging for GHPs. Strategies to address challenges include the management of appointments to accommodate family dynamics, family letters, and follow-up appointments. Clinical practices across Australia vary due to legislation. This thesis is the initial stage of exploration required to understand the perspective of young adults, relatives, and GHPs, before the development of an intervention to improve disclosure rates.
28
Wright, C. M. "The prognostic significance of microsatellite instability in sporadic stage C colorectal cancer." Thesis, The University of Sydney, 2008. https://hdl.handle.net/2123/28955.
Повний текст джерелаАнотація:
Identification and understanding of the molecular events involved in colorectal
cancer (CRC) pathogenesis should lead to better comprehension of the disease
process, hopefully leading to better prognostic stratification, and as a result more
targeted treatment regimens and improved patient outcomes. A sub group of
sporadic CRC exhibit microsatellite instability (MSI). MSI is seen when the
fidelity of DNA replication is impaired. Cancers may be categorized as MSI-high
(MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS), according to the
degree of MSI exhibited.
This research project was designed to analyse the association between MSI—H and
MSI-L, clinicopathological features and survival in an unselected group of
patients with sporadic Australian Clinicopathological Stage (ACPS) C / American
Joint Committee on Cancer (AJCC) stage III CRC, i.e. patients with lymph node
metastases at the time of surgical resection of their cancer. The criteria used to
determine MSI, specifically the type and number of microsatellite markers used,
were also reviewed.
255 patients who underwent resection for sporadic ACPS stage C CRC were
studied; none of these patients received chemotherapy. Archival normal and
tumour DNA were extracted and amplified by polymerase chain reaction using a
radioactive-labelling technique and a panel of internationally recognised
microsatellite markers. MSI-H was defined as instability in 2 40% of 7 markers,
MSI-L as instability at > 0% but < 40% of 11 markers, and M88 as no instability.
Twenty one MSI-H and 33 MSI-L CRC were identified. Significant results
included that MSI-H tumours are more commonly right sided (p < 0.00001);
larger (p 5 0.0005); more likely to be high grade (p = 0.049); and, after adjustment
for age, sex and other pathology variables, associated with improved survival (p =
0.015). No difference was found between the biological characteristics of MSI-L
and MSS CRC. MSI-L CRC showed a trend towards poorer cancer-specific
survival than MSS CRC but this difference did not reach statistical significance.
Although dependent on the number and type of microsatellites used, similar trends
in the results were seen when different criteria were used to determine MSI.
This study has contributed to the rapidly expanding literature on CRC
carcinogenesis and, at the time completed, was one of the first to show an
association between MSI-H and improved survival in clinicopathological stage C
CRC patients who had not received chemotherapy. It supports the view that
identification of MSI status in patients with sporadic ACPS C / AJCC stage III
tumours may help stratify patients according to prognosis and should be
considered in therapeutic decision making and future trials of adjuvant therapy.
However to accurately determine the clinical usefulness of MSI more precise
standardisation of the definition and methodologies used to identify M81 is
required.
29
陳潔盈 and Kit-ying Loucia Chan. "Expression analysis of Candidate cancer genes in non-small cell lung cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011163.
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30
Hussien, M. "Folate status, genetic damage and breast cancer." Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269044.
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31
Ashton, Kevin John, and K. Ashton@griffith edu au. "Genetic Aberrations in Non-Melanoma Skin Cancer." Griffith University. School of Health Science, 2002. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20030818.122305.
Повний текст джерелаАнотація:
Genetic changes are hallmarks of cancer development involving the activation and/or inactivation of oncogenes and tumour suppressor genes, respectively. In non-melanoma skin cancer (NMSC) development, the initiation of genetic mutations results from exposure to solar ultraviolet radiation. Non-melanoma skin cancers are comprised of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Several related cutaneous lesions also exist, of which solar keratoses (SK) are widely accepted as a precursor dysplasia to SCC development. The study of recurrent genetic changes present within NMSC and SK should help reveal causative mutations in skin cancer development. Such analysis could also elucidate links in the genetic similarity of these dysplasia. The rapid screening of numerical changes in DNA sequence copy number throughout the entire genome has been made possible by the advent of comparative genomic hybridisation (CGH). This technique enables the identification of net gains and loss of genetic material within a tumour DNA sample. Chromosomal regions of recurrent gain or loss identify loci containing putative oncogenes and tumour suppressor genes, respectively with potential roles in NMSC tumourigenesis. Used in conjunction with tissue microdissection and universal degenerate PCR techniques this can enable the elucidation of aberrations in small histologically distinct regions of tumour. Such a technique can utilize archival material such as paraffin embedded tissue, which is the major source of neoplastic material available for cancer research. This study used the CGH technique to investigate aberrations in BCC, SCC and SK samples. The screening of copy number abnormalities (CNAs) in BCC revealed that although these tumours were close to diploid and generally genetically stable, they did contain several recurrent aberrations. The loss of genetic material at 9q was identified in a third of BCC tumours studied. This is characteristic of inactivation of the PTCH tumour suppressor gene, a known attribute in some sporadic BCC development. Validation of this loss was performed via loss of heterozygosity, demonstrating good concordance with the CGH data. In addition the over-representation of the 6p chromosome arm was revealed in 47% of biopsies. This novel CNA is also commonly observed in other cutaneous neoplasias, including Merkel cell carcinoma and malignant melanoma. This suggests a possible common mechanism in development and or promotion in these cutaneous dysplasias, the mechanisms of which have yet to be clearly defined. In contrast to BCC, numerical genetic aberrations in SCC and SK were much more frequent. Several regions of recurrent gain were commonly shared between both dysplasias including gain of 3q, 4p, 5p, 8q, 9q, 14q, 17p, 17q and 20q. Common chromosomal regions of loss included 3p, 8p, 9p, 11p, 13q and 17p. In addition loss of chromosome 18 was significantly observed in SCC in comparison to SK, a possible defining event in SK progression to SCC. The identification of shared genetic aberrations suggests a clonal and genetic relationship between the two lesions. This information further supports the notion for re-classification of SK to an SCC in situ or superficial SCC. Finally, the CNAs detected have been similarly observed in other squamous cell-derived tumours, for example cervical and head and neck SCC. This provides further evidence to common mechanisms involved in the initiation, development and progression of SCC neoplasia. This study has identified a number of recurrent chromosomal regions, some of which are novel in NMSC development. The further delineation of these loci should provide additional evidence of their significance and degree of involvement in NMSC tumourigenesis. The identification of the cancer-causing genes mapped to these loci will further demarcate the genetic mechanisms of BCC and SCC progression. An understanding of the events involved in skin cancer formation and progression should shed additional light on molecular targets for diagnostics, management and therapeutic treatment.
32
Gentile, Massimiliano. "Genetic alterations in early onset breast cancer /." Linköping : Univ, 2001. http://www.bibl.liu.se/liupubl/disp/disp2001/med686s.pdf.
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33
Valdman, Alexander. "Molecular genetic markers of prostate cancer development /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-618-9/.
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34
Wedrén, Sara. "Genetic susceptibility to breast and endometrial cancer /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-053-2/.
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35
Fransén, Karin. "Molecular genetic aspects of colorectal cancer development /." Linköping : Univ, 2005. http://www.bibl.liu.se/liupubl/disp/disp2005/med878s.pdf.
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36
Salahshor, Sima. "Different genetic pathways involved in colorectal cancer /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4690-6/.
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37
Lake, Sarah Louise. "Genetic analysis of LPHH1 in lung cancer." Thesis, University of Liverpool, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404506.
Повний текст джерелаАнотація:
This thesis contends that the monarch-centred view of the masque, which has prevailed since the publication in the 1960s and 1970s of Stephen Orgel's seminal works on the genre, needs to be challenged in the light of recent scholarship on the cultural agency of other members of the royal family. In my introduction I argue that while the New Historicism has been crucial in elucidating the theatricalization of power in the early Stuart court, its insistence on the inevitability of the collusion between art and sovereign power needs to be questioned. The masque has long been seen as a monolithic and univocal celebration of monarchical power, despite the fact that it was promoted at court not by King James but by other members of the royal family. Adopting a loosely chronological approach, this thesis retells the story of the 'Jacobean' court masque by recovering the role played in the commissioning and performance of masques by James's wife, his children, and his male favourites. The chapters set out to hear voices other than that of the King, and discover that, while panegyric was part of each masque, it was rarely as unequivocal as traditional criticism has suggested. On the contrary, the annual masques were frequently appropriated to express the oppositional agendas of factions at court, and above all, of members of James's own family. I argue that Queen Anne set a precedent for the disruptive use of the masque which she exploited to present herself as independent from the King, and to emphasise her importance as the mother of the royal children. Prince Henry, and later Prince Charles, both used the masque to contest the pacifist policies of the King, while Buckingham's success as a favourite was linked to his skilful exploitation of the masques as an integral part of his self-fashioning. Above all by shifting the focus away from King James to consider the more active participation in the masque of other members of the royal family, this thesis offers a possibility of moving beyond the current impasse of the subversion / containment debate to a more nuanced reading of the culture of the early Stuart court which recognises the delicate process of negotiation and accommodation in which the masquers and their audiences were engaged.
38
Steggles, Naomi. "Psychological aspects of genetic testing for cancer." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271020.
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39
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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40
Babalghith, Ahmad Omar. "Genetic events involved in bladder cancer progression." Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445140.
Повний текст джерелаАнотація:
Bladder cancer is one of the most common cancers of the genitourinary tract. Transitional cell carcinoma (TCC) of the bladder includes two disease categories. Approximately, 85% of TCC are superficial tumours and the remaining percentage is invasive at presentation. Transurethral resection of the superficial tumours is the standard treatment. High recurrence rate was reported in these tumours and approximately 30% developed invasive tumours. Thus, it is essential to establish and identify molecular markers, which predict recurrence and progression status of bladder cancer patients. This study was divided into three main parts. The first part of this study was to optimise the CGH technique for DNA, extracted from bladder cancer cell lines and tissues. Since the origin of DNA used in CGH is crucial, different optimisation steps were investigated. Labelling of DNA by nick translation was determined to be 45 minutes for cell lines, while 20 minutes was sufficient for DNA extracted from tissues. Then probe mix preparation from cell lines was determined to be 800 ng of green probe and 400 ng of red probe, while in tissue 1600 ng of both probes were shown to have the best hybridisation signals. Denaturation time was the target in optimisation of CGH; denaturation of the human metaphase chromosome for 7 minutes produced the best fluorescent signals. Hybridisation for 6 days showed identical results between cell lines and tissues. In addition, washing the metaphase chromosomes to remove unbounded probes was determined to be 10 seconds for both cell lines and tissues. Furthermore, CGH was tested using DNA with known genetic aberrations and CGH was able to detect these aberrations.
41
Vessey, Carina Jayne. "Genetic predisposition to genomic instability in cancer." Thesis, Open University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262690.
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42
Smith, Joel Anthony. "Molecular genetic investigation of medullary thyroid cancer." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6314/.
Повний текст джерелаАнотація:
Introduction Most familial MTC is caused by a germline mutation of the RET proto-oncogene. Rare families exist with predisposition to MTC in whom no RET mutation has been identified. Identification of novel candidate genes within such families may inform the molecular behaviour of more common, sporadic disease. Whole exome sequencing (WES) enables all protein coding regions of the genome to be sequenced in parallel; a novel paradigm for MTC gene discovery. Methods Patients with MTC were recruited through internationally developed collaborations. WES was completed in three generations of the index family. Germline and tumour DNA were analysed for conformational mutations. In vitro functional analysis of candidate gens was completed to unpick biological pathways. Results Over 20,000 mutations were screened. A frameshift mutation in the oestrogen receptor 2 gene (ESR2) has been identified with familial segregation. Further alterations in ESR2 have been identified in germline DNA from a patient with young onset sporadic disease and tumour DNA from sporadic MTC. The functional protein of the ESR2 gene binds to a response element in the upstream pathway of the RET gene, controlling transcription. In-vitro studies show that ESR2 mutants lead to null proteins and up-regulation or RET at mRNA and protein levels. Further, loss of ESR2 protein is observed in patients with germline ESR2 mutations. Conclusions This study establishes a novel method of gene predisposition identification in the context of MTC. As well as the potential for a genetic test, and as a prognostic biomarker, the on-going functional work may elucidate targets for novel therapies that may include pre-existing anti-oestrogen.
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Bolton, Kelly. "The genetic epidemiology of ovarian cancer survival." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610071.
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44
Mackay, James. "Molecular genetic studies in human breast cancer." Thesis, University of Edinburgh, 1989. http://hdl.handle.net/1842/19076.
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Johns, Neil. "Phenotypes and genetic markers of cancer cachexia." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23392.
Повний текст джерелаАнотація:
Cancer cachexia is a chronic wasting syndrome characterised by loss of weight, composed principally of muscle and fat. Patients with advanced cachexia demonstrate loss of appetite, early satiety, severe weight loss, weakness, anaemia and fluid retention. Affected individuals are also likely to report/experience decreased quality of life, decreased levels of physical performance, increased levels of fatigue, increased risks of treatment failure (be it chemotherapy, radiotherapy or surgery), increased risks of treatment side effects, and an increased mortality rate. Cachexia is therefore an extremely important, yet often underappreciated cause of cancer patient morbidity and mortality which requires urgent attention. Weight loss is significantly associated with cancer morbidity and mortality. It has been observed that half of all cancer patients experience weight loss and one-third lose more than 5% of their original body weight. Skeletal muscle loss appears to be the most significant event in cachexia and is associated with a poor outcome. However it is not known why some patients with the same tumour lose weight and muscle mass whilst others do not. The main aim of this thesis was to determine if the genetic makeup of individual patients might contribute to their propensity to lose weight or skeletal muscle. Previous studies had suggested an association between weight loss and SNPs on genes concerned with innate immunity and particularly the cell adhesion molecule Pselectin, however the strength of any gene association study depends on the precision with which it is possible to characterise the phenotype in question. A second aim of this thesis was to explore refining the clinical phenotyping of patients to discriminate those with evidence of muscle fibre atrophy versus those without. Phenotype The conventional phenotype for cachexia is weight loss (WL) but it is unknown the extent to which loss of body mass reflects loss of muscle or fat mass. Recent progress in cross sectional imaging analysis means that it is now possible to gain a direct measure of muscle mass from routine diagnostic CT scanning. However, in the absence of a longitudinal series of scans it is not possible to estimate whether low muscularity (LM) is longstanding or not. By combining a measure of active weight loss with low muscularity it was hoped that such a composite measure would reflect actual muscle loss/fibre atrophy. Compared with non-cachectic cancer patients, patients with LM or LM+ > 2%WL, mean muscle fibre diameter was reduced by about 25% (p = 0.02 and p = 0.001 respectively). No significant difference in muscle fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either > 5%WL or LM+ > 2%WL. These findings support the use of composite measures (WL and LM) to try and identify those patients with evidence of active muscle fibre atrophy. This novel clinical phenotyping provides an accurate method to enable the conduct of candidate gene studies in the investigation of the genetics of cancer cachexia where the primary focus is on muscle wasting rather than overall weight loss. Genotype In an ideal world it would be possible to explore the entire genome and look for associations with the different phenotypes of cachexia. However, to do so would require considerable resource in terms of the cost of genome wide analysis and the cost of phenotyping large enough cohorts of patients (3000-10000). To address these issues I therefore adopted a candidate gene approach. A total of 154 genes associated with cancer cachexia were identified and explored for associated polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Such election of candidate genes and polymorphisms is a key element of multigene study design. The systematic review provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and to develop their potential as susceptibility biomarkers of cachexia. Phenotype – genotype associations A total of 1276 patients were recruited, phenotyped and genotyped. There were 545 new patients and 731 patients from a previous study. In our new cohort and in keeping with the previous literature, patients who carried the C allele of the rs6136 SNP in the SELP gene, were at a reduced risk of developing cachexia defined by WL. This association applied to all degrees of weight loss ( > 5%, > 10% or > 15%), and not just at the > 10% level as described previously in the literature. When examining newly identified SNPs in a stage 1 analysis for the weight loss phenotype that included 1276 cancer patients, twelve new candidate SNPs were significant. Six of these SNPs are associated with muscle metabolism in five genes (IGF1, CPN1, FOXO1, FOXO3, and ACVR2B), three are associated with adipose tissue metabolism in two genes (LEPR and TOMM40 (APOE on the reverse strand)), two with corticosteroid signalling in one gene (IFT172 (GCKR on the reverse strand)) and one with the immune response in one gene (TLR4). Two polymorphisms (rs1935949 and rs4946935) in the gene encoding for FOXO3 were consistently associated with WL of increasing severity ( > 5% and > 10%). On the basis that WL is a continuum in the cachectic process, the observation that both SELP and FOXO3 associate with the higher degrees of WL suggests that these genetic signatures may be of particular significance. The role of P-selectin in the genesis of cachexia remains to be determined. When examining all SNPs in a stage 1 analysis for the LM phenotype, 5 SNPs were associated significantly with the cachexia phenotype: (i) rs4291 in the angiotensin converting enzyme (ACE) gene in chromosome 17; this gene has been associated with muscle function and metabolism; (ii) rs10636 in chromosome 16 in the metallothionein 2a gene; this gene has been shown to be involved in zinc dyshomeostasis which may contribute to cancer cachexia; (iii) rs1190584 in chromosome 14 in the WDR20 gene; this gene encodes a WD repeat-containing protein that functions to preserve and regulate the activity of the USP12-UAF1 deubiquitinating enzyme complex; (iv) rs3856806 in the peroxisome proliferator-activated receptor gamma (PPARG) gene in chromosome 3 which has been demonstrated to be involved in fatty acid and glucose metabolism; and (v) rs3745012 in chromosome 18 in the lipin 2 (LPIN2) gene; this gene represents a candidate gene for human lipodystrophy, characterised by loss of body fat, fatty liver, hypertriglyceridemia, and insulin resistance. When examining all SNPs in a stage 1 analysis for the LM + > 2%WL phenotype 4 SNPs were associated significantly with the cachexia phenotype. rs12409877 in the leptin receptor (LEPR) located on chromosome 3, LEPR binds leptin and is involved in adipose tissue regulation. rs2268757 located in the activin receptor type-2B (ACVR2B) gene on chromosome 3, ACVR2B is a high affinity activin type 2 receptor which mediates signalling by a subset of TGF-β family ligands including myostatin, activin, GDF11 and others. SNPs in the tumour necrosis factor (TNF) (rs1799964) and ACE (rs4291) genes were also significantly associated with the phenotype. Whether genes demonstrating significant associations with the cachexia phenotypes had altered transcript expression in muscle from cancer patients with or without those phenotypes was also investigated.
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Lam, Man-Yee Josephine. "Genetic Control of Susceptibility to Testicular Cancer." Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1112676217.
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Allan, Lindsey A. "The molecular genetic events of ovarian cancer." Thesis, University of Aberdeen, 1994. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU068634.
Повний текст джерелаАнотація:
The current study has shown by SSCP analysis and direct sequencing that almost 45% of such tumours contain mutations in the p53 tumour suppressor gene. The observed mutational spectrum is consistent mainly with a spontaneous mechanism for ovarian tumourigenesis. A slight excess of A:T > T:A transversions, however, which is not observed generally in ovarian tumours, suggests that ovarian cancer development in Scotland may be partially attributable to an exogenous factor which is not involved substantially in the aetiology of the disease elsewhere. The potential relationship between p53 aberration and patient survival was investigated. Although p53 aberration was not found to be an independent prognostic indicator, it was associated with early disease recurrence and increased patient mortality. Only advanced tumour stage was found to be independently associated with decreased patient survival. A significant association, however, was observed between p53 aberrations and advanced tumour stage. In an attempt to identify other regions involved in the aetiology of ovarian cancer, sporadic ovarian carcinomas were investigated for allele loss on chromosome 17q. Deletion of all or part of chromosome 17q was frequently observed, with 79% of tumours exhibiting allele loss at one or more of the loci studied. Two common regions of deletion (CRD) were identified: CRD1 is defined by the region of chromosome 17q proximal to D17S579 at 17q21; CRD2 includes the region distal to D17S74. These findings suggest that a gene, potentially a tumour suppressor gene, located in each of these regions is frequently deleted in ovarian tumours.
48
Kim, Eejung. "Functional characterization of genetic alterations in cancer." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493591.
Повний текст джерелаАнотація:
The comprehensive identification of genetic alterations is critical to understanding the pathophysiology of cancer. Recent advances in sequencing technology have enabled the detailed description of cancer genomes. However, to translate these findings into a deeper understanding of cancer biology, analyzing the functional impact of cancer-associated genetic aberration is essential. Here I investigate how to accelerate the functional characterization of two classes of genetic alterations, point mutations and amplifications.
The wide spectrum of point mutations that arise in cancer makes them challenging to study comprehensively. I have developed a scalable systematic method to experimentally infer the functional impact of cancer-associated gene variants. I performed pooled in vivo tumor formation assays and gene expression profiling using 474 mutant alleles curated from 5,338 human tumors. I identified 12 transforming alleles including two in genes (PIK3CB, POT1) that have not been previously shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of RAS effector pathways. By correlating gene expression changes induced upon expression of wild type and mutant alleles, I could infer the activity of specific alleles. These approaches enable the interrogation of cancer-associated alleles at scale and demonstrate that rare alleles may be functionally important.
Frequently amplified regions in cancer often harbor oncogenic drivers. However, identifying the driver gene among many other amplified genes is challenging. In high-grade serous ovarian cancer (HGSOC), 1,825 genes are amplified across 63 amplicons. We employed systematic loss-of-function RNAi data to identify amplified genes that were essential in the ovarian lineage. We identified 50 amplified and essential genes and validated FRS2, an adaptor protein in FGFR pathway. FRS2-amplified cancer cell lines were dependent on FRS2 expression and FRS2 overexpression in immortalized cell lines was sufficient to promote anchorage independent growth and tumorigenesis in nude mice. This approach demonstrates that intersecting structural genomics with functional genomics can facilitate the discovery of driver genes in recurrently amplified regions. Collectively, the methods I present here provide a framework to study point mutations and amplifications to accelerate the interpretation of the cancer genome.Medical Sciences
49
Adams, David James. "The Genetic and Therapeutic Landscape of Cancer." Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/29490.
Повний текст джерелаАнотація:
The analysis of cancer genomes and the germline sequence of cancer patients has fundamentally changed our understanding of tumorigenesis and the ways in which we treat the disease. My work has focused on understanding the genetics of skin cancer and the functional analysis of cancer genes using approaches such as genome editing. My thesis describes my contributions to these areas and includes the chapters: Understanding the Genetics of Skin and other Cancers, The Functional Genomics of Cancer and Defining the Function of Mammalian Genes at Scale.
50
Ashton, Kevin John. "Genetic Aberrations in Non-Melanoma Skin Cancer." Thesis, Griffith University, 2002. http://hdl.handle.net/10072/367012.
Повний текст джерелаАнотація:
Genetic changes are hallmarks of cancer development involving the activation and/or inactivation of oncogenes and tumour suppressor genes, respectively. In non-melanoma skin cancer (NMSC) development, the initiation of genetic mutations results from exposure to solar ultraviolet radiation. Non-melanoma skin cancers are comprised of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Several related cutaneous lesions also exist, of which solar keratoses (SK) are widely accepted as a precursor dysplasia to SCC development. The study of recurrent genetic changes present within NMSC and SK should help reveal causative mutations in skin cancer development. Such analysis could also elucidate links in the genetic similarity of these dysplasia. The rapid screening of numerical changes in DNA sequence copy number throughout the entire genome has been made possible by the advent of comparative genomic hybridisation (CGH). This technique enables the identification of net gains and loss of genetic material within a tumour DNA sample. Chromosomal regions of recurrent gain or loss identify loci containing putative oncogenes and tumour suppressor genes, respectively with potential roles in NMSC tumourigenesis. Used in conjunction with tissue microdissection and universal degenerate PCR techniques this can enable the elucidation of aberrations in small histologically distinct regions of tumour. Such a technique can utilize archival material such as paraffin embedded tissue, which is the major source of neoplastic material available for cancer research. This study used the CGH technique to investigate aberrations in BCC, SCC and SK samples. The screening of copy number abnormalities (CNAs) in BCC revealed that although these tumours were close to diploid and generally genetically stable, they did contain several recurrent aberrations. The loss of genetic material at 9q was identified in a third of BCC tumours studied. This is characteristic of inactivation of the PTCH tumour suppressor gene, a known attribute in some sporadic BCC development. Validation of this loss was performed via loss of heterozygosity, demonstrating good concordance with the CGH data. In addition the over-representation of the 6p chromosome arm was revealed in 47% of biopsies. This novel CNA is also commonly observed in other cutaneous neoplasias, including Merkel cell carcinoma and malignant melanoma. This suggests a possible common mechanism in development and or promotion in these cutaneous dysplasias, the mechanisms of which have yet to be clearly defined. In contrast to BCC, numerical genetic aberrations in SCC and SK were much more frequent. Several regions of recurrent gain were commonly shared between both dysplasias including gain of 3q, 4p, 5p, 8q, 9q, 14q, 17p, 17q and 20q. Common chromosomal regions of loss included 3p, 8p, 9p, 11p, 13q and 17p. In addition loss of chromosome 18 was significantly observed in SCC in comparison to SK, a possible defining event in SK progression to SCC. The identification of shared genetic aberrations suggests a clonal and genetic relationship between the two lesions. This information further supports the notion for re-classification of SK to an SCC in situ or superficial SCC. Finally, the CNAs detected have been similarly observed in other squamous cell-derived tumours, for example cervical and head and neck SCC. This provides further evidence to common mechanisms involved in the initiation, development and progression of SCC neoplasia.
This study has identified a number of recurrent chromosomal regions, some of which are novel in NMSC development. The further delineation of these loci should provide additional evidence of their significance and degree of involvement in NMSC tumourigenesis. The identification of the cancer-causing genes mapped to these loci will further demarcate the genetic mechanisms of BCC and SCC progression. An understanding of the events involved in skin cancer formation and progression should shed additional light on molecular targets for diagnostics, management and therapeutic treatment.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Health Sciences
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