Artículos de revistas: "Cancer predisposition genes"

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Orozco-Hernández, Juan Pablo, Daniel Stiven Marín-Medina, Manuel A. Martínez-Muñoz y José W. Martínez. "Breast Cancer Predisposition Genes". Salud Uninorte 34, n.º 3 (15 de febrero de 2019): 766–83. http://dx.doi.org/10.14482/sun.34.3.616.99.

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Black, D. M., F. Harris y A. Renwick. "Breast cancer predisposition genes". European Journal of Cancer 33 (septiembre de 1997): S67. http://dx.doi.org/10.1016/s0959-8049(97)84672-2.

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Zheng, Guoqiao, Calogerina Catalano, Obul Reddy Bandapalli, Nagarajan Paramasivam, Subhayan Chattopadhyay, Matthias Schlesner, Rolf Sijmons et al. "Cancer Predisposition Genes in Cancer-Free Families". Cancers 12, n.º 10 (27 de septiembre de 2020): 2770. http://dx.doi.org/10.3390/cancers12102770.

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Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free (‘cancer-free families’, CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.

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Neiger, Hannah E., Emily L. Siegler y Yihui Shi. "Breast Cancer Predisposition Genes and Synthetic Lethality". International Journal of Molecular Sciences 22, n.º 11 (25 de mayo de 2021): 5614. http://dx.doi.org/10.3390/ijms22115614.

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BRCA1 and BRCA2 are tumor suppressor genes with pivotal roles in the development of breast and ovarian cancers. These genes are essential for DNA double-strand break repair via homologous recombination (HR), which is a virtually error-free DNA repair mechanism. Following BRCA1 or BRCA2 mutations, HR is compromised, forcing cells to adopt alternative error-prone repair pathways that often result in tumorigenesis. Synthetic lethality refers to cell death caused by simultaneous perturbations of two genes while change of any one of them alone is nonlethal. Therefore, synthetic lethality can be instrumental in identifying new therapeutic targets for BRCA1/2 mutations. PARP is an established synthetic lethal partner of the BRCA genes. Its role is imperative in the single-strand break DNA repair system. Recently, Olaparib (a PARP inhibitor) was approved for treatment of BRCA1/2 breast and ovarian cancer as the first successful synthetic lethality-based therapy, showing considerable success in the development of effective targeted cancer therapeutics. Nevertheless, the possibility of drug resistance to targeted cancer therapy based on synthetic lethality necessitates the development of additional therapeutic options. This literature review addresses cancer predisposition genes, including BRCA1, BRCA2, and PALB2, synthetic lethality in the context of DNA repair machinery, as well as available treatment options.

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Garber, Judy E. y Kenneth Offit. "Hereditary Cancer Predisposition Syndromes". Journal of Clinical Oncology 23, n.º 2 (10 de enero de 2005): 276–92. http://dx.doi.org/10.1200/jco.2005.10.042.

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Cancer genetics is increasingly becoming integrated into the practice of modern medical oncology. The ability to distinguish a growing proportion of the 5% to 10% of all cancers that develop in individuals who have inherited a genetic mutation conferring heightened susceptibility to specific cancers may permit targeted efforts in cancer surveillance and prevention. While these individuals comprise a small proportion of the overall burden of cancer, strategies successful in reducing their remarkable cancer risks may be generalizable to the broader population. In this review, we highlight the most common hereditary cancer syndromes, most attributable to genes inherited in an autosomal dominant manner with incomplete penetrance, and a number of rare syndromes in which particular progress has been made. The prevalence, penetrance, tumor spectrum, and underlying genetic defects are discussed and summarized in a large table in which a more comprehensive enumeration of syndromes is provided.

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Hryhorowicz, Szymon, Marta Kaczmarek-Ryś, Emilia Lis-Tanaś, Jakub Porowski, Marcin Szuman, Natalia Grot, Alicja Kryszczyńska, Jacek Paszkowski, Tomasz Banasiewicz y Andrzej Pławski. "Strong Hereditary Predispositions to Colorectal Cancer". Genes 13, n.º 12 (10 de diciembre de 2022): 2326. http://dx.doi.org/10.3390/genes13122326.

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Cancer is one of the most common causes of death worldwide. A strong predisposition to cancer is generally only observed in colorectal cancer (5% of cases) and breast cancer (2% of cases). Colorectal cancer is the most common cancer with a strong genetic predisposition, but it includes dozens of various syndromes. This group includes familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, NTHL1-associated polyposis, Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Lynch syndrome, and Muir–Torre syndrome. The common symptom of all these diseases is a very high risk of colorectal cancer, but depending on the condition, their course is different in terms of age and range of cancer occurrence. The rate of cancer development is determined by its conditioning genes, too. Hereditary predispositions to cancer of the intestine are a group of symptoms of heterogeneous diseases, and their proper diagnosis is crucial for the appropriate management of patients and their successful treatment. Mutations of specific genes cause strong colorectal cancer predispositions. Identifying mutations of predisposing genes will support proper diagnosis and application of appropriate screening programs to avoid malignant neoplasm.

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Hu, Chunling, Holly LaDuca, Hermela Shimelis, Eric C. Polley, Jenna Lilyquist, Steven N. Hart, Jie Na et al. "Multigene Hereditary Cancer Panels Reveal High-Risk Pancreatic Cancer Susceptibility Genes". JCO Precision Oncology, n.º 2 (noviembre de 2018): 1–28. http://dx.doi.org/10.1200/po.17.00291.

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Purpose The relevance of inherited pathogenic mutations in cancer predisposition genes in pancreatic cancer is not well understood. We aimed to assess the characteristics of patients with pancreatic cancer referred for hereditary cancer genetic testing and to estimate the risk of pancreatic cancer associated with mutations in panel-based cancer predisposition genes in this high-risk population. Methods Patients with pancreatic cancer (N = 1,652) were identified from a 140,000-patient cohort undergoing multigene panel testing of predisposition genes between March 2012 and June 2016. Gene-level mutation frequencies relative to Exome Aggregation Consortium and Genome Aggregation Database reference controls were assessed. Results The frequency of germline cancer predisposition gene mutations among patients with pancreatic cancer was 20.73%. Mutations in ATM, BRCA2, CDKN2A, MSH2, MSH6, PALB2, and TP53 were associated with high pancreatic cancer risk (odds ratio, > 5), and mutations in BRCA1 were associated with moderate risk (odds ratio, > 2). In a logistic regression model adjusted for age at diagnosis and family history of cancer, ATM and BRCA2 mutations were associated with personal history of breast or pancreatic cancer, whereas PALB2 mutations were associated with family history of breast or pancreatic cancer. Conclusion These findings provide insight into the spectrum of mutations expected in patients with pancreatic cancer referred for cancer predisposition testing. Mutations in eight genes confer high or moderate risk of pancreatic cancer and may prove useful for risk assessment for pancreatic and other cancers. Family and personal histories of breast cancer are strong predictors of germline mutations.

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Pietragalla, Antonella, Martina Arcieri, Claudia Marchetti, Giovanni Scambia y Anna Fagotti. "Ovarian cancer predisposition beyond BRCA1 and BRCA2 genes". International Journal of Gynecologic Cancer 30, n.º 11 (6 de septiembre de 2020): 1803–10. http://dx.doi.org/10.1136/ijgc-2020-001556.

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Several genes associated with hereditary ovarian cancer have been discovered as a result of the work done with next generation sequencing. It is estimated that approximately 23% of ovarian carcinomas have a hereditary predisposition. The most common hereditary condition is represented by germline mutations in BRCA1 or BRCA2 genes that account for 20–25% of high grade serous ovarian cancer. A number of other hereditary ovarian cancers are associated with different genes, with a crucial role in the DNA damage response pathway, such as the mismatch repair genes in Lynch syndrome, TP53 in Li-Fraumeni syndrome, STK11 in Peutz-Jeghers syndrome, CHEK2, RAD51, BRIP1, and PALB2. The goal of this manuscript is to summarize the published data regarding the molecular pathways involved in the pathogenesis of non-BRCA related hereditary ovarian cancer and to provide a tool that might be useful in discussing risk assessment, genetic testing, prevention strategies, as well as clinical and therapeutic implications for patients with ovarian cancer.

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Deng, Joseph, Burak Altintas, Jeremy Haley, Jung Kim, David J. Carey, Douglas R. Stewart y Lisa J. McReynolds. "Investigation of cancer predisposition in Fanconi anemia heterozygotes: A DiscovEHR cohort population study." Journal of Clinical Oncology 41, n.º 16_suppl (1 de junio de 2023): 10589. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.10589.

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10589 Background: Fanconi anemia (FA) is a cancer predisposition syndrome caused by biallelic pathogenic variants in one of 22 genes involved in DNA intrastrand crosslink repair. 20 of these genes have an autosomal recessive inheritance pattern. Of the FA genes, 5 ( BRCA1, BRCA2, BRIP1, PALB2, RAD51C) are known cancer predisposition genes (CPG) when inherited in monoallelic autosomal dominant manner, though the heterozygous predisposition status of the remaining 15 remains unclear. Large population-level exome sequencing projects with linked health records such as the DiscovEHR cohort serve as promising tools to establish sufficient power to investigate all FA genes. Quantifying cancer risk is important for the counseling and surveillance of FA heterozygotes, especially with the ever-increasing use of genetic testing identifying these individuals. Methods: 170,503 individuals enrolled in the DiscovEHR Cohort were analyzed for pathogenic/likely pathogenic variants in 22 FA genes and identified 5834 subjects, the case group. ICD10 phenotype classifications for these subjects were curated to Phecodes and ICD-O-3 Site Recodes for two control arms of analysis. The first control arm included all DiscovEHR subjects excluding the case group and those with a variant of uncertain significance in the genes of interest with a deleterious in-silico score. The second control arm included individuals from the Surveillance, Epidemiology, and End Results (SEER) database. Phecode analysis yielded odds ratios adjusted for age, sex, race, smoking status, and BMI. SEER analysis yielded Standardized Incidence Ratio scores adjusted for age, sex, and birth cohort. When both arms of the analysis were completed Phecodes and SEER analyses were matched and positive signals for cancer risk were defined by statistically significant ratios in both. Results: The 5 known CPGs demonstrated multiple signals for cancer predisposition as expected (p < 0.0001). Results for FANCA (p = 0.4231) and FANCC (p = 0.8142) heterozygotes validated recent results from our group showing no increased risk of cancer in relatives of FA patients with these genotypes. Ten other FA genes also showed no increased risk of cancer. 3 genes suggested a possible increased risk of specific cancers in heterozygotes and are currently being evaluated in a second large population exome cohort to validate these findings. Conclusions: This is the largest study to date on the cancer predisposition risk in Fanconi anemia heterozygotes. We have confirmed the known risk in 5 well-described CPGs and the lack of risk amongst FANCA and FANCC heterozygotes, the most common in population. Further analysis via an additional large population cohort is underway to validate any possible novel cancer predispositions in 3 genes. For the remaining FA genes, this population analysis supports previous literature on known CPGs and the lack of cancer predisposition in most FA genes.

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Štellmachová, Júlia, Petr Vrtěl, Radek Vrtěl, Mária Janíková, Kristýna Kolaříková, Martin Procházka y Radek Vodička. "Ovarian tumors and genetic predisposition". Česká gynekologie 87, n.º 3 (27 de junio de 2022): 211–16. http://dx.doi.org/10.48095/cccg2022211.

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Objective: Summary of knowledge in the field of ovarian cancer and genetic predisposition. Results: Ovarian tumors are usually diagnosed at advanced stages of the disease and the prognosis for these patients is generally poor. The 5-year overall survival rate, regardless of the histopathological type of tumor, is around 44%. Germline mutations causing hereditary tumor syndromes are predominantly involved in the development of epithelial ovarian tumors. The most common is hereditary breast and ovarian cancer syndrome, which is caused by germline mutations in the tumor suppressor genes BRCA1 and BRCA2. Several other tumor suppressor genes and oncogenes are known to be associated with ovarian tumors and cause other types of tumor syndromes. Inherited tumor syndromes include Lynch syndrome, Peutz-Jegers syndrome, Gorlin syndrome, Li-Fraumeni syndrome and others. The indication for genetic examination of germline mutations is given by a clinical geneticist on the basis of the recommendation of the attending physician. At present, every ovarian tumor, primary peritoneal tumor and tube tumor diagnosed at any age is indicated for genetic testing. Conclusion: Early identification of genes for hereditary cancer syndromes, thanks to rapidly developing molecular genetic methods, is an important step towards personalized treatment of ovarian cancer and preventive measures in families at risk. It is also important to note that a negative molecular genetic test result does not exclude genetic risk. Key words: ovarian cancer – germinal variant – hereditary tumor syndrome – molecular-genetic examination – prevention – familial mutations – genetic risks

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Sylvester, Dianne E., Yuyan Chen, Robyn V. Jamieson, Luciano Dalla-Pozza y Jennifer A. Byrne. "Investigation of clinically relevant germline variants detected by next-generation sequencing in patients with childhood cancer: a review of the literature". Journal of Medical Genetics 55, n.º 12 (4 de octubre de 2018): 785–93. http://dx.doi.org/10.1136/jmedgenet-2018-105488.

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Genetic predisposition is an important underlying cause of childhood cancer, although the proportion of patients with childhood cancer carrying predisposing pathogenic germline variants is uncertain. This review considers the pathogenic or likely pathogenic germline variants reported by six studies that used next-generation sequencing to investigate genetic predisposition in selected cohorts of patients with childhood cancer and used incompletely overlapping gene sets for analysis and interpretation. These six studies reported that 8.5%–35.5% of patients with childhood cancer carried clinically relevant germline variants. Analysis of 52 autosomal dominant cancer predisposition genes assumed common to all six studies showed that 5.5%–25.8% of patients with childhood cancer carried pathogenic or likely pathogenic germline variants in at least one of these genes. When only non-central nervous system solid tumours (excluding adrenocortical carcinomas) were considered, 8.5%–10.3% of the patients carried pathogenic or likely pathogenic germline variants in at least one of 52 autosomal dominant cancer predisposition genes. There was a lack of concordance between the genotype and phenotype in 33.3%–57.1% of the patients reported with pathogenic or likely pathogenic germline variants, most of which represented variants in autosomal dominant cancer predisposition genes associated with adult onset cancers. In summary, germline genetic testing in patients with childhood cancer requires clear definition of phenotypes and genes considered for interpretation, with potential to inform and broaden childhood cancer predisposition syndromes.

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Rotaru, T. V., L. I. Rotaru y N. P. Lapochikina. "Genetic predisposition for cervical cancer". Obstetrics, Gynecology and Reproduction 14, n.º 2 (26 de julio de 2020): 218–28. http://dx.doi.org/10.17749/2313-7347.139.

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Aim: to assess a role of genetic factors and human papillomavirus (HPV) in developing cervical neoplasia based on analyzing current publications on virus-induced carcinogenesis.Materials and methods. A systematic overview on publications dedicated to examining genetic predisposition to developing cervical cancer (CC) available in electronic databases was performed by searching in the International Scientific Databases (ISDB) PubMed/MEDLINE as well as manually by accessing enlisted input documents related to the above noted studies. Full-text publications were solely selected for analysis.Results. CC is a multifactorial disease implicating host genetic predisposition being caused by persistent high oncogenic risk HPV-infection. Immune system plays a major role in HPV-infection. Altered cell-mediated immune response is responsible for impaired potential to HPV eradication. On the other hand, immune evasion contributes to viral persistence and cancer progression. Oncogenes, cancer suppressor genes (Rb and TP53), cytokine (ILs, IFNG) and chemokine (CXCL) genes, the genes involved in antigen processing, as well as an impact for each gene polymorphism or even haplotypes playing a role in cervical carcinogenesis are mainly involved in CC developing.Conclusion. The data obtained allowed to demonstrate a role for genetic polymorphisms in the genes encoding cytokines, chemokines, diverse receptors as well as those involved in antigen processing, and cancer suppressor genes in perpetuation of HPV-infection.

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Rahman, Nazneen. "Mainstreaming genetic testing of cancer predisposition genes". Clinical Medicine 14, n.º 4 (agosto de 2014): 436–39. http://dx.doi.org/10.7861/clinmedicine.14-4-436.

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Capellini, Alexandra, Matthew Williams, Kenan Onel y Kuan-Lin Huang. "The Functional Hallmarks of Cancer Predisposition Genes". Cancer Management and Research Volume 13 (junio de 2021): 4351–57. http://dx.doi.org/10.2147/cmar.s311548.

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Esteban-Jurado, Clara. "New genes emerging for colorectal cancer predisposition". World Journal of Gastroenterology 20, n.º 8 (2014): 1961. http://dx.doi.org/10.3748/wjg.v20.i8.1961.

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Rahman, Nazneen. "Realizing the promise of cancer predisposition genes". Nature 505, n.º 7483 (15 de enero de 2014): 302–8. http://dx.doi.org/10.1038/nature12981.

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Shah, Sidrah, Alison Cheung, Mikolaj Kutka, Matin Sheriff y Stergios Boussios. "Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes". International Journal of Environmental Research and Public Health 19, n.º 13 (1 de julio de 2022): 8113. http://dx.doi.org/10.3390/ijerph19138113.

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Epithelial ovarian cancer (EOC) is one of the cancers most influenced by hereditary factors. A fourth to a fifth of unselected EOC patients carry pathogenic variants (PVs) in a number of genes, the majority of which encode for proteins involved in DNA mismatch repair (MMR) pathways. PVs in BRCA1 and BRCA2 genes are responsible for a substantial fraction of hereditary EOC. In addition, PV genes involved in the MMR pathway account for 10–15% of hereditary EOC. The identification of women with homologous recombination (HR)-deficient EOCs has significant clinical implications, concerning chemotherapy regimen planning and development as well as the use of targeted therapies such as poly(ADP-ribose) polymerase (PARP) inhibitors. With several genes involved, the complexity of genetic testing increases. In this context, next-generation sequencing (NGS) allows testing for multiple genes simultaneously with a rapid turnaround time. In this review, we discuss the EOC risk assessment in the era of NGS.

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Angeli, Davide, Samanta Salvi y Gianluca Tedaldi. "Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?" International Journal of Molecular Sciences 21, n.º 3 (8 de febrero de 2020): 1128. http://dx.doi.org/10.3390/ijms21031128.

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Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. BRCA1 and BRCA2 are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. TP53, PTEN, STK11, and CDH1 have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, PALB2, BRIP1, ATM, CHEK2, BARD1, NBN, NF1, RAD51C, RAD51D and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

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Ouedraogo, Zangbéwendé Guy, Florian Ceruti, Mathis Lepage, Mathilde Gay-Bellile, Nancy Uhrhammer, Flora Ponelle-Chachuat, Yannick Bidet, Maud Privat y Mathias Cavaillé. "Detection Rate and Spectrum of Pathogenic Variations in a Cohort of 83 Patients with Suspected Hereditary Risk of Kidney Cancer". Genes 14, n.º 11 (25 de octubre de 2023): 1991. http://dx.doi.org/10.3390/genes14111991.

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Hereditary predisposition to cancer affects about 3–5% of renal cancers. Testing criteria have been proposed in France for genetic testing of non-syndromic renal cancer. Our study explores the detection rates associated with our testing criteria. Using a comprehensive gene panel including 8 genes related to renal cancer and 50 genes related to hereditary predisposition to other cancers, we evaluated the detection rate of pathogenic variants in a cohort of 83 patients with suspected renal cancer predisposition. The detection rate was 7.2% for the renal cancer genes, which was 2.41-fold higher than the estimated 3% proportion of unselected kidney cases with inherited risk. Pathogenic variants in renal cancer genes were observed in 44.5% of syndromic cases, and in 2.7% of non-syndromic cases. Incidental findings were observed in CHEK2, MSH2, MUTYH and WRN. CHEK2 was associated with renal cancer (OR at 7.14; 95% CI 1.74–29.6; p < 0.003) in our study in comparison to the gnomAD control population. The detection rate in renal cancer genes was low in non-syndromic cases. Additional causal mechanisms are probably involved, and further research is required to find them. A study of the management of renal cancer risk for CHEK2 pathogenic variant carriers is needed.

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Kamihara, Junne, Holly LaDuca, Emily Dalton, Virginia Speare, Judy Ellen Garber y Mary Helen Black. "Germline mutations in cancer predisposition genes among patients with thyroid cancer." Journal of Clinical Oncology 35, n.º 15_suppl (20 de mayo de 2017): 1581. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1581.

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1581 Background: Thyroid cancers are known component tumors of both well-described and emerging hereditary cancer syndromes. To assess the contribution of germline variants in thyroid cancer predisposition, we examined the prevalence of germline mutations among individuals with a history of thyroid cancer, compared to those with thyroid and breast cancer or breast cancer alone. Methods: Clinical histories and molecular results were reviewed for individuals with a history of thyroid and/or breast cancer, ascertained from a cohort of > 140,000 patients who underwent hereditary cancer multigene panel testing at a single commercial laboratory. Clinical history information was obtained from test requisition forms completed by ordering clinicians and from pedigrees/clinic notes, if provided. Results: Among 2,678 thyroid cancer patients, the majority were Caucasian (66.9%), female (92.3%), and/or had an additional cancer primary (71.9%), with nearly half reporting an additional breast cancer primary (49.1%). Among those with available pathology information, 4.1% had medullary thyroid cancer. The median (IQR) age at diagnosis was 38 (26,48) years, and while 94.1% had a family history of cancer, 78.8% had at least one affected 1st degree relative. Overall, 11.1% were identified as mutation carriers, defined as ≥1 pathogenic or likely pathogenic variant. Among those with thyroid cancer alone, 9.7% had a mutation, similar to those with breast cancer alone (9.7%) and those with breast and thyroid cancer only (10.5%). Genes most frequently mutated in the thyroid only group included CHEK2 (3.1%), MUTYH (monoallelic) (2.4%), APC (2.0%), ATM (1.6%), and PALB2 (1.2%). CHEK2 was the most frequently mutated gene observed in all groups, with a higher frequency seen among those with thyroid and breast cancer (5.5%) compared to breast cancer (2.5%) or thyroid cancer (3.1%) alone (p < 0.001). Conclusions: A high rate of germline mutations is observed among individuals with thyroid cancer presenting for clinical genetic testing, even in the absence of other primary cancer diagnoses. Thyroid cancer may be an under-recognized component tumor of hereditary cancer predisposition syndromes suggesting the need for further investigation.

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Tedaldi, Gianluca, Michela Tebaldi, Valentina Zampiga, Ilaria Cangini, Francesca Pirini, Elisa Ferracci, Rita Danesi et al. "Male Breast Cancer: Results of the Application of Multigene Panel Testing to an Italian Cohort of Patients". Diagnostics 10, n.º 5 (30 de abril de 2020): 269. http://dx.doi.org/10.3390/diagnostics10050269.

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Male breast cancer (MBC) is a rare tumor, accounting for less than 1% of all breast cancers. In MBC, genetic predisposition plays an important role; however, only a few studies have investigated in depth the role of genes other than BRCA1 and BRCA2. We performed a Next-Generation Sequencing (NGS) analysis with a panel of 94 cancer predisposition genes on germline DNA from an Italian case series of 70 patients with MBC. Moreover, we searched for large deletions/duplications of BRCA1/2 genes through the Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Through the combination of NGS and MLPA, we identified three pathogenic variants in the BRCA1 gene and six in the BRCA2 gene. Besides these alterations, we found six additional pathogenic/likely-pathogenic variants in PALB2, CHEK2, ATM, RAD51C, BAP1 and EGFR genes. From our study, BRCA1 and BRCA2 emerge as the main genes associated with MBC risk, but also other genes seem to be associated with the disease. Indeed, some of these genes have already been implicated in female breast cancer predisposition, but others are known to be involved in other types of cancer. Consequently, our results suggest that novel genes could be involved in MBC susceptibility, shedding new light on their role in cancer development.

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Plon, Sharon E. y Philip J. Lupo. "Genetic Predisposition to Childhood Cancer in the Genomic Era". Annual Review of Genomics and Human Genetics 20, n.º 1 (31 de agosto de 2019): 241–63. http://dx.doi.org/10.1146/annurev-genom-083118-015415.

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Developments over the past five years have significantly advanced our ability to use genome-scale analyses—including high-density genotyping, transcriptome sequencing, exome sequencing, and genome sequencing—to identify the genetic basis of childhood cancer. This article reviews several key results from an expanding number of genomic studies of pediatric cancer: ( a) Histopathologic subtypes of cancers can be associated with a high incidence of germline predisposition, ( b) neurodevelopmental disorders or highly penetrant cancer predisposition syndromes can result from specific patterns of variation in genes encoding the SMARC family of chromatin remodelers, ( c) genome-wide association studies with relatively small pediatric cancer cohorts have successfully identified single-nucleotide polymorphisms with large effect sizes and provided insight into population differences in cancer risk, and ( d) multiple exome or genome analyses of unselected childhood cancer cohorts have yielded a 7–10% incidence of pathogenic variants in cancer predisposition genes. This work supports the increasing use of genomic sequencing in the care of pediatric cancer patients and at-risk family members.

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Wei, Ran, Yao Yao, Wu Yang, Chun-Hou Zheng, Min Zhao y Junfeng Xia. "dbCPG: A web resource for cancer predisposition genes". Oncotarget 7, n.º 25 (12 de mayo de 2016): 37803–11. http://dx.doi.org/10.18632/oncotarget.9334.

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Imyanitov, E., K. Hanson y B. Zhivotovsky. "Polymorphic variations in apoptotic genes and cancer predisposition". Cell Death & Differentiation 12, n.º 8 (20 de mayo de 2005): 1004–7. http://dx.doi.org/10.1038/sj.cdd.4401674.

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Zhang, Jinghui, Michael F. Walsh, Gang Wu, Michael N. Edmonson, Tanja A. Gruber, John Easton, Dale Hedges et al. "Germline Mutations in Predisposition Genes in Pediatric Cancer". New England Journal of Medicine 373, n.º 24 (10 de diciembre de 2015): 2336–46. http://dx.doi.org/10.1056/nejmoa1508054.

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Rebuzzi, Francesca, Paola Ulivi y Gianluca Tedaldi. "Genetic Predisposition to Colorectal Cancer: How Many and Which Genes to Test?" International Journal of Molecular Sciences 24, n.º 3 (21 de enero de 2023): 2137. http://dx.doi.org/10.3390/ijms24032137.

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Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li–Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz–Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

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Tung, Nadine, Nancy U. Lin, John Kidd, Brian A. Allen, Nanda Singh, Richard J. Wenstrup, Anne-Renee Hartman, Eric P. Winer y Judy E. Garber. "Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer". Journal of Clinical Oncology 34, n.º 13 (1 de mayo de 2016): 1460–68. http://dx.doi.org/10.1200/jco.2015.65.0747.

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Purpose Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. Methods Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. Results Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Conclusion Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2.

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Couch, Fergus J., Hermela Shimelis, Chunling Hu, Steven N. Hart, Eric C. Polley, Jie Na, Emily Hallberg et al. "Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer". JAMA Oncology 3, n.º 9 (1 de septiembre de 2017): 1190. http://dx.doi.org/10.1001/jamaoncol.2017.0424.

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Woodward, Emma R. y Stefan Meyer. "Fanconi Anaemia, Childhood Cancer and the BRCA Genes". Genes 12, n.º 10 (27 de septiembre de 2021): 1520. http://dx.doi.org/10.3390/genes12101520.

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Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications.

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Couch, Fergus J., Steven N. Hart, Priyanka Sharma, Amanda Ewart Toland, Xianshu Wang, Penelope Miron, Janet E. Olson et al. "Inherited Mutations in 17 Breast Cancer Susceptibility Genes Among a Large Triple-Negative Breast Cancer Cohort Unselected for Family History of Breast Cancer". Journal of Clinical Oncology 33, n.º 4 (1 de febrero de 2015): 304–11. http://dx.doi.org/10.1200/jco.2014.57.1414.

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Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.

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Funchain, Pauline, Ying Ni, Brandon Bungo, Brandie Heald, Michelle Arbesman, Tapas Ranjan Behera, Sarah M. Nielsen et al. "Germline predisposition in oncologic and dermatologic melanoma cohorts." Journal of Clinical Oncology 40, n.º 16_suppl (1 de junio de 2022): 10523. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10523.

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10523 Background: Melanoma has recently been suggested to be a highly heritable cancer with high twin-twin concordance. In contrast, prior studies on patients with familial atypical multiple mole melanoma (FAMMM) syndrome, multiple primary melanomas and early age of onset, all known to be associated with germline CDKN2A/CDK4 pathogenic variants, suggest that individuals with melanoma who carry germline alterations are rare. We studied the overall prevalence of germline cancer predisposition in a large prospective oncologic cohort with comparison to other defined cohorts of individuals with melanoma with available germline data. Methods: Individuals who presented to medical oncology clinic with a diagnosis of melanoma and personal or family history of multiple cancers were offered germline testing with a commercially available next generation sequencing panel (Invitae, San Francisco, CA). Eligibility criteria required ≥ 2 melanomas in an individual or family; melanoma and other cancer(s) in an individual; melanoma and at least 2 other cancers in 1st- or 2nd-degree relatives; age ≤35 at diagnosis; or limited family structure. Comparative analysis of germline NGS data from 3 additional selected and non-selected melanoma datasets was performed. Results: In a cohort of 400 oncology patients with melanoma who consented to commercial germline testing of 85 cancer-associated genes, a germline pathogenic/likely pathogenic (gP/LP) positive rate of 15.3% (n = 61) was observed. Genes previously associated with inherited melanoma ( BAP1, BRCA1/2, CDKN2A, MITF, TP53) comprised less than one-third of gP/LP variants (20, 32.7%); the majority of germline variants were in cancer predisposition genes not traditionally associated with melanoma (e.g. BRIP1, CHEK2, MSH2, PMS2, MLH1, RAD51C, BLM). Family history of non-cutaneous cancer (42, 69%) and personal history of melanoma with ≥ 1 non-cutaneous cancer (22, 36%) were the most common eligibility criteria met in gP/LP variant carriers. Analysis of germline data from other large oncologic and dermatologic melanoma datasets yielded gP/LP variant positive rates of 10.6% in an unselected oncologic melanoma cohort (TCGA, n = 470), 15.8% in a selected commercial testing cohort (Invitae, n = 12,571), and 14.5% in a highly selected, primarily dermatologic subset (Boston-Athens, n = 289). Conclusions: In oncologic and dermatologic cohorts, germline testing of selected individuals with melanoma yields rates of clinically impactful P/LP variant detection which exceed consensus standards for pretest probability. Most P/LP variants were found in genes associated with non-cutaneous cancers. Obtaining a family and personal history of cancer, particularly non-cutaneous cancers, and referring for broad panel-based germline testing in all individuals with melanoma are recommended.

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Palmer, Julie R., Chunling Hu, Steven Hart, Rohan David Gnanaolivu, Chi Gao, Hoda Anton-Culver, Amy Trentham-Dietz et al. "Genetic predisposition to breast cancer among African American women." Journal of Clinical Oncology 37, n.º 15_suppl (20 de mayo de 2019): 104. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.104.

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104 Background: The identification of pathogenic mutations in breast cancer susceptibility genes through clinical genetic testing leads to focused screening and prevention strategies for women at increased risk of cancer. However, the frequency of mutations and the risks of cancer associated with breast cancer predisposition genes has not been established for the African American population. Methods: Germline DNA samples from African American women (5,054 breast cancer cases and 4,993 age-matched unaffected controls) from 10 U.S. studies were tested for mutations in 20 established breast cancer predisposition genes using a QIAseq multiplex amplicon panel as part of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study. The frequency of mutations in each gene and associations between mutations and breast cancer risk, adjusted for study design, age, and first-degree family history of breast cancer, were evaluated. Results: The mean age at diagnosis of breast cancer cases was 54.4 years and the mean age of controls was 55.2 years. 18.2% of cases and 10.8% of controls reported a first-degree family history of breast cancer. Pathogenic mutations in any of the 20 breast cancer predisposition genes were identified in 7.6% of breast cancer cases and 2.4% of controls. In multivariable analyses, mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (odds ratio (OR) > 5.0). Mutations in CHEK2 were associated with moderate risks of breast cancer (OR > 2.0), whereas mutations in ATM had lower clinical relevance (OR = 1.8). Mutations in BRCA1, BRCA2, PALB2, and RAD51D, but not CHEK2 or ATM, were associated with increased risks of estrogen receptor negative breast cancer. Conclusions: Cancer predisposition genes confer similar risks of breast cancer in the African American population as in non-Hispanic Whites. These studies provide important insights into the risks of breast cancer associated with predisposition gene mutations in the African American population.

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Brandão, Andreia, Paula Paulo y Manuel R. Teixeira. "Hereditary Predisposition to Prostate Cancer: From Genetics to Clinical Implications". International Journal of Molecular Sciences 21, n.º 14 (16 de julio de 2020): 5036. http://dx.doi.org/10.3390/ijms21145036.

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Prostate cancer (PrCa) ranks among the top five cancers for both incidence and mortality worldwide. A significant proportion of PrCa susceptibility has been attributed to inherited predisposition, with 10–20% of cases expected to occur in a hereditary/familial context. Advances in DNA sequencing technologies have uncovered several moderate- to high-penetrance PrCa susceptibility genes, most of which have previously been related to known hereditary cancer syndromes, namely the hereditary breast and ovarian cancer (BRCA1, BRCA2, ATM, CHEK2, and PALB2) and Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) genes. Additional candidate genes have also been suggested, but further evidence is needed to include them in routine genetic testing. Recommendations based on clinical features, family history, and ethnicity have been established for more cost-efficient genetic testing of patients and families who may be at an increased risk of developing PrCa. The identification of alterations in PrCa predisposing genes may help to inform screening strategies, as well as treatment options, in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PrCa, the current genetic screening recommendations, and the implications for clinical management of the disease.

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Yadav, Siddhartha, Chunling Hu, Steven N. Hart, Nicholas Boddicker, Eric C. Polley, Jie Na, Rohan Gnanaolivu et al. "Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer". Journal of Clinical Oncology 38, n.º 13 (1 de mayo de 2020): 1409–18. http://dx.doi.org/10.1200/jco.19.02190.

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PURPOSE To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes ( ATM , BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

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Wei, Grace, Marilin Rosa, Maxine Chang, Brian J. Czerniecki y Xia Wang. "Breast cancer ER, PR, and HER2 expression variance by germline cancer predisposition genes." Journal of Clinical Oncology 39, n.º 15_suppl (20 de mayo de 2021): 10526. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.10526.

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10526 Background: The association between breast cancer characteristics and survival with estrogen receptor (ER) and progesterone receptor (PR) expression has been primarily studied via binomial categories, ER-positive and ER-negative. In order to better characterize germline genetic influences on these markers, we investigated their IHC expression semi-quantitatively in cancer predisposition germline pathogenic variant (PV) carriers of the following genes: BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1, ATM, CHEK2, and Lynch syndrome genes. The HER2 expression was also analyzed. Methods: We conducted a retrospective chart review of patients with germline panel genetic testing for cancer predisposition genes at Moffitt Cancer Center’s GeneHome clinic. Inclusion criteria included 1) women ≥18 years old, 2) breast cancer diagnosis, 3) cancer predisposition germline panel genetic test results, 4) available ER and PR expression levels, and 5) available HER expression and/or amplification status. ER, PR, and HER2 status were compared between PV carriers and non-PV carriers via Mann-Whitney U at p>0.05. Results: A total of 847 cases were reviewed for the study. Among 658 patients with a breast cancer diagnosis and complete ER PR data, 365 cases (55.5%) were non-PV carriers and 293 cases (44.5%) carried a PV in at least one of the genes listed above. Among 635 cases with available HER2 expression/amplification status, 355 (55.9%) cases were non-PV carriers and 288 (45.4%) cases were PV-carriers. When compared with non-PV carrier controls, BRCA1 PV carriers’ breast tumors had significantly lower ER and/or PR expression. Further, BRCA2 and TP53 PV tumors also displayed moderately lower ER expression. Contrarily, CHEK2 tumors displayed higher ER and PR expression compared to controls. Further, BRCA1 and BRCA2 PV carriers were more likely to have HER2- breast cancers. Conclusions: Differences in ER, PR, HER2 expression levels were observed in germline PV carrier breast cancers, signaling differential impacts by germline PVs on the tumor evolution process. It is likely that tumor differences in PV carriers influence responses to therapies, including hormone therapy, anti-HER2 therapy, and subsequent survival.[Table: see text]

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Yanus, G. A., A. G. Iyevleva, E. N. Suspitsin, A. V. Tumakova, E. V. Belogubova, S. N. Aleksakhina, A. V. Togo y E. N. Imyanitov. "Hereditary predisposition to kidney cancer: cancer syndromes, multisystemic disorders, and nephropathies". Sechenov Medical Journal 14, n.º 2 (14 de agosto de 2023): 5–20. http://dx.doi.org/10.47093/2218-7332.2023.14.2.5-20.

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Kidney cancer (KC) is a common disease characterized by extreme heterogeneity. There are nine known monogenic diseases associated with a significantly elevated KC risk: von Hippel-Lindau disease, MET-associated papillary renal cancer, familial multiple leiomyomatosis and renal cell cancer, SDHx-associated familial pheochromocytoma/ paraganglioma, Birt-Hogg-Dube syndrome, tuberous sclerosis, Cowden syndrome, BAP1- and MITF-associated melanoma-KC predisposition. These syndromes differ in the degree of cancer risk, the quantity, growth and progression rates of associated precancerous lesions, the morphology, and clinical presentations of malignancy itself, and in the response to therapy. Identification of causative germline lesion allows planning the surveillance of a mutation carrier, choosing the right time and extent of surgery, and optimizing treatment regimen. Hereditary KC research often brings forward novel approaches to the management of sporadic “phenocopies” of hereditary syndromes, i.e. sporadic cancers with somatic mutations in similar genes. The main directions for further study of genetic factors of KC are to find novel KC genes, to study risk modifiers in carriers of highly penetrant mutations, to clarify the involvement of hereditary nephropathies in the occurrence of renal cancers.

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Stolarova, Lenka, Petra Kleiblova, Marketa Janatova, Jana Soukupova, Petra Zemankova, Libor Macurek y Zdenek Kleibl. "CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate". Cells 9, n.º 12 (12 de diciembre de 2020): 2675. http://dx.doi.org/10.3390/cells9122675.

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Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.

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Maciaszek, Jamie L., Ninad Oak y Kim E. Nichols. "Recent advances in Wilms’ tumor predisposition". Human Molecular Genetics 29, R2 (15 de mayo de 2020): R138—R149. http://dx.doi.org/10.1093/hmg/ddaa091.

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Abstract Wilms’ tumor (WT), the most common childhood kidney cancer, develops in association with an underlying germline predisposition in up to 15% of cases. Germline alterations affecting the WT1 gene and epigenetic alterations affecting the 11p15 locus are associated with a selective increase in WT risk. Nevertheless, WT also occurs in the context of more pleiotropic cancer predispositions, such as DICER1, Li-Fraumeni and Bloom syndrome, as well as Fanconi anemia. Recent germline genomic investigations have increased our understanding of the host genetic factors that influence WT risk, with sequencing of rare familial cases and large WT cohorts revealing an expanding array of predisposition genes and associated genetic conditions. Here, we describe evidence implicating WT1, the 11p15 locus, and the recently identified genes CTR9, REST and TRIM28 in WT predisposition. We discuss the clinical features, mode of inheritance and biological aspects of tumorigenesis, when known. Despite these described associations, many cases of familial WT remain unexplained. Continued investigations are needed to fully elucidate the landscape of germline genetic alterations in children with WT. Establishing a genetic diagnosis is imperative for WT families so that individuals harboring a predisposing germline variant can undergo surveillance, which should enable the early detection of tumors and use of less intensive treatments, thereby leading to improved overall outcomes.

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Wieme, Greet, Jan Kral, Toon Rosseel, Petra Zemankova, Bram Parton, Michal Vocka, Mattias Van Heetvelde et al. "Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients". Cancers 13, n.º 17 (2 de septiembre de 2021): 4430. http://dx.doi.org/10.3390/cancers13174430.

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(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34–0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.

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Kim, Yena, Min Kyeong Kim, Kum Hei Ryu, Hyoeun Shim, Ji Sun Han, Jung Won Chun, Yun-Hee Kim et al. "Abstract 5800: Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 5800. http://dx.doi.org/10.1158/1538-7445.am2022-5800.

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Abstract Purpose: Genetic attribution for pancreatic cancer has been reported as 2-10%. However, the incidence of genetic predisposition and germline pathogenic variants (PVs) in Korean pancreatic cancer patients has not been well investigated. Therefore we studied to identify the clinical characteristics of the causative gene mutations and incidence of PV for future treatment strategies in pancreatic cancer. Methods: Total of 283 (145 male and 138 female) patients were enrolled in National Cancer Center in Korea (IRB no. NCC2019-0034, NCC2021-0338) and their median age was 67 years (range: 33-90). Resectable (25.1%), borderline resectable or locally advanced (25.5%), and metastatic (46.3%) stages were included. Germline hereditary cancer panel tests with 28 genes and BRCA1/2 gene were done in 97.2% (n=275) and 2.8% (n=8) of patients, respectively. Results: PVs were detected in 17 patients (median age 64, range 49-80) in ATM (n=5, 29.4%), BRCA1 (n=3, 17.6%), BRCA2 (n=2, 11.8%), RAD51D (n=2, 11.8%), TP53 (n=1, 5.9%), PALB2 (n=1, 5.9%), PMS2 (n=1, 5.9%), RAD50 (n=1, 5.9%), and SPINK1 (n=1, 5.9%). Eight patients (4 ATM PVs, 2 BRCA1 1 BRCA2, 1 PALB2 PV) presented various type of cancers in their families and three patients with ATM PVs showed pancreatic cancer in their first degree relatives. Nine patients without family cancer history represented median age as 66 (49-80) which was not significantly different of those with family history as 63 (51-75). Conclusions: This study showed 6.0% of incidence of germline PVs in Korean pancreatic cancer patients. Though we still don’t have guidelines for germline predisposition gene test in pancreatic cancer patients in Korea, this result showed that the incidence of PVs were comparable with that of the country which have recommendation to do genetic tests for all pancreatic cancer patients. To expand our knowledge for the incidence and involving genes of cancer predisposition for Korean pancreatic cancer patients, further analysis in larger number of patients is needed. (This study was supported by National cancer center, Korea, Grant no. 2110181).Keywords: Germ-line Mutation; Pancreatic Neoplasms; Incidence Citation Format: Yena Kim, Min Kyeong Kim, Kum Hei Ryu, Hyoeun Shim, Ji Sun Han, Jung Won Chun, Yun-Hee Kim, Ju Sun Song, Young-gon Kim, Sang Myung Woo, Sun-Young Kong. Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5800.

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Akras, Zade, Brandon Bungo, Brandie H. Leach, Jessica Marquard, Manmeet Ahluwalia, Hetty Carraway, Petros Grivas, Davendra P. S. Sohal y Pauline Funchain. "Primer on Hereditary Cancer Predisposition Genes Included Within Somatic Next-Generation Sequencing Panels". JCO Precision Oncology, n.º 3 (diciembre de 2019): 1–11. http://dx.doi.org/10.1200/po.18.00258.

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PURPOSE It has been estimated that 5% to 10% of cancers are due to hereditary causes. Recent data sets indicate that the incidence of hereditary cancer may be as high as 17.5% in patients with cancer, and a notable subset is missed if screening is solely by family history and current syndrome-based testing guidelines. Identification of germline variants has implications for both patients and their families. There is currently no comprehensive overview of cancer susceptibility genes or inclusion of these genes in commercially available somatic testing. We aimed to summarize genes linked to hereditary cancer and the somatic and germline panels that include such genes. METHODS Germline predisposition genes were chosen if commercially available for testing. Penetrance was defined as low, moderate, or high according to whether the gene conferred a 0% to 20%, 20% to 50%, or 50% to 100% lifetime risk of developing the cancer or, when percentages were not available, was estimated on the basis of existing literature descriptions. RESULTS We identified a total of 89 genes linked to hereditary cancer predisposition, and we summarized these genes alphabetically and by organ system. We considered four germline and six somatic commercially available panel tests and quantified the coverage of germline genes across them. Comparison between the number of genes that had germline importance and the number of genes included in somatic testing showed that many but not all germline genes are tested by frequently used somatic panels. CONCLUSION The inclusion of cancer-predisposing genes in somatic variant testing panels makes incidental germline findings likely. Although somatic testing can be used to screen for germline variants, this strategy is inadequate for comprehensive screening. Access to genetic counseling is essential for interpretation of germline implications of somatic testing and implementation of appropriate screening and follow-up.

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Levine, E. G., R. A. King y C. D. Bloomfield. "The role of heredity in cancer." Journal of Clinical Oncology 7, n.º 4 (abril de 1989): 527–40. http://dx.doi.org/10.1200/jco.1989.7.4.527.

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Heredity is generally felt to play a minor role in the development of cancer. This review critically examines this assumption. Topics discussed include evidence for heritable predisposition in animals and humans; the potential importance of genetic-environmental interactions; approaches that are being used to successfully locate genes responsible for heritable predisposition; comparability of genetic findings among heritable and corresponding sporadic malignancies; and future research directions. Breast, colon, and lung cancer are used to exemplify clinical and research activity in familial cancer; clinical phenotypes, segregation and linkage analyses, models for environmental interactions with inherited traits, and molecular mechanisms of tumor development are discussed. We conclude that the contribution of heredity to the cancer burden is greater than generally accepted, and that study of heritable predisposition will continue to reveal carcinogenic mechanisms important to the development of all cancers.

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Umarane, Pankaja, R. B. Nerli y Rangrez Shadab. "ASSOCIATION OF FAMILIAL PROSTATE CANCER WITH BREAST CANCER SUSCEPTIBILITY GENE MUTATIONS". Journal of Advanced Scientific Research 14, n.º 03 (31 de marzo de 2023): 15–19. http://dx.doi.org/10.55218/jasr.2023140303.

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Genetic alterations are one of the important known risk factors of prostate cancer. The family predisposition of breast and ovarian cancers may cause the severe progression of familial prostate cancer in some men. The association of germline mutations in BRCA1 and BRCA2 genes can cause breast cancer in almost 35% of women and 9% of men. Carriers of these pathogenic variants have a higher risk of causing prostate cancer. This study focused on the analysis of mutations causing prostate cancer around the world, associated with breast cancer susceptibility genes

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Makridakis, Nick, M. "Androgen metabolic genes in prostate cancer predisposition and progression". Frontiers in Bioscience 10, n.º 1-3 (2005): 2892. http://dx.doi.org/10.2741/1745.

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Rahman, Nazneen. "Erratum: Corrigendum: Realizing the promise of cancer predisposition genes". Nature 510, n.º 7503 (junio de 2014): 176. http://dx.doi.org/10.1038/nature13431.

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Qian, Yaping, Debora Mancini-DiNardo, Thaddeus Judkins, Hannah C. Cox, Krystal Brown, Maria Elias, Nanda Singh et al. "Identification of pathogenic retrotransposon insertions in cancer predisposition genes". Cancer Genetics 216-217 (octubre de 2017): 159–69. http://dx.doi.org/10.1016/j.cancergen.2017.08.002.

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Rajendran, Senthilkumar, Clara Benna, Alberto Marchet, Donato Nitti y Simone Mocellin. "Germline polymorphisms of circadian genes and gastric cancer predisposition". Cancer Communications 40, n.º 5 (3 de abril de 2020): 234–38. http://dx.doi.org/10.1002/cac2.12008.

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Kassem, Nawal M., Sandra K. Althouse, Patrick O. Monahan, Lisa Hayes, Sarah M. Nielsen, Brandie Heald, Edward D. Esplin, Kathryn E. Hatchell y Tarah J. Ballinger. "Racial disparities in cascade testing for cancer predisposition genes". Preventive Medicine 172 (julio de 2023): 107539. http://dx.doi.org/10.1016/j.ypmed.2023.107539.

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Shen, Jingnan, Xiaomo Li, Xianbiao Xie, Si Liu y Tonghui Ma. "Abstract 5777: Germline variants of cancer predisposition genes in a large cohort of Chinese sarcoma patients". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 5777. http://dx.doi.org/10.1158/1538-7445.am2022-5777.

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Abstract Background: Sarcomas represent a rare and heterogeneous group of soft tissue and bone cancers, including more than 100 histological subtypes. Although genomic profiling has identified oncogenic fusion genes as the major molecular drivers of many sarcoma subtypes, direct targeting of these fusion genes is clinically challenging and novel treatment approaches are needed. Methods: To explore new therapeutic targets in sarcoma, we performed germline testing of 148-cancer predisposition genes (OncoPanscan࣪, Genetronhealth) on genomic DNA from a cohort of 822 unselected Chinese sarcoma patients. Results: The median age of this cohort was 45 (1-88) years, and 84% were soft tissue sarcoma (STS), 16% were osteosarcoma. 9.3% (n =82) of patients harbored at least one predicted pathogenic germline variant in 37 cancer disposition genes including APC, BRCA1, BRCA2, CDKN2A, CHEK2, DICER1, MSH6, PMS2, SBDS, SMARCA4, and TP53. Twenty-four (2.9%) patients had a variant that mapped to a known sarcoma-associated cancer predisposition syndrome gene (CHEK2, DICER1, NF1, RECQL4, SMARCA4, TP53, WRN). The most frequently mutated genes are involved in the DNA damage repair pathway, with a prevalence of 6.3% (n =52). Twelve patients carried pathogenic mutations in TP53, which was associated with cancer-predisposing Li-Fraumeni syndrome (LFS). Interestingly, we also observed 12 patients harboring the same SBDS c.258+2T>C variant. Biallelic SBDS mutations were linked to Shwachman-Diamond Syndrome (SDS) associated with leukemia predisposition. Additionally, four patients carried pathogenic mutations in SMARCA4 (n =2) and SMARCE1 (n =2), two genes encoding key components of the BAF chromatin-remodeling complex. Patients with pathogenic SMARCA4 germline variants could participate in clinical trials of EZH2 inhibitor tazemetostat. Four patients harbored pathogenic germline variants in core homologous recombination genes (BRCA1/2 and PALB2), which may be targeted with platinum-based chemotherapy or PARP inhibitor olaparib. Conclusions: In summary, our genomic profiling approach revealed novel predisposition variants associated with sarcoma, and some of them can serve as therapeutic targets for future clinical investigation. Our work provided proof of principle that sarcoma patients may benefit from genetic counseling and participate in genomically-matched clinical trials. Citation Format: Jingnan Shen, Xiaomo Li, Xianbiao Xie, Si Liu, Tonghui Ma. Germline variants of cancer predisposition genes in a large cohort of Chinese sarcoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5777.

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Alba-Pavón, Piedad, Lide Alaña, Itziar Astigarraga y Olatz Villate. "Splicing-Disrupting Mutations in Inherited Predisposition to Solid Pediatric Cancer". Cancers 14, n.º 23 (2 de diciembre de 2022): 5967. http://dx.doi.org/10.3390/cancers14235967.

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The prevalence of hereditary cancer in children was estimated to be very low until recent studies suggested that at least 10% of pediatric cancer patients carry a germline mutation in a cancer predisposition gene. A significant proportion of pathogenic variants associated with an increased risk of hereditary cancer are variants affecting splicing. RNA splicing is an essential process involved in different cellular processes such as proliferation, survival, and differentiation, and alterations in this pathway have been implicated in many human cancers. Hereditary cancer genes are highly susceptible to splicing mutations, and among them there are several genes that may contribute to pediatric solid tumors when mutated in the germline. In this review, we have focused on the analysis of germline splicing-disrupting mutations found in pediatric solid tumors, as the discovery of pathogenic splice variants in pediatric cancer is a growing field for the development of personalized therapies. Therapies developed to correct aberrant splicing in cancer are also discussed as well as the options to improve the diagnostic yield based on the increase in the knowledge in splicing.

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