scholarly journals Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes

2017 ◽  
Author(s):  
Mykyta Artomov ◽  
Vijai Joseph ◽  
Grace Tiao ◽  
Tinu Thomas ◽  
Kasmintan Schrader ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Search Space ◽  
Separate Analysis ◽  
Control Analysis ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Cancer Susceptibility Genes ◽  
Predisposing Genes ◽  
Germline Variation

ABSTRACTTraditionally, genetic studies in cancer are focused on somatic mutations found in tumors and absent from the normal tissue. Identification of shared attributes in germline variation could aid discrimination of high-risk from likely benign mutations and narrow the search space for new cancer predisposing genes. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfil missing classification for rare germline variation we assembled datasets of whole exome sequences from >2,000 patients with different types of cancers: breast cancer, colon cancer and cutaneous and ocular melanomas matched to more than 7,000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease associated mutations and new candidate cancer susceptibility genes. Lists of all cancer predisposing genes were divided into subclasses according to the mode of inheritance of the related cancer syndrome or contribution to known major cancer pathways. Out of all subclasses only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this subclass of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI<0.1), while ultra-rare missense mutations were significantly overrepresented in cases only in constrained genes (pLI>0.9). Taken together, our findings provide insights into the distribution and types of mutations underlying inherited cancer predisposition.

scholarly journals One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene

2019 ◽  
Vol 57 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Florentia Fostira ◽  
Irene Kostantopoulou ◽  
Paraskevi Apostolou ◽  
Myrto S Papamentzelopoulou ◽  
Christos Papadimitriou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Gene Panel ◽  
Control Analysis ◽  
Loss Of Function ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Clinical Changes

BackgroundGene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.MethodsTo further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case–control analysis.ResultsHerein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively.ConclusionStudying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

scholarly journals Case–control analysis identifies shared properties of rare germline variation in cancer predisposing genes

2019 ◽  
Vol 27 (5) ◽  
pp. 824-828
Author(s):  
Mykyta Artomov ◽  
Vijai Joseph ◽  
Grace Tiao ◽  
Tinu Thomas ◽  
Kasmintan Schrader ◽  
...  
Keyword(s):  
Case Control ◽  
Control Analysis ◽  
Predisposing Genes ◽  
Germline Variation ◽  
Case Control Analysis

scholarly journals Von Hippel-Lindau disease and endocrine tumour susceptibility

2006 ◽  
Vol 13 (2) ◽  
pp. 415-425 ◽  
Author(s):  
Emma R Woodward ◽  
Eamonn R Maher
Keyword(s):  
Target Genes ◽  
Phenotypic Variability ◽  
Familial Cancer ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Cancer Syndrome ◽  
Pancreatic Islet Cell ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Vhl Disease

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by mutations in the VHL tumour suppressor gene. VHL disease is characterised by marked phenotypic variability and the most common tumours are haemangioblastomas of the retina and central nervous system and clear cell renal cell carcinoma. However, endocrine tumours, most commonly phaeochromocytoma and non-secretory pancreatic islet cell cancers, demonstrate marked interfamilial variations in frequency and are significant causes of morbidity and, sometimes, mortality. Genotype–phenotype correlations have revealed that certain missense mutations are associated with a high risk of phaeochromocytoma but total loss of function mutations are associated with a low risk. Furthermore, rare mutations may predispose to a phaeochromocytoma-only phenotype. Germline VHL mutations may be detected in 5–11% of all phaeochromocytoma cases and mutation analysis of VHL and other phaeochromocytoma susceptibility genes (SDHB, SDHD and RET) should be performed in all cases of familial, multiple or early onset phaeochromocytomas, and considered in other cases. The VHL gene product has a key role in regulating the stability of hypoxia-inducible factors (HIF-1 and HIF-2) such that inactivation of VHL leads to up-regulation of HIF-1 and HIF-2 protein expression and activation of hypoxic gene response pathways. Germline SDHB and SDHD mutations also lead to increased expression of HIF target genes, but it appears that phaeochromocytoma susceptibility in VHL disease cannot be attributed to HIF activation alone. Recently, it has been suggested that an HIF-independent failure of developmental apoptosis is a common feature of all inherited phaeochromocytoma susceptibility syndromes.

scholarly journals Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 442 ◽  
Author(s):  
Magdalena Koczkowska ◽  
Natalia Krawczynska ◽  
Maciej Stukan ◽  
Alina Kuzniacka ◽  
Izabela Brozek ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Susceptibility ◽  
Clinical Importance ◽  
Susceptibility Genes ◽  
Polish Population ◽  
Loss Of Function ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Personalized Risk Assessment

Constitutional loss-of-function pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2 are widely associated with an elevated risk of ovarian cancer (OC). As only ~15% of OC individuals carry the BRCA1/2 pathogenic variants, the identification of other potential OC-susceptibility genes is of great clinical importance. Here, we established the prevalence and spectrum of the germline pathogenic variants in the BRCA1/2 and 23 other cancer-related genes in a large Polish population of 333 unselected OC cases. Approximately 21% of cases (71/333) carried the BRCA1/2 pathogenic or likely pathogenic variants, with c.5266dup (p.Gln1756Profs*74) and c.3700_3704del (p.Val1234Glnfs*8) being the most prevalent. Additionally, ~6% of women (20/333) were carriers of the pathogenic or likely pathogenic variants in other cancer-related genes, with NBN and CHEK2 reported as the most frequently mutated, accounting for 1.8% (6/333) and 1.2% (4/333) of cases, respectively. We also found ten pathogenic or likely pathogenic variants in other genes: 1/333 in APC, 1/333 in ATM, 2/333 in BLM, 1/333 in BRIP1, 1/333 in MRE11A, 2/333 in PALB2, 1/333 in RAD50, and 1/333 in RAD51C, accounting for 50% of all detected variants in moderate- and low-penetrant genes. Our findings confirmed the presence of the additional OC-associated genes in the Polish population that may improve the personalized risk assessment of these individuals.

scholarly journals Germline Variation in Cancer-Susceptibility Genes in a Healthy, Ancestrally Diverse Cohort: Implications for Individual Genome Sequencing

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94554 ◽  
Author(s):  
Dale L. Bodian ◽  
Justine N. McCutcheon ◽  
Prachi Kothiyal ◽  
Kathi C. Huddleston ◽  
Ramaswamy K. Iyer ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Individual Genome ◽  
Cancer Susceptibility Genes ◽  
Germline Variation

scholarly journals Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

2015 ◽  
Vol 33 (26) ◽  
pp. 2901-2907 ◽  
Author(s):  
Honglin Song ◽  
Ed Dicks ◽  
Susan J. Ramus ◽  
Jonathan P. Tyrer ◽  
Maria P. Intermaggio ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Odds Ratio ◽  
Case Control Study ◽  
Cancer Susceptibility ◽  
Case Control ◽  
Control Analysis ◽  
Deleterious Mutations ◽  
Brca1 And Brca2 ◽  
Cancer Susceptibility Genes ◽  
Control Study

Purpose The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. Patients and Methods The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. Results In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). Conclusion These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

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