Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer
Copyright policy )Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 ( P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10(-7)).Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.
- University College London United Kingdom
- Roswell Park Cancer Institute United States
- Imperial College London United Kingdom
- University of California, San Francisco United States
- University of Cambridge United Kingdom
Prevention (rcdc), DNA-Binding Proteins (mesh), Women's Health (rcdc), Ovarian Cancer Association Consortium, Cell Cycle Proteins, Carcinoma, Ovarian Epithelial, RNA Helicases (mesh), Cell Cycle Proteins (mesh), Clinical Research (rcdc), Missense (mesh), Ubiquitin-Protein Ligases (mesh), Ovarian Epithelial, Neoplasms, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, 32 Biomedical and Clinical Sciences (for-2020), genes, Genetic Predisposition to Disease (mesh), White People (mesh), Cancer, Cancer (rcdc), Ovarian Neoplasms, Humans (mesh), 3 Good Health and Well Being (sdg), Fanconi Anemia Complementation Group N Protein (mesh), Glandular and Epithelial (mesh), Fanconi Anemia Complementation Group Proteins (mesh), High-Throughput Nucleotide Sequencing (mesh), Glandular and Epithelial, High-Throughput Nucleotide Sequencing, Nuclear Proteins, 1112 Oncology and Carcinogenesis (for), Middle Aged, Fanconi Anemia Complementation Group Proteins, Ovarian Cancer, DNA-Binding Proteins, ovarian cancer, Germ-Line Mutation (mesh), Risk (mesh), Genetic Testing (rcdc), Female, Fanconi Anemia Complementation Group N Protein, germ-line mutation, United States (mesh), RNA Helicases, Tumor Suppressor Proteins (mesh), Adult, Risk, palb2 gene, Predictive Value of Tests (mesh), Ubiquitin-Protein Ligases, Oncology and Carcinogenesis, Mutation, Missense, 610, Ovarian Neoplasms (mesh), Ovarian Epithelial (mesh), White People, Rare Diseases (rcdc), Rare Diseases, Ovarian Cancer (rcdc), bard1 gene, Nuclear Proteins (mesh), Clinical Research, Predictive Value of Tests, 616, Middle Aged (mesh), Genetics, 3211 Oncology and carcinogenesis (for-2020), Humans, Genetic Predisposition to Disease, Genetic Testing, Oncology & Carcinogenesis, Germ-Line Mutation, Aged, Biomedical and Clinical Sciences, Genetics (rcdc), Aged (mesh), Prevention, Tumor Suppressor Proteins, Carcinoma, 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), AOCS Study Group, United States, Good Health and Well Being, 3211 Oncology and Carcinogenesis (for-2020), Oncology & Carcinogenesis (science-metrix), Female (mesh), Mutation, Adult (mesh), Women's Health, Missense
Prevention (rcdc), DNA-Binding Proteins (mesh), Women's Health (rcdc), Ovarian Cancer Association Consortium, Cell Cycle Proteins, Carcinoma, Ovarian Epithelial, RNA Helicases (mesh), Cell Cycle Proteins (mesh), Clinical Research (rcdc), Missense (mesh), Ubiquitin-Protein Ligases (mesh), Ovarian Epithelial, Neoplasms, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, 32 Biomedical and Clinical Sciences (for-2020), genes, Genetic Predisposition to Disease (mesh), White People (mesh), Cancer, Cancer (rcdc), Ovarian Neoplasms, Humans (mesh), 3 Good Health and Well Being (sdg), Fanconi Anemia Complementation Group N Protein (mesh), Glandular and Epithelial (mesh), Fanconi Anemia Complementation Group Proteins (mesh), High-Throughput Nucleotide Sequencing (mesh), Glandular and Epithelial, High-Throughput Nucleotide Sequencing, Nuclear Proteins, 1112 Oncology and Carcinogenesis (for), Middle Aged, Fanconi Anemia Complementation Group Proteins, Ovarian Cancer, DNA-Binding Proteins, ovarian cancer, Germ-Line Mutation (mesh), Risk (mesh), Genetic Testing (rcdc), Female, Fanconi Anemia Complementation Group N Protein, germ-line mutation, United States (mesh), RNA Helicases, Tumor Suppressor Proteins (mesh), Adult, Risk, palb2 gene, Predictive Value of Tests (mesh), Ubiquitin-Protein Ligases, Oncology and Carcinogenesis, Mutation, Missense, 610, Ovarian Neoplasms (mesh), Ovarian Epithelial (mesh), White People, Rare Diseases (rcdc), Rare Diseases, Ovarian Cancer (rcdc), bard1 gene, Nuclear Proteins (mesh), Clinical Research, Predictive Value of Tests, 616, Middle Aged (mesh), Genetics, 3211 Oncology and carcinogenesis (for-2020), Humans, Genetic Predisposition to Disease, Genetic Testing, Oncology & Carcinogenesis, Germ-Line Mutation, Aged, Biomedical and Clinical Sciences, Genetics (rcdc), Aged (mesh), Prevention, Tumor Suppressor Proteins, Carcinoma, 2.1 Biological and endogenous factors (hrcs-rac), Cancer (hrcs-hc), AOCS Study Group, United States, Good Health and Well Being, 3211 Oncology and Carcinogenesis (for-2020), Oncology & Carcinogenesis (science-metrix), Female (mesh), Mutation, Adult (mesh), Women's Health, Missense
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