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The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.



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Cicek, Mine S 
Harrington, Patricia 
Ramus, Susan J 


The aim of this study was to estimate the contribution of deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the population. The coding sequence and splice site boundaries of all six genes were amplified in germline DNA from 2240 invasive EOC cases and 1535 controls. Barcoded fragment libraries were sequenced using the Illumina GAII or HiSeq and sequence data for each subject de-multiplexed prior to interpretation. GATK and Annovar were used for variant detection and annotation. After quality control 2222 cases (99.2%) and 1528 controls (99.5%) were included in the final analysis. We identified 193 EOC cases (8.7%) carrying a deleterious mutation in at least one gene compared with 10 controls (0.65%). Mutations were most frequent in BRCA1 and BRCA2, with 84 EOC cases (3.8%) carrying a BRCA1 mutation and 94 EOC cases (4.2%) carrying a BRCA2 mutation. The combined BRCA1 and BRCA2 mutation prevalence was 11% in high-grade serous disease. Seventeen EOC cases carried a mutation in a mismatch repair gene, including 10 MSH6 mutation carriers (0.45%) and 4 MSH2 mutation carriers (0.18%). At least 1 in 10 women with high-grade serous EOC has a BRCA1 or BRCA2 mutation. The development of next generation sequencing technologies enables rapid mutation screening for multiple susceptibility genes at once, suggesting that routine clinical testing of all incidence cases should be considered.



Adult, Age of Onset, Aged, BRCA1 Protein, BRCA2 Protein, DNA Mismatch Repair, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Middle Aged, Mutation, Missense, Ovarian Neoplasms, Risk Factors, Young Adult

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Hum Mol Genet

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Oxford University Press (OUP)


DSpace@Cambridge license
National Cancer Institute (R01CA178535)
This work was funded by Cancer Research UK (C490/A10119 and C490/A10124) (SEARCH) and National Institute of Health (R01 CA122443), P50-CA136393, Fred C. and Katherine B. Andersen Foundation (Mayo Clinic study), Cancer Research UK grant C1005/A12677 and National Institute of Health grant R01 CA178535 (USC), and the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge.