IDENTIFICATION OF SIX NOVEL COMMON VARIANT SUSCEPTIBILITY LOCI FOR INVASIVE EPITHELIAL OVARIAN CANCER

BRCA1 and BRCA2 are well known genes that run in families with breast and ovarian cancers. We conducted a GWAS study with patients carrying BRCA1 and/or BRCA2 mutations to identify risk associated with these genetic backgrounds. The study involved ~15k BRCA1 carriers and ~8k BRCA2 carriers amongst the cases and controls. We identified variants associated with WNT4, SYNPO2, ABO, ATAD5, as well as GPX6 which was specifically associated with the serous subtype.

Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

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RELEVANCE TO OC

Although this study used an example from prostate cancer, we are use this strategy to investigate all known genetic loci that have been identified as predisposing to ovarian cancer. This includes 4 different histological subtypes: High-grade Serous, Mucinous, Endometrial, and Clear Cell. Ex from 29610480

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