Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Abstract

Background The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. Methods Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). Results No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. Conclusions We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk

“…EOC is a collection of five major histotypes, namely high-grade serous (HGSOC), endometrioid, clear cell, low-grade serous (LGS) and mucinous, which are thought to have distinct etiology 2 . HGSOC is the most prevalent accounting for 60-70% of EOC diagnoses 2,3 , and accounting for most EOCs diagnosed in BRCA1 and BRCA2 pathogenic variant (PV) carriers 4–11 . Furthermore, HGSOC accounts for the majority of EOC mortality 12,13 .…”

Global characterization of RNA editing in genetic regulation of multiple ovarian cancer subtypes

“…Ovarian cancer (OV) is a disease with clinical diversity and high histological and molecular heterogeneity, 1 , 2 , 3 and its histological phenotype is associated with distinct genetic patterns. 4 Each subtype has a different histopathology and a different response to treatment. 5 , 6 Based on histopathological examination, pathologists classify OV into high-grade serous OV (HGSC), low-grade serous OV (LGSC), clear cell OV (CCOC), endometrioid OV (EOC), and mucinous OV (MOC).…”