Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes — Providing evidence of cancer predisposition genes

Germline mutations occurring in the highly penetrant genes BRCA1 and BRCA2 are responsible for only certain cases of familial breast cancer (BC) and ovarian cancer (OC). Thus, the use of NGS multi-gene panel (MGP) testing has recently become very popular. To estimate a reliable BC and OC risk associ...

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Bibliographic Details
Published in:Gynecologic oncology 2019-05, Vol.153 (2), p.452-462
Main Authors: Suszynska, Malwina, Klonowska, Katarzyna, Jasinska, Anna J., Kozlowski, Piotr
Format: Article
Language:English
Subjects:
Breast cancer
Cancer predisposition genes
Meta-analysis
Multi-gene panel testing
Ovarian cancer
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Summary:Germline mutations occurring in the highly penetrant genes BRCA1 and BRCA2 are responsible for only certain cases of familial breast cancer (BC) and ovarian cancer (OC). Thus, the use of NGS multi-gene panel (MGP) testing has recently become very popular. To estimate a reliable BC and OC risk associated with pathogenic variants in the selected candidate BC/OC predisposition genes, a comprehensive meta-analysis of 48 MGP-based studies analyzing BC/OC patients was conducted. The role of 37 genes was evaluated, comparing, in total, the mutation frequency in ~120,000 BC/OC cases and ~120,000 controls, which guaranteed strong statistical support with high confidence for most analyzed genes. We characterized the strategies of MGP analyses and the types and localizations of the identified mutations and showed that 13 and 11 of the analyzed genes were significantly associated with an increased BC and OC risk, respectively. The risk attributed to some of these genes (e.g., CDKN2A and PALB2 for BC) was similar to that observed for BRCA2. The analysis also showed a substantial difference in the profile of genes contributing to either BC or OC risk, including genes specifically associated with a high risk of OC but not BC (e.g., RAD51C, and RAD51D). Our study provides strong statistical proof, defines the risk for many genes often considered candidates for BC/OC predisposition and excludes the role of other genes frequently analyzed in the MGPs. In the context of clinical diagnostics, the results support the knowledge-based interpretation of identified mutations. •37 genes were evaluated in the context of breast and ovarian cancer predisposition.•Several non-BRCA1/2 genes were attributed to high breast/ovarian cancer risk.•Mutations in CDKN2A contribute to high risk of breast cancer, comparable to BRCA2.•Profiles of genes contributing to breast and ovarian cancer differ substantially.•RAD51C, RAD51D, and BRIP1 are proved to be high-risk ovarian, but not breast cancer genes.
ISSN:0090-8258
1095-6859
DOI:10.1016/j.ygyno.2019.01.027