Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants

BWX Lim; N Li; S Mahale; S McInerny; M Zethoven; SM Rowley; J Huynh; T Wang; JEA Lee; M Friedman; L Devereux; RJ Scott; EK Sloan; PA James; IG Campbell

Journal article

Somatic inactivation of breast cancer predisposition genes in tumors associated with pathogenic germline variants

BWX Lim, N Li, S Mahale, S McInerny, M Zethoven, SM Rowley, J Huynh, T Wang, JEA Lee, M Friedman, L Devereux, RJ Scott, EK Sloan, PA James, IG Campbell

Journal of the National Cancer Institute | Published : 2023

DOI: 10.1093/jnci/djac196

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Abstract

Background: Breast cancers (BCs) that arise in individuals heterozygous for a germline pathogenic variant in a susceptibility gene, such as BRCA1 and BRCA2, PALB2, and RAD51C, have been shown to exhibit biallelic loss in the respective genes and be associated with triple-negative breast cancer (TNBC) and distinctive somatic mutational signatures. Tumor sequencing thus presents an orthogonal approach to assess the role of candidate genes in BC development. Methods: Exome sequencing was performed on paired normal-breast tumor DNA from 124 carriers of germline loss-of-function (LoF) or missense variant carriers in 15 known and candidate BC predisposition genes identified in the BEACCON case-con..

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Funding Acknowledgements

This work was supported by the National Breast Cancer Foundation (IF-15-004, IGC and PAJ), Cancer Australia/National Breast Cancer Foundation (PdCCRS_1107870, IGC and PAJ), Cancer Australia/National Breast Cancer Foundation (PdCCRS_1188547, IGC and PAJ), the Victorian Cancer Agency (Tumor Stream Grant, PAJ), the National Health and Medical Research Council of Australia (GNT1023698, PAJ; GNT1041975, IGC) and Cancer Australia (PdCCRS_1188547, IGC, PAJ, and EKS). EKS is supported by the National Health and Medical Research Council GNT114749, the <EM><STRONG> </STRONG></EM>National Breast Cancer Foundation IIRS-20-025 and Cancer Council Victoria Grants-in-Aid. NL is supported by Cancer Council Victoria.