Somatic Inactivation of Breast Cancer Predisposition Genes in Tumours Associated with Pathogenic Germline Variants

J Natl Cancer Inst. 2022 Oct 31;djac196. doi: 10.1093/jnci/djac196. Online ahead of print.


Background: Breast cancers (BC) that arise in individuals heterozygous for a germline pathogenic variant in a susceptibility gene, such as BRCA1/2, PALB2 and RAD51C, have been shown to exhibit bi-allelic loss in the respective genes, and be associated with triple-negative (TN) BC and distinctive somatic mutational signatures. Tumour 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 tumour DNA from 124 carriers of germline loss-of-function (LoF) or missense (MS) mutations carriers in 15 known and candidate BC predisposition genes identified in the BEACCON case-control study. Bi-allelic inactivation and association with tumour genome features including mutational signatures and homologous recombination deficiency (HRD) score were investigated.

Results: BARD1-carrying TN BC (4/5) displayed bi-allelic loss and associated high HRD scores and mutational signature 3, as did a RAD51D-carrying TN BC and ovarian cancer. Bi-allelic loss was less frequent in BRIP1 BCs (4/13) and had low HRD scores. In contrast to other established BC genes, BCs from carriers of CHEK2 LoF (6/17) or MS (2/20) carriers had low rates of bi-allelic loss. Exploratory analysis of BC from carriers of LoF mutations in candidate genes such as BLM, FANCM, PARP2 and RAD50 found little evidence of bi-allelic inactivation.

Conclusions: BARD1 and RAD51D behave as classic BRCA-like genes with bi-allelic inactivation but this was not observed for any of the candidate genes. However, as demonstrated for CHEK2, the absence of bi-allelic inactivation does not provide definitive evidence against the gene's involvement in BC predisposition.