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

Abstract

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.

Clinicopathologic and genetic analysis of invasive breast carcinomas in women with germline CHEK2 variants

“…Most but not all CHEK2 -associated BCs showed biallelic CHEK2 alteration via LOH, which is in keeping with incomplete rates of LOH seen in prior studies [ 18 , 19 , 29 , 30 ]. A recent study found high rates of CHEK2 LOH in BCs arising in c.1100delC carriers compared to lower rates in other CHEK2 variants [ 19 ].…”

“…Taken together, our findings and those of others raise consideration that at least some CHEK2 variants may function via haploinsufficiency in driving BC, whereas others (such as c.1100delC) may require bilallelic inactivation. This is in contrast to most other germline BC risk genes, such as BRCA1 / 2, PALB2 , and ATM , PVs of which often show biallelic loss of function in BC [ 29 ]. Alternatively, CHK2 inactivation may also be due to non-genetic mechanisms in cases without LOH, and future studies may help address this issue.…”

CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience

“…We identified germline CHEK2 variants in 2% of our pediatric/young adult cohort, with no clear discernment toward a particular tumor type. Biallelic alteration of CHEK2 was not identified within this cohort, although biallelic germline or somatic alterations are uncommonly found in adults with CHEK2 -associated cancers [ 54 , 55 , 56 ]. Nonetheless, the variants identified in our study may represent secondary findings amid individuals in a pediatric cancer cohort.…”

A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers

“…Failure to properly repair the DNA damage leads to tumor cell death. Germline mutations in BRCA1 and BRCA2 are found in roughly 17% of women with epithelial ovarian cancer (EOCs) and 10%–20% of triple negative breast cancers (TNBCs), while somatic mutations are found in approximately 7% of ovarian tumors and 3%–5% of TNBCs 1–6 . Roughly 40%–50% of EOCs have HR deficiencies, while HRD is a frequent occurrence in TNBCs 5–9 .…”

“…Germline mutations in BRCA1 and BRCA2 are found in roughly 17% of women with epithelial ovarian cancer (EOCs) and 10%–20% of triple negative breast cancers (TNBCs), while somatic mutations are found in approximately 7% of ovarian tumors and 3%–5% of TNBCs. 1 , 2 , 3 , 4 , 5 , 6 Roughly 40%–50% of EOCs have HR deficiencies, while HRD is a frequent occurrence in TNBCs. 5 , 6 , 7 , 8 , 9 PARP inhibition of tumors with HRD has led to a dramatic change in the management of EOCs with statistically and clinically significant improvements in outcomes.…”