One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene

Abstract

BackgroundGene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations.MethodsTo further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case–control analysis.ResultsHerein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively.ConclusionStudying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry

“…Case-control studies have estimated a 3-4-fold increased risk of breast cancer associated with pathogenic CHEK2 variants [ 21 , 23 , 24 , 25 , 26 ]. This has firmly consolidated CHEK2 as a bona fide breast cancer predisposition gene but information suitable for estimating age-specific cumulative risk (penetrance) has been lacking.…”

Comprehensive analysis and ACMG‐based classification of CHEK2 variants in hereditary cancer patients

“…Nonetheless, the median age at first cancer diagnosis in our study was not very different amongst carriers of truncating and missense LP/P variants, being 42 (range, 25–65) and 40 (range, 22–51) years, respectively. Bilateral BC has been mainly reported in c.1100delC carriers (M. Kriege et al, 2014), and truncating variants in this gene have been associated to other nonbreast second primary tumor diagnosis in a study using multigene panel testing (Fostira et al, 2020). In our cohort, four cases with two or multiple cancers were carriers of truncating variants, and only one was a carrier of an LP missense, confirming a higher aggressiveness of truncating variants over missense variants.…”

“…According to a study of 13,087 BC cases and 5,488 controls, the OR for 73 CHEK2 rare missense variants was 1.36 (95% confidence interval [CI], 0.99–1.87) and 1.51 (95% CI, 1.02–2.24) if considering only variants in functional domains (Decker et al, 2017; Han et al, 2013). Furthermore, in a recent study of 1355 BC cases, the OR for CHEK2 missense variants varied between 3.79 and 5.9 (95% CI, 1.86–7.12 and 2.38–14.78) when compared with ExAC and FLOSSIES controls, respectively (Fostira et al, 2020).…”

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects

“…Carriers of p.(Ile157Thr) were excluded. These carriers have been previously identified through a number of studies, involving genetic testing among Greek patients with breast cancer [ 11 , 14 , 15 , 16 ]. All patients fulfilled the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing and were referred to Molecular Diagnostics Laboratory (MDL) of NCSR “Demokritos”, between years 2007–2020, from several collaborating oncology clinics.…”