RT Journal Article
SR Electronic
T1 One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 53
OP 61
DO 10.1136/jmedgenet-2019-106189
VO 57
IS 1
A1 Florentia Fostira
A1 Irene Kostantopoulou
A1 Paraskevi Apostolou
A1 Myrto S Papamentzelopoulou
A1 Christos Papadimitriou
A1 Eleni Faliakou
A1 Christos Christodoulou
A1 Ioannis Boukovinas
A1 Evangelia Razis
A1 Dimitrios Tryfonopoulos
A1 Vasileios Barbounis
A1 Andromache Vagena
A1 Ioannis S Vlachos
A1 Despoina Kalfakakou
A1 George Fountzilas
A1 Drakoulis Yannoukakos
YR 2020
UL http://jmg.bmj.com/content/57/1/53.abstract
AB Background Gene 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.Methods To 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.Results Herein, 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.Conclusion Studying 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.