Τίτλος:
One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2020 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Συγγραφείς:
Fostira, F.
Kostantopoulou, I.
Apostolou, P.
Papamentzelopoulou, M.S.
Papadimitriou, C.
Faliakou, E.
Christodoulou, C.
Boukovinas, I.
Razis, E.
Tryfonopoulos, D.
Barbounis, V.
Vagena, A.
Vlachos, I.S.
Kalfakakou, D.
Fountzilas, G.
Yannoukakos, D.
Περιοδικό:
JOURNAL OF MEDICAL GENETICS
Εκδότης:
BMJ Publishing Group
Λέξεις-κλειδιά:
ATM protein; BRCA1 protein; BRCA2 protein; checkpoint kinase 2; partner and localizer of BRCA2; protein; protein p53; RAD51C protein; unclassified drug; DNA ligase, adult; allele; Article; breast cancer; cancer patient; cancer risk; cancer susceptibility; case control study; cohort analysis; controlled study; family history; female; genetic variability; Greece; human; loss of function mutation; major clinical study; missense mutation; pathogenicity; priority journal; risk assessment; tumor gene; breast tumor; DNA repair; genetic predisposition; genetics; loss of function mutation; middle aged; missense mutation; single nucleotide polymorphism; young adult, Adult; Breast Neoplasms; Case-Control Studies; Cohort Studies; DNA Repair; DNA Repair Enzymes; Female; Genetic Predisposition to Disease; Greece; Humans; Loss of Function Mutation; Middle Aged; Mutation, Missense; Polymorphism, Single Nucleotide; Risk Assessment; Young Adult
DOI:
10.1136/jmedgenet-2019-106189
