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J Med Genet. 2020 Jan;57(1):53-61. doi: 10.1136/jmedgenet-2019-106189. Epub 2019 Jul 12.

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

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InRaSTES, Molecular Diagnostics Laboratory, National Centre for Scientific Research NCSR Demokritos, Athens, Greece
InRaSTES, Molecular Diagnostics Laboratory, National Centre for Scientific Research NCSR Demokritos, Athens, Greece.
Second Department of Surgery, Oncology Unit, National and Kapodistrian University of Athens, Aretaiio Hospital, Athens, Greece.
Breast Cancer Unit, Mitera Maternity Hospital, Athens, Greece.
Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece.
Department of Medical Oncology, Bioclinic of Thessaloniki, Thessaloniki, Greece.
Third Department of Medical Oncology, Hygeia Hospital, Athens, Greece.
Second Department of Medical Oncology, 'Agios Savvas' Anticancer Hospital, Athens, Greece.
Third Medical Oncology Department, Metropolitan Hospital Athens, Athens, Greece.
Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.



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.


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.


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.


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.


BRCA1; BRCA2; NGS; PALB2; gene panel; genetic testing; hereditary breast cancer

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