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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.01005

Exome Sequencing in BRCA1/2 Negative Greek Families Identifies MDM1 and NBEAL1 as Candidate Risk Genes for Hereditary Breast Cancer

 Stavros Glentis1, 2,  Alexandros C. Dimopoulos1,  Konstantinos Rouskas1,  George Ntritsos3, Evangelos Evangelou3, 4,  Steven Narod5, 6, Anne-Marie Mes-Masson7, William D. Foulkes8, 9, 10, Barbara Rivera8, 9,  Patricia N. Tonin11,  Jiannis (. Ragoussis12* and  Antigone S. Dimas1*
  • 1Alexander Fleming Biomedical Sciences Research Center, Greece
  • 2Division of Pediatric Hematology/Oncology, Agia Sophia Children's Hospital, Greece
  • 3Department of Hygiene and Epidemiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece
  • 4Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, United Kingdom
  • 5Dalla Lana School of Public Health, University of Toronto, Canada
  • 6Women's College Hospital, Canada
  • 7Centre de recherche du Centre hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Canada
  • 8Departments of Oncology, Faculty of Medicine, McGill University, Canada
  • 9Lady Davis Institute (LDI), Canada
  • 10Department of Medical Genetics, The Research Institute of the McGill University Health Centre, Canada
  • 11Departments of Medicine & Human Genetics, McGill University; Cancer Research Program, The Research Institute of the McGill University Health Centre, Canada
  • 12McGill University and Génome Québec Innovation Centre, Canada

Approximately 10% of breast cancer (BC) cases are hereditary (HBC), with HBC most commonly encountered in the context of hereditary breast and ovarian cancer syndrome (HBOC). Although thousands of loss-of-function (LoF) alleles in over 20 genes have been associated with HBC susceptibility, the genetic etiology of approximately 70% of cases remains unexplained. We focused on one of the least-studied European populations and applied whole exome sequencing (WES) to 52 individuals from 17 Greek HBOC families, in which at least one patient was negative for known HBC risk mutations. Initial screening revealed mutations in known cancer genes, including BARD1:p.Trp91* detected in a cancer-free individual, and MEN1:p.Glu260Lys detected in a BC patient. Gene and variant-based approaches were applied to exome data to identify candidate risk variants outside of known risk genes. Findings were verified in a collection of Canadian HBOC patients of European ancestry (FBRCAX), in an independent group of Canadian BC patients and controls, as well as in individuals from The Cancer Genome Atlas (TCGA) and the UK Biobank (UKB). Rare LoF variants were uncovered in MDM1 and NBEAL1 in Greek and Canadian HBOC patients. We also report prioritized missense variants SETBP1:c.4129G>C and C7orf34:c.248C>T. These variants comprise promising candidates whose role in cancer pathogenicity needs to be explored further.

Keywords: hereditary breast cancer, exome sequencing, Greek population, candidate risk variants, MDM1, Nbeal1

Received: 01 Mar 2019; Accepted: 20 Sep 2019.

Copyright: © 2019 Glentis, Dimopoulos, Rouskas, Ntritsos, Evangelou, Narod, Mes-Masson, Foulkes, Rivera, Tonin, Ragoussis and Dimas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Jiannis (. Ragoussis, McGill University and Génome Québec Innovation Centre, Montreal, H3A 0G1, Quebec, Canada,
Dr. Antigone S. Dimas, Alexander Fleming Biomedical Sciences Research Center, Athens, Greece,