Exome Sequencing in BRCA1- and BRCA2-Negative Greek Families Identifies MDM1 and NBEAL1 as Candidate Risk Genes for Hereditary Breast Cancer
Autor: | Stavros Glentis, Alexandros C. Dimopoulos, Konstantinos Rouskas, George Ntritsos, Evangelos Evangelou, Steven A. Narod, Anne-Marie Mes-Masson, William D. Foulkes, Barbara Rivera, Patricia N. Tonin, Jiannis Ragoussis, Antigone S. Dimas |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
1801 Law lcsh:QH426-470 NBEAL1 03 medical and health sciences 0302 clinical medicine Breast cancer MDM1 Genetics Medicine Missense mutation Allele Gene Exome Exome sequencing Genetics (clinical) Original Research 0604 Genetics business.industry 1103 Clinical Sciences hereditary breast cancer medicine.disease Biobank lcsh:Genetics 030104 developmental biology 030220 oncology & carcinogenesis Molecular Medicine business Ovarian cancer candidate risk variants exome sequencing Greek population |
Zdroj: | Frontiers in Genetics, Vol 10 (2019) Frontiers in Genetics |
ISSN: | 1664-8021 |
Popis: | Approximately 10% of breast cancer (BC) cases are hereditary BC (HBC), with HBC most commonly encountered in the context of hereditary breast and ovarian cancer (HBOC) syndrome. Although thousands of loss-of-function (LoF) alleles in over 20 genes have been associated with HBC susceptibility, the genetic etiology of approximately 50% of cases remains unexplained, even when polygenic risk models are considered. 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 variants. Initial screening revealed pathogenic variants 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 (CHUM-BC) and controls (CARTaGENE), 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. |
Databáze: | OpenAIRE |
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