Journal
HUMAN MUTATION
Volume 42, Issue 3, Pages 290-299Publisher
WILEY-HINDAWI
DOI: 10.1002/humu.24158
Keywords
BRCAX; breast cancer predisposition; hereditary breast and ovarian cancer predisposition syndrome; hereditary cancer; whole‐ exome sequencing
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Funding
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior [PROSUP]
- Ministerio da Saude [PRONON 25000.056766/2015-64]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [2013/24633-2]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- Faculty of Medicine, McGill University
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The study utilized whole-exome sequencing to identify potential new breast and/or ovarian cancer predisposition genes in high-risk individuals. Pathogenic variants were found in known cancer genes, DNA repair genes, and other cancer-related genes. This is the largest Brazilian study on this topic and has provided new insights into genetic risk factors for hereditary breast and ovarian cancer.
The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2, and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, and RAD54L) and other cancer-related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high-risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer.
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