Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. Howev...

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Published in:	BMC medical genomics Vol. 13; no. 1; pp. 21 - 24
Main Authors:	da Costa E Silva Carvalho, Simone, Cury, Nathalia Moreno, Brotto, Danielle Barbosa, de Araujo, Luiza Ferreira, Rosa, Reginaldo Cruz Alves, Texeira, Lorena Alves, Plaça, Jessica Rodrigues, Marques, Adriana Aparecida, Peronni, Kamila Chagas, Ruy, Patricia de Cássia, Molfetta, Greice Andreotti, Moriguti, Julio Cesar, Carraro, Dirce Maria, Palmero, Edenir Inêz, Ashton-Prolla, Patricia, de Faria Ferraz, Victor Evangelista, Silva, Jr, Wilson Araujo
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 10-02-2020 BioMed Central BMC
Subjects:	Adult Aged Algorithms Association analysis Autosomal dominant inheritance Brazil BRCA genes BRCA1 BRCA1 protein BRCA2 protein Breast Breast cancer Cancer genetics Computer Simulation Deoxyribonucleic acid DNA DNA repair DNA repair genes E-cadherin Female Gene frequency Genes Genetic disorders Genetic research Genetic variation Genetics Genomics Germ-Line Mutation HBOC Health aspects Hereditary Breast and Ovarian Cancer Syndrome - genetics Heredity Humans INDEL Mutation Middle Aged MLH1 protein Molecular diagnosis MRE11 protein MSH2 protein MSH6 protein Multi-gene panel screening Neoplasm Proteins - genetics Next-generation sequencing Novels Older people Ovarian cancer p53 Protein Phenotypes Population genetics PTEN protein Risk assessment Software Tumor proteins Brazil DNA repair genes Molecular diagnosis Next-generation sequencing BRCA1 BRCA2 Multi-gene panel screening HBOC
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Summary:	The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20-30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN, and TP53 genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients. We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53 and UIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in BRCA1/BRCA2 genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms. We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in BRCA1, BRCA2 and TP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in ATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2, and PMS2 genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in BRCA1/BRCA2 genes. This study embodies the third report of a multi-gene analysis in the Brazilian population, and addresses the first report of many germline variants associated with HBOC in Brazil. Although further functional analyses are necessary to better characterize the contribution of those variants to the phenotype, these findings would improve the risk estimation and clinical follow-up of patients with HBOC clinical suspicion.
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ISSN:	1755-8794 1755-8794
DOI:	10.1186/s12920-019-0652-y