Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer

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Torrezan, Giovana T. ^{[1, 2]} ; de Almeida, Fernanda G. dos Santos R. ^[1] ; Figueiredo, Marcia C. P. ^[1] ; de Figueiredo Barros, Bruna D. ^[1] ; de Paula, Claudia A. A. ^[1] ; Valieris, Renan ^[3] ; de Souza, Jorge E. S. ^{[4, 5, 6]} ; Ramalho, Rodrigo F. ^[1] ; da Silva, Felipe C. C. ^[1] ; Ferreira, Elisa N. ^{[7, 1]} ; de Nobrega, Amanda F. ^[8] ; Felicio, Paula S. ^[9] ; Achatz, Maria I. ^{[8, 10]} ; de Souza, Sandro J. ^{[11, 2, 6]} ; Palmero, Edenir I. ^{[9, 12]} ; Carraro, Dirce M. ^{[1, 2]}

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^[1] CIPE AC Camargo Canc Ctr, Int Res Ctr, Lab Genom & Mol Biol, Sao Paulo - Brazil

^[2] Natl Inst Sci & Technol Oncogen & Therapeut Innov, Sao Paulo - Brazil

^[3] CIPE AC Camargo Canc Ctr, Int Res Ctr, Lab Bioinformat & Computat Biol, Sao Paulo - Brazil

^[4] Inst Bioinformat & Biotecnol 2Bio, Natal, RN - Brazil

^[5] Univ Fed Rio Grande do Norte, Inst Metropole Digital, Natal, RN - Brazil

^[6] Univ Fed Rio Grande do Norte, Bioinformat Multidisciplinary Environm, Natal, RN - Brazil

^[7] Fleury Grp, Res & Dev, Sao Paulo - Brazil

^[8] AC Camargo Canc Ctr, Oncogenet Dept, Sao Paulo - Brazil

^[9] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo - Brazil

^[10] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 - USA

^[11] Univ Fed Rio Grande do Norte, Brain Inst, Natal, RN - Brazil

^[12] Dr Paulo Prata FACISB, Barretos Sch Hlth Sci, Barretos - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN GENETICS; v. 9, MAY 7 2018.
• Citações Web of Science: 4

Resumo

Pathogenic variants in known breast cancer (BC) predisposing genes explain only about 30% of Hereditary Breast Cancer (HBC) cases, whereas the underlying genetic factors for most families remain unknown. Here, we used whole-exome sequencing (WES) to identify genetic variants associated to HBC in 17 patients of Brazil with familial BC and negative for causal variants in major BC risk genes (BRCA1/2, TP53, and CHEK2 c. 1100delC). First, we searched for rare variants in 27 known HBC genes and identified two patients harboring truncating pathogenic variants in ATM and BARD1. For the remaining 15 negative patients, we found a substantial vast number of rare genetic variants. Thus, for selecting the most promising variants we used functional-based variant prioritization, followed by NGS validation, analysis in a control group, cosegregation analysis in one family and comparison with previous WES studies, shrinking our list to 23 novel BC candidate genes, which were evaluated in an independent cohort of 42 high-risk BC patients. Rare and possibly damaging variants were identified in 12 candidate genes in this cohort, including variants in DNA repair genes (ERCC1 and SXL4) and other cancer-related genes (NOTCH2, ERBB2, MST1R, and RAF1). Overall, this is the first WES study applied for identifying novel genes associated to HBC in Brazilian patients, in which we provide a set of putative BC predisposing genes. We also underpin the value of using WES for assessing the complex landscape of HBC susceptibility, especially in less characterized populations. (AU)

• Processo FAPESP: 13/23277-8 - Aspectos moleculares envolvidos no risco, desenvolvimento e progressão do carcinoma ductal de mama: busca de novos genes de susceptibilidade e investigação da progressão do carcinoma in situ e do papel da mutação em BRCA1 no tumor triplo negativo
• Beneficiário: Dirce Maria Carraro
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/24633-2 - Caracterização molecular de famílias de alto risco para câncer de mama hereditário, negativas para mutações nos genes BRCA1/BRCA2: à procura do BRCAx
• Beneficiário: Edenir Inêz Palmero
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/57887-9 - Instituto Nacional de Oncogenômica
• Beneficiário: Luiz Paulo Kowalski
• Modalidade de apoio: Auxílio à Pesquisa - Temático