title: Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil.
abstract: Approximately 8-15% epithelial ovarian cancer patients are BRCA1 or BRCA2 germline mutation carriers. Brazilian inhabitants may have peculiar genetic characteristics associated with ethnic diversity, and studies focusing on the entire BRCA1/BRCA2 gene sequencing in Brazilian ovarian cancer patients are still lacking. The aim of this study was to evaluate BRCA1/2 mutations, through entire gene sequencing, in a Brazilian population of women with epithelial ovarian cancer.
  
  
  
  In a cross sectional study performed in one reference centre for cancer treatment in São Paulo, Brazil, 100 patients diagnosed with epithelial ovarian cancer unselected for family history of breast and/or ovarian cancer were included. The complete coding sequence of BRCA1/2 genes was evaluated through Next-Generation or capillary sequencing. Large deletions were investigated through Multiplex Ligation-dependent Probe Amplification (MLPA).
  
  
  
  Nineteen pathogenic mutations (BRCA1: n = 17 and BRCA2: n = 2) featuring 14 different mutations, including two large deletions in BRCA1 (exon 1-2 deleted and exon 5-7 deleted) were identified. Three mutations were detected more than once (c.3331_3334delCAAG, c.5266dupC and c.4484G > T). Two novel frameshift mutations were identified, one in BRCA1 (c.961_962delTG) and one in BRCA2 (c.1963_1963delC). BRCA1/2 mutations were seen in 35.5% of the patients with first and/or second-degree relatives with breast and/or ovarian cancer. Nineteen variants of uncertain significance (VUS) were detected (BRCA1: n = 2 and BRCA2: n = 17), including five distinct missense variants (BRCA1: c.5348 T > C; BRCA2: c.2350A > G, c.3515C > T, c.7534C > T, and c.8351G > A).
  
  
  
  Among epithelial ovarian cancer patients unselected for family history of cancer, 19% were BRCA1/2 germline mutation carriers. Almost ¾ of the BRCA mutations, including two large deletions, were detected only once. Our work emphasizes the need of entire gene sequencing and MLPA screening in Brazil.
authors.affiliation: Departamento de Radiologia e Oncologia, Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Simone
authors.initials: S
authors.lastname: Maistro
authors.affiliation: Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Natalia
authors.initials: N
authors.lastname: Teixeira
authors.affiliation: Departamento de Radiologia e Oncologia, Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Giselly
authors.initials: G
authors.lastname: Encinas
authors.affiliation: Departamento de Radiologia e Oncologia, Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Maria Lucia Hirata
authors.initials: ML
authors.lastname: Katayama
authors.affiliation: Departamento de Doenças Infecciosas, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.|Departamento de Diagnóstico Molecular, DASA, São Paulo, Brazil.
authors.forename: Vivian Dionisio Tavares
authors.initials: VD
authors.lastname: Niewiadonski
authors.affiliation: Departamento de Radiologia e Oncologia, Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Larissa Garcia
authors.initials: LG
authors.lastname: Cabral
authors.affiliation: Departamento de Doenças Infecciosas, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Roberto Marques
authors.initials: RM
authors.lastname: Ribeiro
authors.affiliation: Departamento de Diagnóstico Molecular, DASA, São Paulo, Brazil.
authors.forename: Nelson
authors.initials: N
authors.lastname: Gaburo Junior
authors.affiliation: Divisão de Oncologia Clínica, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Ana Carolina Ribeiro Chaves
authors.initials: AC
authors.lastname: de Gouvêa
authors.affiliation: International Reasearch Center, A.C.Camargo Cancer Center, São Paulo, SP, Brazil.
authors.forename: Dirce Maria
authors.initials: DM
authors.lastname: Carraro
authors.affiliation: Departamento de Doenças Infecciosas, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Ester Cerdeira
authors.initials: EC
authors.lastname: Sabino
authors.affiliation: Divisão de Oncologia Clínica, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Maria Del Pilar Estevez
authors.initials: MD
authors.lastname: Diz
authors.affiliation: Departamento de Radiologia e Oncologia, Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.affiliation: Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Geertruida Hendrika
authors.initials: GH
authors.lastname: de Bock
authors.affiliation: Departamento de Radiologia e Oncologia, Centro de Investigação Translacional em Oncologia, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil. maria.folgueira@fm.usp.br.
authors.forename: Maria Aparecida Azevedo Koike
authors.identifier: 0000-0002-2334-0919
authors.initials: MA
authors.lastname: Folgueira
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001938:Brazil; D000077216:Carcinoma, Ovarian Epithelial; D003430:Cross-Sectional Studies; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: BRCA1; BRCA2; MLPA; Next generation sequencing; Ovarian cancer