title: Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.
abstract: Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.
authors.affiliation: Laboratory of Genomics and Molecular Biology, A.C. Camargo Hospital, São Paulo, Brazil. dirce.carraro@cipe.accamargo.org.br
authors.forename: Dirce Maria
authors.initials: DM
authors.lastname: Carraro
authors.forename: Maria Aparecida Azevedo
authors.initials: MA
authors.lastname: Koike Folgueira
authors.forename: Bianca Cristina
authors.initials: BC
authors.lastname: Garcia Lisboa
authors.forename: Eloisa Helena
authors.initials: EH
authors.lastname: Ribeiro Olivieri
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Vitorino Krepischi
authors.forename: Alex Fiorini
authors.initials: AF
authors.lastname: de Carvalho
authors.forename: Louise Danielle
authors.initials: LD
authors.lastname: de Carvalho Mota
authors.forename: Renato David
authors.initials: RD
authors.lastname: Puga
authors.forename: Maria
authors.initials: M
authors.lastname: do Socorro Maciel
authors.forename: Rodrigo Augusto Depieri
authors.initials: RA
authors.lastname: Michelli
authors.forename: Eduardo Carneiro
authors.initials: EC
authors.lastname: de Lyra
authors.forename: Stana Helena Giorgi
authors.initials: SH
authors.lastname: Grosso
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
authors.forename: Maria Isabel Alves de Souza Waddington
authors.initials: MI
authors.lastname: Achatz
authors.forename: Helena
authors.initials: H
authors.lastname: Brentani
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Moreira-Filho
authors.forename: Maria Mitzi
authors.initials: MM
authors.lastname: Brentani
mesh_terms: D000328:Adult; D017668:Age of Onset; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001938:Brazil / Q000453:epidemiology; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006801:Humans; D040582:Inheritance Patterns; D010375:Pedigree; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C492913:BRCA1 protein, human; C551750:BRCA2 protein, human; C495901:TP53 protein, human; C508053:ERBB2 protein, human