ROBO1 deletion as a novel germline alteration in breast and colorectal cancer patients

Autor(es)

Villacis, Rolando A. R. ^[1] ; Abreu, Francine B. ^[1] ; Miranda, Priscila M. ^[1] ; Domingues, Maria A. C. ^[2] ; Carraro, Dirce M. ^[1] ; Santos, Erika M. M. ^[3] ; Andrade, Victor P. ^[4] ; Rossi, Benedito M. ^[3] ; Achatz, Maria I. ^[5] ; Rogatto, Silvia R. ^{[1, 6]}

Afiliação do(s) autor(es)

^[1] AC Camargo Canc Ctr, Int Res Ctr CIPE, Rua Tagua 440, BR-01508010 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo State UNESP, Fac Med, Dept Pathol, Botucatu, SP - Brazil

^[3] Sirio Libanes Hosp, Ctr Oncol, Sao Paulo, SP - Brazil

^[4] AC Camargo Canc Ctr, Dept Pathol, Rua Tagua 440, BR-01508010 Sao Paulo, SP - Brazil

^[5] AC Camargo Canc Ctr, Dept Oncogenet, Rua Tagua 440, BR-01508010 Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo State UNESP, Fac Med, Dept Urol, BR-18618970 Botucatu, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: TUMOR BIOLOGY; v. 37, n. 3, p. 3145-3153, MAR 2016.
• Citações Web of Science: 6

Resumo

Despite one third of breast (BC) and colorectal cancer (CRC) cases having a hereditary component, only a small proportion can be explained by germline mutations. The aim of this study was to identify potential genomic alterations related to cancer predisposition. Copy number variations (CNVs) were interrogated in 113 unrelated cases fulfilling the criteria for hereditary BC/CRC and presenting non-pathogenic mutations in BRCA1, BRCA2, MLH1, MSH2, TP53, and CHEK2 genes. An identical germline deep intronic deletion of ROBO1 was identified in three index patients using two microarray platforms (Agilent 4x180K and Affymetrix CytoScan HD). The ROBO1 deletion was confirmed by quantitative PCR (qPCR). Six relatives were also evaluated by CytoScan HD Array. Genomic analysis confirmed a co-segregation of the ROBO1 deletion with the occurrence of cancer in two families. Direct sequencing revealed no pathogenic ROBO1 point mutations. Transcriptomic analysis (HTA 2.0, Affymetrix) in two breast carcinomas from a single patient revealed ROBO1 down-expression with no splicing events near the intronic deletion. Deeper in silico analysis showed several enhancer regions and a histone methylation mark in the deleted region. The ROBO1 deletion in a putative transcriptional regulatory region, its down-expression in tumor samples, and the results of the co-segregation analysis revealing the presence of the alteration in affected individuals suggest a pathogenic effect of the ROBO1 in cancer predisposition. (AU)

• Processo FAPESP: 11/07742-7 - Alterações genômicas em pacientes e seus familiares com a síndrome do câncer colorretal hereditário
• Beneficiário: Rolando André Rios Villacis
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/15901-5 - Variação no número de cópias genômicas na avaliação de genes principais de predisposição em pacientes com síndrome de Mama-Cólon triados para mutações nos genes BRCA1, BRCA2, TP53 e CHEK2
• Beneficiário: Francine Blumental de Abreu
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 08/57887-9 - Instituto Nacional de Oncogenômica
• Beneficiário: Luiz Paulo Kowalski
• Modalidade de apoio: Auxílio à Pesquisa - Temático