Abstract A24: Germline deletion at 3p12.3 in patients with hereditary breast and colorectal carcinoma

Lynch syndrome (LS) is a common hereditary syndrome that predisposes to colorectal cancer (CRC). Breast carcinoma has been described as the most common extracolonic tumors among Brazilian patients with LS. In this study, it was investigated members of two families with breast and colorectal carcinomas. The patient 1 (SM56) had breast carcinoma at age of 50. The patient 2 (SM37) had CRC at 52 years old, presented bilateral breast carcinoma (73 and 76 years old) and reported a reproductive history of four abortions. The daughter of patient 2 (SM37-2) had breast cancer at 55 years old. In both families, their relatives had history of CCR, breast cancer, endometrium carcinoma and prostate cancer. The patients were screened for BRCA1, BRCA2, CHEK2, TP53, MLH1 and MSH2 mutations by Sanger9s sequencing method. All of them were negative for pathogenic mutations. Copy number alterations (CNAs) were investigated by array comparative genomic hybridization (aCGH) using a platform of 4×180K (Agilent). Genomic data were extracted with Feature Extraction software and analyzed using Genomic Workbench Standard 5.0.14, statistical algorithm ADM2 and sensitivity threshold of 6.7. The data were compared with the Database of Genomic Variations (DGV) and with a reference dataset obtained from 82 healthy Brazilian individuals. Alterations identified in more than 5% of the reference dataset were excluded from both patients. All three cases presented the same microdeletion on 3p12.3 (79.951 pb) where is mapped the ROBO1 gene. Quantitative Real Time PCR (qPCR) using primers flanking the region confirmed the ROBO1 microdeletion. CNAs mapped on ROBO1 or involving the same region microdeleted are not previously described in DGV or in our dataset from Brazilian health individuals. ROBO1 is involved in the regulation of cell migration, cell death and angiogenesis. The 5′ region contains a CpG island and was found to be hypermethylated and showing allelic losses in 3p12 in sporadic primary invasive breast carcinomas (Dallol et al, Oncogene 21:3020, 2002). At first time, ROBO1 was associated with Hereditary Breast and Colorectal Carcinomas in two different families suggesting to be a highly penetrant mutation associated with elevated risk to develop cancer among the relatives. Further studies in tumor samples from these patients could demonstrate the Knudson9s two hit hypothesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A24.