Abstract 1665: High resolution genome profile in familial colorectal cases without mutations on mismatch repair genes

Colorectal cancer (CRC) represents the fourth leading cause of cancer mortality. Approximately 30% of all CRC cases have a hereditary component, but only 5% are associated with inherited mutations in known genes. The most common hereditary syndrome of CRC is the Lynch syndrome (LS) and is caused by mutations in mismatch repair genes, mainly MLH1 and MSH2. In ∼50% of families classified with the Amsterdam criteria not show germline mutations in mismatch repair genes, suggesting that other genetic factors are associated with predisposition to CRC. In this study, it was evaluated germline copy number alterations (CNAs) in 57 LS patients without pathogenic mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS1 and PMS2), as well as in CHEK2 and TP53, by array comparative genomic hybridization (aCGH) using a platform of 4x180K (Agilent). Genomic data were extracted with Feature Extraction software and analyzed using Nexus 6.0 software, statistical algorithm FASST2 Segmentation and sensitivity threshold of 5.0E-6. The aCGH data showed a total of 361 CNAs (in average, 6.3±3.8 CNA/individual) including 144 gains and 217 genomic losses. After the comparison with a reference dataset obtained from 100 healthy Brazilian individuals (Krepischi et al, 2011; personal communication) and exclusion of the CNAs detected in more than 5% of this reference dataset, it was identified ∼100 rare CNAs. Most of them were detected in only one case, however, six CNAs were common at least in five cases: 1p11.2, 1p36.32, 7p22.3, 8q24.3, 9p11.2 and 18q11.1. The ROCK1 gene, mapped on 18q11.1, was found as involved in nine cases (three losses and six gains). This gene was associated with carcinogenesis and progression of human tumors, including colon cancer (Nakashima et al, Int J Oncol. 36:585, 2010). Amplification on 7p22.3 (5 cases), where is mapped the homeobox gene UNCX, a transcription factor involved in somitogenesis and neurogenesis. Mutations in rare constitutional CNAs may affect genes or major pathways associated with cancer, offering an explanation for families with high cancer risk. In CRC, the large scale analysis of germline CNAs in patients and their relatives can allow the identification of new genes involved in tumor predisposition. Financial support: FAPESP and CNPq Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1665. doi:1538-7445.AM2012-1665