Abstract 2754: Novel germline copy number variations in patients with hereditary colorectal carcinoma with no mutation in the mismatch repair genes
Authors: Villacis Rolando André Rios , Santos Érika Maria Monteiro , Carraro Dirce Maria , Rossi Benedito Mauro , Rogatto Silvia Regina 
Published: August 2015

Abstract
Colorectal cancer (CRC) is estimated to be the third most frequent of cancer worldwide in both sexes combined (http://globocan.iarc.fr). Lynch Syndrome (LS), the main hereditary disease related to CRC, is associated with germline mutations in DNA mismatch repair (MMR) genes in ∼50% of the patients. Therefore, a significant number of cases have no mutations in known genes suggesting that other genetic and epigenetic alterations may play a role in the molecular etiology of CRC predisposition. In this study, we evaluated copy number variations (CNVs) in 58 individuals from families with LS with no pathogenic mutations in the MMR genes using the Agilent 4×180K microarray platform. Genomic data were analyzed using Genomic Workbench v6.5 (Agilent Technologies) software and compared with the Database of Genomic Variants (DGV), 100 healthy Brazilian individuals (evaluated with 180K Agilent platform) and 1038 phenotypically healthy individuals (Affymetrix database). It was identified 263 CNVs: 86 were classified as rare (≤ 1% of reference databases) and 10 (in different chromosomes and cases) were completely new. Eleven out of 58 cases were re-evaluated using a higher-density microarray platform (Affymetrix CytoScan HD, 2.6 million probes), being the data analyzed with the Chromosome Analysis Suite v2.1 (Affymetrix) software. We identified more CNVs per case with the Affymetrix platform compared to the Agilent platform (179 to 68). Six rare CNVs were confirmed by both microarray platforms in five different cases: gains of 8p23.3 (95Kb/two genes), 9p21.2 (104Kb/three genes) and 9p24.3 (152Kb/two genes), and loss of 2p23.3 (324Kb/three genes), 2q21.2 (49Kb/one gene) and 3p12.3 (43Kb/one gene). Five of these genes, mapped in four regions, have been related to cancer development. By using Affymetrix CytoScan HD platform, two unrelated cases presented a rare duplication of 82kb on chromosome 2p22.3 encompassing two genes and one microRNA, that were previously associated with CRC. The differences in the detection of both array platforms may be explained in part by the technical procedures used, location of probes and the type of analysis performed to call CNVs. In overall, the findings suggest that rare CNVs might be associated with CRC predisposition in LS patients negative for mutations in MMR genes.
Financial Support: FAPESP (2011/07742-7 and INCiTO (FAPESP: 2008/57887-9 and CNPq 573589/08-9.)
Citation Format: Rolando André Rios Villacis, Érika Maria Monteiro Santos, Dirce Maria Carraro, Benedito Mauro Rossi, Silvia Regina Rogatto. Novel germline copy number variations in patients with hereditary colorectal carcinoma with no mutation in the mismatch repair genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2754. doi:10.1158/1538-7445.AM2015-2754