Abstract 3055: Identification of potential colorectal cancer driver genes in focal chromosomal aberrations

Abstract

Abstract Introduction: Microsatellite stable colorectal cancer (MSS-CRC) is characterized by frequent chromosomal amplifications and deletions. Even though most of these aberrations are random and case specific, some of them are common indicating a potentially important role in cancer development. However, most of the common aberrations affect large chromosomal segments which provide a challenge for the identification of cancer driver genes within these areas. But, some of these common aberrations are focal in size (<3Mb) and harbor small number of genes which facilitates the detection of candidate driver genes. Array comparative genome hybridization (aCGH) allows the analysis of chromosomal abnormalities across the whole cancer genome with high spatial resolution. When applied to a large number of cancer cases, high resolution aCGH helps in the identification of common focal chromosomal aberrations that play an important role in carcinogenesis. The aim of this study is to identify novel and common focal aberrations in CRC. Hypothesis: Common focal deletions and amplifications play an important role in MSS-CRC development through affecting key genes and microRNAs. Methods: Thirty eight CRC samples were investigated for MSI status using quantitative fluorescent PCR and a set of 5 mono-nucleotide microsatellites (BAT25, BAT26, NR21, NR24 and MONO27). High resolution Agilent 44K and 180K CGH arrays were applied on 6 and 32 CRC DNA samples respectively. The arrays contained 60-mer oligonucleotides probes for 42494 (44K) and 170334 (180K) distinct chromosomal locations distributed over the genome. The resolutions of the arrays were 43kb (44K) and 13kb (180K). All the tumor DNA samples were referenced against peripheral blood DNA extracted from the same patients. aCGH analysis was performed using the Agilent genomic workbench software (v5.0) and the aberrations were called using the aberration detection method 2 (ADM2) algorithm. Common aberration analysis was performed using the context corrected common aberration algorithm with a chromosomal scope. Results: All the samples were shown to be MSS and to carry mutations in APC (50%), TP53 (50%), KRAS (39.4%) and BRAF (5.2%). A Large number of common and focal deletions and amplifications were identified, some of which are novel. Some of the identified focal aberrations contained only single genes such as the deletion of PARK2 (∼18.4%), RGS12 (∼18.4%), FHIT (15.8%), NAALADL2 (10.5%) and the amplification of KCNMA1 (15.8%) or microRNAs such as the deletion of miR661 (13.2%) and the amplification of miR885 (15.8%). A list of novel candidate CRC-related genes and microRNAs was established. Conclusion: A number of novel candidate CRC-related genes have been identified. These results will be followed up by gene over-expression and knock-down studies in CRC cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3055. doi:10.1158/1538-7445.AM2011-3055