Abstract 105: Characterizing the exomic profile of MSI colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is the third most common cancer in Western countries. Of all CRC tumors, 15% display microsatellite instability (MSI) caused by defective cellular mismatch repair. Cells displaying MSI accumulate a high number of mutations throughout the genome, especially in short repeat areas called microsatellites. Also point mutations occur in excess in these tumors. Sporadic MSI CRCs are caused by biallelic inactivation of the MLH1 gene, usually by promoter hypermethylation. The MSI tumors have a genetic and clinopathological profile that significantly differs from microsatellite stable (MSS) CRC. Overall, MSI tumors have been studied much less than MSS tumors, mainly due to the high number of mutations in MSI tumors, which makes data analysis and identification of relevant mutations challenging. To date, several genes have been proposed as MSI target genes based on targeted searches of their mutation frequency in microsatellite areas. A few systematic sequencing studies on colorectal cancer have been published, but none of them focus on MSI tumors, making this study first of a kind. In this study, the exome of 25 sporadic MSI tumors and corresponding normal samples are sequenced to identify changes of somatic origin. Bioinformatical tools are used to rank the genes and identify true driver genes based on clustering of missense mutations. The most interesting findings will be validated by direct Sanger sequencing. In addition to corresponding normal specimens, samples from healthy Finnish blood donors as well as data from other ongoing sequencing projects and sequence databases are used as controls to exclude polymorphisms. The data of all the 25 tumors has been analyzed and validation of the potential clusters of missense mutations is in process. The pathological nature of the changes will be confirmed by possible functional studies. This way we wish to identify new driver genes in MSI CRC. A detailed understanding of the molecular background of this tumor type is important for the development of more efficient screening methods and personalized treatments. By characterizing changes typical for different MSI tumors, we wish to identify subtypes within the MSI tumor category that could be exploited in treatment. Such understanding of MSI tumors could improve the treatment and hence prognosis of patients diagnosed with MSI type CRC. 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 105. doi:1538-7445.AM2012-105