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Arizona Cancer Evolution Center

October 10

2011

Biodesign Auditorium
727 E. Tyler St. Tempe
AZ 85287

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Colorectal cancer arises as the consequence of the accumulation of genetic alterations (e.g. gene mutations, gene amplification, etc.) and epigenetic alterations (e.g. aberrant DNA methylation, chromatin modifications, etc.) that transform colonic epithelial cells into colon adenocarcinoma cells. The loss of genomic and epigenomic stability and resulting gene alterations appears to be a key molecular and pathogenic step that occurs early in the tumorigenesis process and permits the acquisition of a sufficient number of alterations in tumor suppressor genes and oncogenes in a clone of cells to result in their ultimate transformation into cancer. It has also become clear that epigenetic alterations are common in many cancers and affect the formation and behavior of the tumors. With regards to DNA methylation, it is present normally throughout the majority of the genome and is maintained in relatively stable patterns that are established during development. In humans, approximately 70{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of CpG dinucleotides carry this epigenetic modification. However, there are regions that are enriched for CpG dinucleotides, called CpG islands, that are present in the 5’ region of approximately 50-60{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of genes and are normally maintained in an unmethylated state. In cancers, many of these CpG islands become aberrantly methylated, and this aberrant methylation can be accompanied by transcriptional repression. The significance of these epigenetic alterations in the pathogenesis of cancer has been a point of significant controversy. Nonetheless, there is sufficient data to demonstrate that the aberrant methylation of at least some of these genes, such as MLH1, can be pathogenetic in cancer. The aberrant methylation of MLH1 occurs in approximately 80{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of sporadic MSI colorectal cancers, and the restoration of MLH1 expression and function by demethylating the MLH1 promoter in MSI colorectal cancer cell lines, strongly supports the idea that such aberrant methylation is a cause rather than a consequence of colorectal carcinogenesis. Furthermore, the epigenetic inactivation of MLH1 appears to proceed the onset of mutations in genes with coding region microsatellite repeats, such as TGFBR2, suggesting epigenetic events can predispose tumor cells to mutations that drive the tumorigenesis process. Indeed, aberrantly methylated genes HLTF SLC5A8, MGMT, MINT1, and MINT31 can be found in aberrant crypt foci, demonstrating that aberrant promoter methylation occurs early in the adenoma sequence, although it does not confirm that the aberrant methylation is a primary rather than a secondary event in the tumorigenesis process. The aberrant methylation of genes affects genes that are commonly targets of mutational inactivation in colon cancers and contributes to the deregulation of signaling pathways that are known to be important in these tumors. Finally, a subset of colorectal cancers that hypermethylate genes belong to a distinct subclass of colorectal cancers, termed the CpG island methylator phenotype (CIMP) has been identified and appear to have a worse prognosis. These aberrantly methylated genes have been shown to be early detection markers and prognostic markers for a variety of cancers and some methylated genes are already being used in clinically available assays in the United States. The potential for methylated genes to be used as risk stratification markers, early detection markers, and predictive markers is high, and it is anticipated that they will move into common clinical use in the future. Finally, therapies directed at these genetic and epigenetic alterations are under active development and hold the promise to improve the treatment of colorectal cancer.