William M. Grady – The Role of Epigenetic Alterations in Colon Cancer

Speaker: William M. Grady, MD, is a physician-scientist at the Fred Hutchinson Cancer Research Center and the University of Washington Medical School, Seattle, WA. He is the Roger C. Haggitt Professor of Medicine and section Chief of the Gastroenterology Division at the University of Washington Medical School. He is also a full member of the Clinical Research Division of the Fred Hutchinson Cancer Research Center. In addition to being the PI of a translational research program in GI oncology, he is a practicing gastroenterologist and is the Medical Director of the GI Cancer Prevention Program Clinic at the Seattle Cancer Care Alliance, which specializes in the care of individuals who have cancer family syndromes.
He is an independent NIH funded PI with experience in the study of the molecular and cell biology of gastrointestinal cancer. He is the PI of an R01 funded study to assess the role of deregulated signaling pathways in the formation of colon cancer and is a recognized expert in the study of transforming growth factor ß (TGF-ß) signaling in colon cancer. He is also the PI of an Early Detection Research Network (NCI) Project to identify novel early detection markers for colon neoplasms as well as a project PI of a P01 (RecQ helicases and Colon Cancer) to identify predictive molecular markers for colorectal cancers. He has received numerous awards including the Damon Runyon-Lilly Clinical Investigator Award, Presidential Early Career Award for Scientists and Engineers, Burroughs Wellcome Clinical Scientist Award in Translational Research, and is a member of the American Society of Clinical Investigation.

Location: Biodesign Auditorium

Web Cast: View Web Cast Video
William Grady gave a great lecture.
Since the audio to the first 2 slides didn’t record, we have retained the slides for the record but cut down their duration on screen. His audio now appears at 1’08.

A brief summery of the first 2 slides:

Colorectal cancer is one of the most common cancers that affects people around the world. In the United States, 155,000 people per year are diagnosed with colorectal cancer. Virtually all colon cancers develop from colon polyps, which are benign tumors called adenomas. These adenomas occur in 1/3 of people over the age of 40 and over time can become cancer. It takes roughly 10-15 years for an adenoma to become a cancer and only about 10{236bd5e292587b885399ce1fe93b84c86ca4f34851d3c4bf06f3f0da35a3ccbb} of adenomas will become cancer. The long duration of the adenoma-carcinoma sequence has allowed a study of gene mutations that occurduring this process. Some mutations, such as APC (adenomatous polyposis coli gene) occur early in the process and are thought to initiate the formation of the adenomas, whereas others are found in more advanced adenomas or cancers and are thought to drive the progression of the adenomas to cancer.

Grady began by explaining that colorectal cancer takes many years – up to 2 decades to manifest from the initial event of a mutated cell in the colon epithelium to invasive cancer. He went on to describe how several different mutations are responsible for the development of cancer.

Date & Time: October 10th, 2011 12:00 p.m.

Title: The Role of Epigenetic Alterations in Colon Cancer

Abstract: 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.

Thank you and if you have questions please contact Amanda Wilber! And don’t forget, coffee will be served!

Amanda Wilber, Center for the Convergence of Physical Science and Cancer Biology

Arizona State University | P.O. Box 871504 | Tempe, AZ 85287

480.965.3860 | Fax: 480.965.6362
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