Epigenetic alterations in the initiation and progression of gastrointestinal cancer

The field of epigenetic alterations in cancer has undergone rapid development in the last decade and has been the subject of intense investigation during this time. Dr. Grady provided one of the first studies that demonstrated a causal role for aberrant gene methylation in the formation of cancer. His research group has gone on to demonstrate the role of aberrant gene methylation in the polyp-cancer progression sequence in both sporadic and familial colorectal cancer and has discovered several novel genes that are aberrantly methylated in colorectal cancer. This has not only led to publications in high-impact journals,(Nature Genetics, Cancer Research, Clinical Cancer Research, Gastroenterology, etc) but also to patented assays for methylated MLH1 and EVL/miR-324 (patent pending). His lab has also revealed the functional role of specific methylated genes in colorectal cancer. Furthermore, studies in his lab demonstrated that methylated genes can be used as blood and stool based biomarkers for colorectal cancer and have provided novel advances in technical performance of these assays. More recently, his lab has assessed the use of mouse models of colorectal cancer for the study of methylated genes in colorectal cancer pathogenesis.

Biomarkers for colorectal polyps and cancer

Methylated genes are promising biomarkers for the early detection of colon polyps and cancer and for the prognosis of CRC. Dr. Grady’s lab has been on the forefront of the discovery and development of methylated gene biomarkers for colon polyps and CRC. His lab published the first study in CRC patients showing methylated MLH1 is a serum biomarker for CRC. He has also published feasibility studies showing methylated genes can be used as polyp detection biomarkers. Most recently, he has shown that a hypermethylator CRC molecular subtype, the CpG Island Methylator Phenotype (CIMP), is particularly sensitive to adjuvant therapy containing irinotecan, which may lead to changes in the treatment of people with CIMP CRCs. In a recent study, his lab has defined unique molecular subgroups of colon polyps based on their “methylomes” and also identified potential methylated gene field cancerization markers. These results have the potential to lead to refinements in risk stratification strategies used for people with colon polyps and to new approaches for CRC chemoprevention. To advance this line of investigation, his lab has assessed the use of mouse models of colorectal cancer for the study of methylated genes in colorectal cancer pathogenesis.

Biomarkers for Barrett's esophagus

As with CRC, epigenetic alterations are found in esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), which is specialized intestinal metaplasia of the esophagus. Dr. Grady’s lab has defined the global aberrant DNA methylation changes in BE and EAC and has also identified specific aberrantly methylated genes that appear to regulate the progression of BE to EAC. Currently his lab is assessing several of these aberrant methylation sites for potential clinical predictive and/or diagnostic use. Dr. Grady is a lead investigator in the NCI funded Barrett's Esophagus Translational Research Network (BETRNet), which is composed of prominent investigators in the field of BE and EAC.

TGF-ß signaling deregulation and colorectal cancer

A primary aspect of cancer development is the accumulation of gene mutations and epigenetic alterations that lead to the transformation of normal cells into cancer cells. These mutations promote cancer formation as a consequence of deregulating fundamental cellular behaviors (i.e. cell proliferation, apoptosis, invasive behavior, immortalization, etc.) and disrupting signaling pathways in the cells. In colorectal cancer (CRC), one of the most commonly affected pathways is the transforming growth factor beta (TGF-ß) signaling pathway, which is disrupted in 80% of colorectal cancers. An important aspect of TGF-ß’s role in cancer is that it can have paradoxical (oncogenic and tumor suppressive) effects, which appear to be context dependent. Dr. Grady’s lab has played a central role in defining TGF-ß’s role in CRC formation through the study of human tissues and cutting edge mouse models of CRC.