John Carethers, M.D.
C. Richard Boland Distinguished University Professor
Chair, Department of Internal Medicine
Dr. Carethers received his B.S. degree in Biological Sciences with a minor in Chemistry from Wayne State University, and his M.D. with high distinction from the same institution. Dr. Carethers did his internship and residency in Internal Medicine at Massachusetts General Hospital, followed by a fellowship in gastroenterology at the University of Michigan. He was then recruited to the University of California San Diego where he grew his laboratory-based research in the area of DNA mismatch repair and colorectal cancer pathogenesis, saw medicine and gastroenterology patients, including serving as the main physician for hereditary colon cancer referrals in Southern California. He served in leadership roles including the gastroenterology fellowship director, the gastroenterology Section Chief for the San Diego VA Hospital, then Division Chief for UC San Diego before being recruited to Michigan as Chair of Internal Medicine. He was the founding Director of the NIH-funded UCSD Gastroenterology Center grant, and was the director of the gastroenterology T32 training grant. His laboratory research continues to be funded by the NIH. Dr. Carethers also has interests in colorectal cancer disparities as it relates to genetics and outcomes. He is the former PI of the SDSU/UCSD Cancer Center Comprehensive Partnership U54 grant, which addresses cancer disparities. He has published over 200 manuscripts and book chapters. He recently completed the role of Senior Associate Editor for Gastroenterology, the highest impact GI journal. He completed a 2-year appointment on the National Commission for Digestive Diseases, a U.S. Congressional Commission after his appointment by Elias Zerhouni, M.D., then Director of the NIH. He was elected a member of the American Society for Clinical Investigation, and elected a member of the American Association of Physicians (AAP), and serves on the AAP Council and will be President beginning April 2018. He was elected a member of the National Academy of Medicine in 2012, and elected a Fellow of the American Academy of Arts & Sciences in 2016. He was named the C. Richard Boland Distinguished University Professor at the University of Michigan as of September 2017.
The Carethers’ laboratory studies the pathogenesis of sporadic and hereditary colorectal cancer. The laboratory focuses on the function and consequences of the DNA mismatch repair system which when affected, is involved in both inherited and sporadic colorectal cancer. There are 4 areas of investigation at present. (1) We seek to understand the basic mechanisms of DNA mismatch repair in human cells. Our recent focus has been on the DNA mismatch repair gene MSH3. We have created constructs containing tetranucleotide microsatellites fused with GFP and out of frame to measure template strand and newly-synthesized strand insertion/deletion mutations in the setting of MSH3 deficiency. (2) We investigate the role of inflammation and DNA mismatch repair regulation. The laboratory has identified that colorectal cancers exhibiting increased inflammatory cells showcase a biomarker called EMAST, for which we and others show is caused by MSH3 dysfunction. The dysfunction is not due to mutation or epimutation of MSH3; we discovered that IL-6 induced signaling reversibly shifts MSH3 protein from its normal location in the nucleus to the cytosol where it cannot repair DNA. Continued studies are examining the shuttling mechanism for the nuclear-to-cytosol shift. (3) We seek to undertsand the role of EMAST and MSH3 dysfunction in colorectal cancer metastasis. We discovered that EMAST colorectal cancers, which are associated with higher levels of metastasis and poor patient survival, are enriched for loss of heterozygosity at specific genetic loci that is further amplified in the liver metastasis. These sites are being further examined for functional genes or regulators, expression differences between normal, primary colorectal cancer, and liver metastasis, as well as the function loss or gained from the affected loci. (4) We examine biological determinants of disparities in colorectal cancer. The laboratory strives to understand possible biological differences and possible approaches to the racial disparity seen in the morbidity and mortality from colorectal cancer. We have demonstrated that African American colorectal cancers possess less frequent microsatellite instability (a good prognosticator) than Caucasians, but possess more frequent EMAST, a poor prognosticator. We have also discovered that infiltration of granzyme B immune cells at the invasive tumor borders was markedly lower in African American tumors. Moving forward, the laboratory is examining the relationship between EMAST and race, as well as a determining the role of granzyme B immune cells and how it relates to EMAST.