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Program Director/Principal Investigator (Last, First, Middle): Owyang, Chung BIOGRAPHICAL SKETCH Provide the following information for the key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FOUR PAGES. NAME POSITION TITLE JOHN M. CARETHERS, M.D. John G. Searle Professor of Internal Medicine Chair, Department of Internal Medicine (effective 11/01/2009) eRA COMMONS USER NAME (credential, e.g., agency login) jcarethers EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.) INSTITUTION AND LOCATION DEGREE (if applicable) YEAR(s) FIELD OF STUDY Wayne State University B.S. 1985 Biological Sciences Wayne State University M.D. 1989 Medicine Massachusetts General Hospital Residency 1992 Internal Medicine University of Michigan Hospitals Fellowship 1995 Gastroenterology A. Positions and Employment 1995-2001 Assistant Professor of Medicine in Residence, University of California, San Diego 2000-2004 Gastroenterology Fellowship Director, University of California, San Diego 2001-2005 Associate Professor of Medicine, University of California, San Diego 2002-2005 Chief, Gastroenterology Section, VA San Diego Healthcare System 2004-2009 Chief, Division of Gastroenterology, University of California, San Diego 2005-2009 Professor of Medicine (tenured), University of California, San Diego 2007-2010 Director, UCSD Gastroenterology NIH T32 Training Grant 2007-2009 Director, UCSD NIH Digestive Diseases Research Development Center (DDRDC) 2008-2009 co-Program Leader, Reducing Cancer Disparities, UCSD Comprehensive Cancer Center 11/2009John G. Searle Endowed Professor of Internal Medicine, University of Michigan 11/2009Chairman, Department of Internal Medicine, University of Michigan Other Experience and Professional Memberships 2000-2003 Editorial Board, American Journal of Physiology: Gastrointestinal & Liver Physiology 2000-2003 Associate Editor, Encyclopedia of Gastroenterology, Elsevier Academic Press 2002-2006 NIH CSR Gastrointestinal Cell and Molecular Biology Study Section (GCMB) 2006-2011 Board of Editors, Gastroenterology; Section Editor, This Month in Gastroenterology 2006-2008 National Commission on Digestive Diseases (appointed by Elias Zerhouni, M.D.) 2007-2011 AGA Council; elected Vice-Chair (07-09) and Chair (09-11) of Gastrointestinal Oncology Section 2009-2010 AGA Underrepresented Minorities Committee Honors Alpha Omega Alpha Honor Medical Society (1988); Commonwealth Fund Medical Research Fellow, National Medical Fellowships (1988); Henry J. Kaiser Family Foundation Award, National Medical Fellowships (1989); Franklin C. McLean Award, National Medical Fellowships (1989); UCSD Department of Medicine Graduating House Staff Teaching Award (1999); Fellow, American College of Physicians (FACP) (1999); Fellow, American College of Gastroenterology (FACG) (2001); UCSD Gastroenterology Fellows Excellence in Clinical Teaching Award (2004); Fellow, American Gastroenterological Association (AGAF) (2005); Western Association of Physicians (2006); UCSD School of Medicine Vice-Chancellor’s Award for Mentoring Excellence (2006); American Society for Clinical Investigation (2008) B. Selected peer-reviewed publications (in chronological order) 1. Koi M, Umar A, Chauhan DP, Cherian SP, Carethers JM, Kunkel TA, Boland CR. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N’-nitro-Nnitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res 1994;54:4308-4312. PMID: 8044777 PHS 398/2590 (Rev. 11/07) Page Biographical Sketch Format Page Principal Investigator/Program Director (Last, First, Middle): CARETHERS, John M. 2. Hawn MT, Umar A, Carethers JM, Marra G, Kunkel TA, Boland CR, Koi M. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res 1995;55:3721-3725. 3. Luce MC, Marra G, Chauhan DP, Laghi L, Carethers JM, Cherian SP, Hawn MT, Binnie CG, Kam-Morgan LNW, Cayouette MC, Koi M, Boland CR. In vitro transcription/translation assay for the screening of hMLH1 and hMSH2 mutations in familial colon cancer. Gastroenterology 1995;109:1368-1374. PMID: 7557107 4. Carethers JM, Hawn MT, Chauhan DP, Luce MC, Marra G, Koi M, Boland CR. Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N’-nitro-N-nitrosoguanidine. J Clin Invest 1996; 98:199-206. PMID: 8690794 5. Zigman AF, Lavine JE, Jones MC, Boland CR, Carethers JM. Localization of Bannayan-Riley-Ruvalcaba syndrome gene to chromosome 10q23. Gastroenterology 1997; 113:1433-1437. PMID: 9352843 6. Carethers JM, Hawn MT, Greenson JK, Hitchcock CL, Boland CR. Prognostic significance of allelic loss at chromosome 18q21 for stage II colorectal cancer. Gastroenterology 1998; 114:1188-1195. PMID: 9609755 7. Carethers JM, Furnari FB, Zigman AF, Lavine JE, Jones MC, Graham GE, Teebi AS, Huang H-JS, Ha HT, Chauhan DP, Chang CL, Cavenee WK, Boland CR. Absence of PTEN/MMAC1 germline mutations in sporadic Bannayan-Riley-Ruvalcaba syndrome. Cancer Res 1998; 58:2724-2726. PMID: 9661881 8. Carethers JM, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB, Boland CR. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology 1999; 117: 123-131. PMID: 1038191 9. Carethers JM. Racial and ethnic factors in the genetic pathogenesis of colorectal cancer. J Assoc Acad Minor Phys 1999; 10:59-67. PMID: 10826011 10. Carethers JM, Pham T-TT. Mutations of transforming growth factor 1 type II receptor, BAX, and insulinlike growth factor II receptor genes in microsatellite unstable cell lines. In Vivo 2000; 14:13-20. PMID: 10757056 11. Yashiro M, Carethers JM, Laghi L, Saito K, Slezak P, Jaramillo E, Rubio C, et. al. Genetic pathways in the evolution of morphologically distinct colorectal neoplasms. Cancer Res 2001; 60:2676-2683. PMID: 11289147 12. Huang SC, Lavine JE, Boland PS, Newbury RO, Kolodner R, Pham T-TT, Boland CR, Carethers JM. Germline characterization of early-aged onset of hereditary non-polyposis colorectal cancer. J Pediatr 2001; 138:629-635. PMID: 11343035 13. Gervaz P, Efron J, Poza AA, Chun SW, Pham T-TT, Woodhouse S, Wexner SD, Carethers JM. Loss of heterozygosity and HIV infection in patients with anal squamous-cell carcinoma. Dis Colon Rectum 2001;44:1503-8. PMID: 11598481 14. Gervaz P, Cerottini J-P, Bouzourene H, Benhattar J, Chaubert P, Secic M, Gillet M, Carethers JM. Comparison of microsatellite instability and chromosomal instability in predicting survival of patients with T3N0 colorectal cancer. Surgery 2002; 131:190-197. PMID: 11854698 15. Chang CL, Marra G, Chauhan DP, Ha HT, Chang DK, Ricciardiello L, Carethers JM, et. al. Oxidative stress inactivates the DNA mismatch repair system. Am J Physiol Cell Physiol 2002; 283:C148-C154. PMID: 12055083 16. Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Wasserman L, Compton C, et. al. Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res 2003; 63:1608-11614. PMID: 12670912 17. Ashkortab H, Smoot DT, Carethers JM, Rahmanian M, Kittles R, Vosganian G, Doura M, Nidhiry E, Naab T, Momen B, Shakhani S, Giardiello FM, High incidence of microsatellite instability in colorectal cancer from African Americans. Clinical Cancer Res 2003; 9:1112-1117. PMID: 12631615 18. Chang D, Goel A, Ricciardiello L, Lee DH, Chang CL, Carethers JM, Boland CR. Effect of H2O2 on cell cycle and survival in DNA mismatch repair-deficient and -proficient cell lines. Cancer Letters, 2003;195:243-251. PMID: 12767533 19. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR. Use of 5-fluorouracil and survival in patients with microsatellite unstable colorectal cancer. Gastroenterology 2004; 126: 394-401. PMID: 14762775 20. Jung B, Doctolero RT, Tajima A, Nguyen AK, Keku T, Sandler RS, Carethers JM. Loss of activin receptor type 2 protein expression in microsatellite unstable colorectal cancers. Gastroenterology 2004; 126:654659. PMID: 14988818 21. Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli M, Boland CR. Frequent inactivation of PTEN by promoter hypermethylation and its association with PHS 398/2590 (Rev. 11/07) Page Biographical Sketch Format Page Principal Investigator/Program Director (Last, First, Middle): CARETHERS, John M. microsatellite instability-high (MSI-H) in sporadic colorectal cancers. Cancer Res 2004; 64:3014-3021. PMID: 15126336 22. Tajima A, Hess M, Cabrera BL, Kolodner R, Carethers JM. The mismatch repair complex hMutS recognizes 5-fluoruracil-modified DNA as a mechanism for chemosensitivity. Gastroenterology 2004; 127:1678-1684. PMID: 15578504 23. Iwamoto M, Hoffenberg EJ, Carethers JM, Doctolero R, Tajima A, Sugano K, Franklin WA, Ahnen DJ. Nuclear accumulation of -catenin occurs commonly in the epithelial cells of juvenile polyps. Pediatric Res 2005; 57:4-9. PMID: 15557107 24. Satia JA, Keku T, Galanko JA, Martin C, Doctolero RT, Tajima A, Sandler RS, Carethers JM. Diet, lifestyle, and genomic instability in the North Carolina Colon Cancer Study. Cancer, Epidemiol, Biomarkers, and Prevention 2005; 14:429-436. PMID: 15734969 25. Ashktorab H, Smoot DT, Farzanmehr H, Fidelia-Lambert M, Momen B, Hylind L, Iacosozio-Dononue C, Carethers JM, Goel A, Boland CR, Giardiello FM. Clinicopathological features and MSI in colorectal cancers from African Americans. International Journal of Cancer 2005; 116:914-919. PMID: 15856472 26. Eaton, AM, Sandler RS, Carethers JM, Millikan RC, Galanko J, Keku TO. MTHFR 677 and 1298 polymorphisms, folate intake and microsatellite instability in colon cancer. Cancer, Epidemiology, Biomarkers, and Prevention 2005; 14:2023-2029. PMID: 16103455 27. Carethers JM. Should African Americans be screened for colorectal cancer earlier? Nature Clinical Practice Gastroenterology and Hepatology 2005; 2:352-353. PMID: 16265401 28. Yashiro M, Laghi L, Saito K, Carethers JM, Slezak P, Rubio C, Hirakawa K, Boland CR. Serrated adenomas have a pattern of genetic alterations that distinguishes them from other colorectal polyps. Cancer Epidemiol Biomarkers Prev 2005, 14:2253-2256. PMID: 16172239 29. Carethers JM. Unwinding the heterogeneous nature of hamartomatous polyposis syndromes. JAMA 2005; 294:2498-2500. PMID: 16287964 30. Carethers JM. Prospective evaluation of fluorouracil chemotherapy based on the genetic make-up of colorectal cancer. Gut 2006; 55: 759-761. PMID: 16698750 31. Jung B, Smith EJ, Doctolero RT, Gervaz P, Alonso JC, Miyai K, Keku T, Sandler RS, Carethers JM. Influence of target gene mutation on survival, stage, and histology in sporadic microsatellite unstable colon cancers. International Journal of Cancer 2006; 118:2509-2513. PMID: 16380996 32. Beck SE, Jung BH, Fiorino A, Gomez J, Del Rosario E, Cabrera BL, Huang SC, Chow JYC, and Carethers JM. Bone morphogenetic protein signaling and growth suppression in colon cancer. Am J Physiology GI & Liver Physiology 2006; 291:G135-G145. PMID: 16769811 33. Jo, W-S, Carethers JM. Chemotherapeutic implications in microsatellite unstable colorectal cancer. Cancer Biomarkers 2006; 2:51-60. PMID: 17192059 34. Jung BH, Beck SE, Cabral J, Chau E, Cabrera BL, Fiorino A, Smith EJ, Bocanegra M, Carethers JM. Activin type 2 receptor restoration in MSI-H colon cancer suppresses growth and enhances migration with activin. Gastroenterology 2007; 132:633-644. PMID: 17258738 35. Kurland J, Beck SE, Solomon C, Doctolero RT, Brann O, Carethers JM, Huang SC. Cyclooxygenase 2 expression in polyps from a juvenile polyposis syndrome patient with mutant BMPR1A. J Ped Gastroenterol Nutrition 2007; 44:318-325. PMID: 17325551 36. Beck SE, Jung B, Del Rosario E, Gomez J, Carethers JM. BMP-induced growth suppression in colon cancer cells is mediated by p21/WAF1 stabilization and modulated by RAS/ERK. Cell Signal 2007; 19:1465-1472. PMID: 17317101 37. Beck SE, Carethers JM. BMP suppresses PTEN expression via RAS/ERK signaling. Cancer Biol & Ther, 6:1313-1317, 2007. PMID: 18059158 38. Chow JYC, Quach KT, Cabrera BL, Cabral JA, Beck SE, Carethers JM. RAS/ERK modulates TGFregulated PTEN expression in human pancreatic adenocarcinoma cells. Carcinogenesis; 28:2321-2327, 2007. PMID: 17638924 39. Shin SK, Nagasaka T, Jung BH, Matsubara N, Kim WH, Carethers JM, Boland CR, Goel A. Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer. Gastroenterology; 133:1849-1857, 2007. PMID: 18054557 40. Chow JYC, Dong H, Quach KT, Nguyen PNV, Chen K, Carethers JM. TGF mediates PTEN suppression and cell motility through calcium-mediated PKC activation in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol, 294:G899-G905, 2008. PMID: 18239055 PHS 398/2590 (Rev. 11/07) Page Biographical Sketch Format Page Principal Investigator/Program Director (Last, First, Middle): CARETHERS, John M. 41. Grady WM and Carethers JM. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135:1079-1099,2008. PMID: 18773902 42. Chow JYC, Cabral JA, Chang J, Carethers JM. TGF-beta modulates PTEN expression independently of SMAD signaling for growth proliferation in colon cancer cells. Cancer Biol & Ther 7:1694-1699, 2008. PMID: 18769113 43. Chung H, Young DJ, Lopez C, Le T-AT, Lee JK, Ream-Robinson D, Huang SC, Carethers JM. Mutation rates of TGFBR2 and ACVR2 coding microsatellites in human cells with defective DNA mismatch repair. PLoS ONE 3:e3463, 2008. PMID: 18941508 44. Carethers JM. Intersection of TGF-beta and Wnt signaling pathways in colorectal cancer and metastasis. Gastroenterology 137:33-36, 2009. PMID: 19482104 45. Chung H, Lopez CG, Young DJ, Ream-Robinson D, Cabrera BL, Carethers JM. Flanking sequence specificity determines coding microsatellite heteroduplex and mutation rates with defective DNA mismatch repair. Oncogene, 2009 (accepted). PMID: pending C. Research Support ongoing or completed during the last three years R01 DK067287 (Carethers) 07/1/05 to 06/30/10 NIH/NIDDK Microsatellite Instability and the DNA Mismatch Repair System Major goals: To determine the mutational rates of DNA microsatellites in various DNA mismatch repairdeficient backgrounds, and to examine DNA structural changes upon the mutation rates. Role: PI R24 DK080506 (Carethers) 04/10/08 to 02/28/13 NIH/NIDDK UCSD Digestive Diseases Research Development Center (DDRDC) Major goals: To provide the framework to facilitate research productivity, foster new research directions, and encourage collaborations for participating members through the use of 3 basic science cores centered on a theme continuum of digestive disease organ inflammation to repair to transformation. Role: PI U54 CA132379 (Carethers and Navarro) 09/01/08 to 08/31/13 NIH/NCI Comprehensive SDSU/UCSD Cancer Center Partnership Major goals: To enhance research, training, and education in cancer disparities between SDSU and UCSD. Role: co-PI Full Project, U54 CA132384 (Carethers and McGuire) 11/01/08 to 8/31/11 NIH/NCI Genomic instability, race, and immune relationships in colorectal cancer Major goals: To evaluate the role of genomic instability and immune cell infiltration within colorectal cancers in determining survival between African Americans and Caucasians. Role: co-PI P30 CA023100 (Carson) 05/01/07 to 04/30/12 NIH/NCI UCSD Moores Comprehensive Cancer Center Major goals: This grant provides support for the infrastructure and shared resources of the University of California, San Diego Moores Comprehensive Cancer Center. Role: Member and co-Program Leader for Reducing Cancer Disparities Program PHS 398/2590 (Rev. 11/07) Page Biographical Sketch Format Page