Stephen Baylin, M.D
Phone: 410-955-8506
Fax: 410-614-9884
Titles
Deputy Director, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Virginia and D.K. Ludwig Professor for Cancer Research
Professor of Oncology and Medicine
Schools/Degrees
M.D., Duke University, Durham, NC
Training
Intern, in Internal Medicine, Duke University, Durham, NC
Resident in Internal Medicine, Duke University, Durham, NC
Fellow in Endocrinology and Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD
Certifications
2005 Simon M. Shubitz Cancer Prize and Lectureship
Clinical Interests
The work of the Baylin lab has highly translational connotations which are pursued in close liaison with clinical activities in the Cancer Center and, particularly with Drs. Herman and Brock within the Cancer Biology Program. First, the critical goal of using promoter hypermethylation as molecular markers for cancer risk assessement, early diagnosis, and prognostic monitoring is being intensely pursued. Studies currently ongoing include lymph node detection of the markers, and tumor profiles, for predicting prognosis of breast and lung carcinomas. The former work includes determining whether the markers can predict breast ductal carcinoma in-situ at high risk for recurrence. The methylation markers are also being studied in stool DNA to determine their utility for early colon cancer detection and/or risk of this disease and similarly for this purpose for lung cancer using sputum DNA. Dr. Baylin's lab plays a particular collaborative role in these studies by helping to contribute gene markers and assisting in some translational studies.
Second, the use of reversing gene silencing as a strategy for cancer prevention and/or therapy is the other major translational implication of the work. The chromatin work is pivotal to concepts, which will be incorporated in these strategies. The translational implications are contributing to the work ongoing in the Herman lab to make direct clinical use of these concepts. This lab work supports the efforts of Drs. Steve Gore and Mike Carducci to conduct clinical trials of demethylating agents and histone deacetylase inhibitors in all forms of cancer.
Research Summary
Our research has contributed heavily to the concept that epigenetically mediated loss of gene function is a major player in the progression of human cancer. This process, for which aberrant gene promoter hypermethylation is a signature and a component of aberrant loss of transcription for involved genes, is now known to be an alternative to coding region mutations for loss of function of more than half the classic tumor suppressor genes and for a growing list of candidate tumor suppressor genes in virtually every type of human cancer. We are attempting to understand the abnormalities of chromatin and methylation assembly that may account for the appearance of these epigenetic abnormalities during tumor development and how they mediate the transcriptional repression. We are learning, in this regard, that an interaction between the DNA methylation, histone de-acetylase (HDAC) and histone methylating enzymes mediates the transcriptional silencing. We have also discovered that the enzymes that catalyze DNA methylation, the DNA methyltransferases (DNMTs), are more complex than previously thought and can both inhibit transcription and interact with HDACs, independent of mediating the methylation. In collaboration with the Vogelstein-Kinzler lab, we have identified that an interaction between DNMTs is required in colon cancer cells to maintain the abnormal promoter methylation and silencing of important tumor suppressor genes. All of these studies are giving us a much more complete picture of the machinery that mediates aberrant promoter methylation in cancer. They also are contributing to the translational goal of targeting reversal of abnormal gene silencing as a cancer prevention and/or therapy strategy.
Journal Citations
Briggs, K.J., Corcoran-Schwartz, I.M., Zhang, W., Harcke, T., Devereux, W.L., Baylin, S.B., Eberhart, C.G., and Watkins, D.N. (2008). Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma. Genes Dev 22, 770-785.
Chan, T.A., Glockner, S., Yi, J.M., Chen, W., Van Neste, L., Cope, L., Herman, J.G., Velculescu, V., Schuebel, K.E., Ahuja, N., and Baylin, S.B. (2008). Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med 5, e114.
Dhir, M., Montgomery, E.A., Glockner, S.C., Schuebel, K.E., Hooker, C.M., Herman, J.G., Baylin, S.B., Gearhart, S.L., and Ahuja, N. (2008). Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia. J Gastrointest Surg 12, 1745-1753.
Jiemjit, A., Fandy, T.E., Carraway, H., Bailey, K.A., Baylin, S., Herman, J.G., and Gore, S.D. (2008). p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage. Oncogene 27, 3615-3623.
Winter, J.M., Ting, A.H., Vilardell, F., Gallmeier, E., Baylin, S.B., Hruban, R.H., Kern, S.E., and Iacobuzio-Donahue, C.A. (2008). Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin Cancer Res 14, 412-418.
Yi, J.M., Tsai, H.C., Glockner, S.C., Lin, S., Ohm, J.E., Easwaran, H., James, C.D., Costello, J.F., Riggins, G., Eberhart, C.G., Laterra, J., Vescovi, A.L., Ahuja, N., Herman, J.G., Schuebel, K.E., and Baylin, S.B. (2008).
Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res 68, 8094-8103.
Zhang, W., Glockner, S.C., Guo, M., Machida, E.O., Wang, D.H., Easwaran, H., Van Neste, L., Herman, J.G., Schuebel, K.E., Watkins, D.N., Ahuja, N., and Baylin, S.B. (2008). Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res 68, 2764-2772.
Gore, S. D., S. B. Baylin, and J. G. Herman. In Press, 2008. Histone Deacetylase Inhibitors and Demethylating Agents. In J. Vincent T. DeVita, T. S. Lawrence, and S. A. Rosenberg (ed.), DeVita, Hellman and Rosenberg's Cancer: Principles & Practice of Oncology, 8e, 8e ed, vol. 8e, Section 11. Lippincott Williams and Wilkins, York, PA.
Brock, M.V., Hooker, C.M., Ota-Machida, E., Han, Y., Guo, M., Ames, S., Glockner, S., Piantadosi, S., Gabrielson, E., Pridham, G., Pelosky, K., Belinsky, S.A., Yang, S.C., Baylin, S.B., and Herman, J.G. (2008). DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 358, 1118-1128.
Huang, Y., E. Greene, T. Murray Stewart, A. C. Goodwin, S. B. Baylin, P. M. Woster, and R. A. Casero, Jr. 2007. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci U S A 104:8023-8.
Licchesi, J., W. H. Westra, C. M. Hooker, E. O. Machida, S. B. Baylin, and J. G. Herman. 2008. Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. . Carcinogenesis In Press.
McGarvey, K. M., E. Greene, J. A. Fahrner, T. Jenuwein, and S. B. Baylin. 2007. DNA methylation and complete transcriptional silencing of cancer genes persist after depletion of EZH2. Cancer Res 67:5097-102.
Ohm, J. E., and S. B. Baylin. 2007. Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation? Cell Cycle 6:1040-3.
Riojas, M. A., M. Guo, S. C. Glockner, E. O. Machida, S. B. Baylin, and N. Ahuja. 2007. Methylation-Induced Silencing of ASC/TMS1, a Pro-Apoptotic Gene, is a Late-Stage Event in Colorectal Cancer. Cancer Biol Ther 6.
Schuebel, K. E., W. Chen, L. Cope, S. C. Glockner, H. Suzuki, J. M. Yi, T. A. Chan, L. Van Neste, W. Van Criekinge, S. van den Bosch, M. van Engeland, A. H. Ting, K. Jair, W. Yu, M. Toyota, K. Imai, N. Ahuja, J. G. Herman, and S.
B. Baylin. 2007. Comparing the DNA hypermethylome with gene mutations in human colorectal cancer. PLoS Genet 3:1709-23.
Zinn, R. L., K. Pruitt, S. Eguchi, S. B. Baylin, and J. G. Herman. 2007. hTERT is expressed in cancer cell lines despite promoter DNA methylation by preservation of unmethylated DNA and active chromatin around the transcription start site. Cancer Res 67:194-201.
Brock, M. V., J. G. Herman, and S. B. Baylin. 2007. Cancer as a manifestation of aberrant chromatin structure. Cancer J 13:3-8.
Gibbons, M. C., M. Brock, A. J. Alberg, T. Glass, T. A. LaVeist, S. Baylin, D. Levine, and C. E. Fox. 2007. The sociobiologic integrative model (SBIM): enhancing the integration of sociobehavioral, environmental, and biomolecular knowledge in urban health and disparities research. J Urban Health 84:198-211.
Gore, S. D., Baylin, S., Sugar, E., Carraway, H., Miller, C. B., Carducci, M., Grever, M., Galm, O., Dauses, T., Karp, J. E., Rudek, M. A., Zhao, M., Smith, B. D., Manning, J., Jiemjit, A., Dover, G., Mays, A., Zwiebel, J., Murgo, A., Weng, L. J. & Herman, J. G. (2006). Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66, 6361-9.
Guo, M., House, M. G., Akiyama, Y., Qi, Y., Capagna, D., Harmon, J., Baylin, S. B., Brock, M. V. & Herman, J. G. (2006). Hypermethylation of the GATA gene family in esophageal cancer. Int J Cancer 119, 2078-83.
Jair, K. W., Bachman, K. E., Suzuki, H., Ting, A. H., Rhee, I., Yen, R. W., Baylin, S. B. & Schuebel, K. E. (2006). De novo CpG island methylation in human cancer cells. Cancer Res 66, 682-92.
Machida, E. O., Brock, M. V., Hooker, C. M., Nakayama, J., Ishida, A., Amano, J., Picchi, M. A., Belinsky, S. A., Herman, J. G., Taniguchi, S. & Baylin, S. B. (2006). Hypermethylation of ASC/TMS1 is a sputum marker for late-stage lung cancer. Cancer Res 66, 6210-8.
McGarvey, K. M., Fahrner, J. A., Greene, E., Martens, J., Jenuwein, T. & Baylin, S. B. (2006). Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res 66, 3541-9.
Pruitt, K., Zinn, R. L., Ohm, J. E., McGarvey, K. M., Kang, S. H., Watkins, D. N., Herman, J. G. & Baylin, S. B. (2006). Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2, e40.
Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., Brock, M. V. & Biswal, S. (2006). Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 3, e420.
Ting, A. H., Jair, K. W., Schuebel, K. E. & Baylin, S. B. (2006). Differential requirement for DNA methyltransferase 1 in maintaining human cancer cell gene promoter hypermethylation. Cancer Res 66, 729-35.
Ting, A. H., McGarvey, K. M. & Baylin, S. B. (2006). The cancer epigenome--components and functional correlates. Genes Dev 20, 3215-31.
Ting, A. H., Schuebel, K. E., Herman, J. G. & Baylin, S. B. (2005). Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation. Nat Genet 37, 906-10.
Baylin, S. B. & Chen, W. Y. (2005). Aberrant gene silencing in tumor progression: implications for control of cancer. Cold Spring Harb Symp Quant Biol 70, 427-33.
Baylin, S. B. & Mufti, G. J. (2005). Myelodysplastic syndromes (MDSs) and acute myelogenous leukemia (AML) comprise a closely linked continuum of malignant hematologic diseases. Introduction. Nat Clin Pract Oncol 2 Suppl 1, S1-3.
Baylin, S. B. & Ohm, J. E. (2006). Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6, 107-16.
Baylin, S. B. (2005). DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2 Suppl 1, S4-11.
Brock, M. V., Hooker, C. M., Engels, E. A., Moore, R. D., Gillison, M. L., Alberg, A. J., Keruly, J. C., Yang, S. C., Heitmiller, R. F., Baylin, S. B., Herman, J. G. & Brahmer, J. R. (2006). Delayed diagnosis and elevated mortality in an urban population with HIV and lung cancer: implications for patient care. J Acquir Immune Defic Syndr 43, 47-55.
Brock, M. V., Hooker, C. M., Syphard, J. E., Westra, W., Xu, L., Alberg, A. J., Mason, D., Baylin, S. B., Herman, J. G., Yung, R. C., Brahmer, J., Rudin, C. M., Ettinger, D. S. & Yang, S. C. (2005). Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: Its time has come. J Thorac Cardiovasc Surg 129, 64-72.
Brock, M. V., Hooker, C. M., Yung, R., Guo, M., Han, Y., Ames, S. E., Chang, D., Yang, S. C., Mason, D., Sussman, M., Baylin, S. B. & Herman, J. G. (2005). Can we improve the cytologic examination of malignant pleural effusions using molecular analysis? Ann Thorac Surg 80, 1241-7.
Chen, W. Y. & Baylin, S. B. (2005). Inactivation of tumor suppressor genes: choice between genetic and epigenetic routes. Cell Cycle 4, 10-2.
Chen, W. Y., Wang, D. H., Yen, R. C., Luo, J., Gu, W. & Baylin, S. B. (2005). Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123, 437-48.
Galm, O., Suzuki, H., Akiyama, Y., Esteller, M., Brock, M. V., Osieka, R., Baylin, S. B. & Herman, J. G. (2005). Inactivation of the tissue inhibitor of metalloproteinases-2 gene by promoter hypermethylation in lymphoid malignancies. Oncogene 24, 4799-805.
Chen, W., Cooper, T. K., Zahnow, C. A., Overholtzer, M., Zhao, Z., Ladanyi, M., et al. 2004. Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell. 6:387-398.
Chen, W. Y., Wang, D. H., Yen, R. Y. C., Luo, J., Gu, W., & Baylin, S. B. 2005. Tumor suppressor HIC1 directly regulates SIRT1 and modulates p53 dependent apoptotic DNA damage responses. Cell. 123:437-448.
Suzuki, H., Watkins, D. N., Jair, K. W., Schuebel, K. E., Markowitz, S. D., Chen, W. D., et al. 2004. Epigenetic inactivation of the SFRP allows constitutive WNT signaling in colorectal cancer. Nat. Genet. 36:417-422.
Ting, A. H., Jair, K. W., Suzuki, H., Yen, R. W., Baylin, S. B., & Schuebel, K. E. 2004. CpG island hypermethylation is maintained in human colorectal cancer cells after RNAi-mediated depletion of DNMT-1. Nat. Genet. 36:582-584.
Ting, A. H., Schuebel, K. E., Herman, J. G., & Baylin, S. B. 2005. Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation. Nat. Genet. 37:906-910.
Watkins, D. N., Berman, D. M, Burkholder, S. G., Wang, B., Beachy, P. A., & Baylin, S. B. 2003. Hedgehog signaling within airway epithelial progenitors and small cell lung cancer. Nature. 422:313-317.
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