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Dr. Stephen Baylin

M.D.
Stephen Baylin
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.
 

Clinical Research

Epigenetics

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

Baylin, S.B.; Ohm, J.E. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer. 2006 Feb;6(2):107-116.

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. Delayed diagnosis and elevated mortality in an urban population with HIV and lung cancer: implications for patient care. J Acquir Immune Defic Syndr. 2006 Sep;43(1):47-55.

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. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006 Jun 15;66(12):6361-6369.

Guo, M.; House, M.G.; Akiyama, Y.; Qi, Y.; Capagna, D.; Harmon, J.; Baylin, S.B.; Brock, M.V.; Herman, J.G. Hypermethylation of the GATA gene family in esophageal cancer. Int J Cancer. 2006 Nov 1;119(9):2078-2083.

Jair, K.W.; Bachman, K.E.; Suzuki, H.; Ting, A.H.; Rhee, I.; Yen, R.W.; Baylin, S.B.; Schuebel, K.E. De novo CpG island methylation in human cancer cells. Cancer Res. 2006 Jan 15;66(2):682-692.

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. Hypermethylation of ASC/TMS1 is a sputum marker for late-stage lung cancer. Cancer Res. 2006 Jun 15;66(12):6210-6218.

McGarvey, K.M.; Fahrner, J.A.; Greene, E.; Martens, J.; Jenuwein, T.; Baylin, S.B. Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res. 2006 Apr 1;66(7):3541-3549.

Pruitt, K.; Zinn, R.L.; Ohm, J.E.; McGarvey, K.M.; Kang, S.H.; Watkins, D.N.; Herman, J.G.; Baylin, S.B. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2006 Mar;2(3):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. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006 Oct;3(10):e420.

Ting, A.H.; Jair, K.W.; Schuebel, K.E.; Baylin, S.B. Differential requirement for DNA methyltransferase 1 in maintaining human cancer cell gene promoter hypermethylation. Cancer Res. 2006 Jan 15;66(2):729-735.

Ting, A.H.; McGarvey, K.M.; Baylin, S.B. The cancer epigenome--components and functional correlates. Genes Dev. 2006 Dec 1;20(23):3215-3231.

Biankin, S.A.; Collector, M.I.; Biankin, A.V.; Brown, L.J.; Kleeberger, W.; Devereux, W.L.; Zahnow, C.A.; Baylin, S.B.; Watkins, D.N.; Sharkis, S.J.; Leach, S.D. A histological survey of green fluorescent protein expression in 'green' mice: implications for stem cell research. Pathology. 2007 Apr;39(2):247-251.

Brock, M.V.; Herman, J.G.; Baylin, S.B. Cancer as a manifestation of aberrant chromatin structure. Cancer J. 2007 Jan-Feb;13(1):3-8.

Gibbons, M.C.; Brock, M.; Alberg, A.J.; Glass, T.; LaVeist, T.A.; Baylin, S.; Levine, D.; Fox, C.E. The sociobiologic integrative model (SBIM): enhancing the integration of sociobehavioral, environmental, and biomolecular knowledge in urban health and disparities research. J Urban Health. 2007 Mar;84(2):198-211.

Huang, Y.; Greene, E.; Murray Stewart, T.; Goodwin, A.C.; Baylin, S.B.; Woster, P.M.; Casero, R.A., Jr. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8023-8028.

McGarvey, K.M.; Greene, E.; Fahrner, J.A.; Jenuwein, T.; Baylin, S.B. DNA methylation and complete transcriptional silencing of cancer genes persist after depletion of EZH2. Cancer Res. 2007 Jun 1;67(11):5097-5102.
Ohm, J.E.; Baylin, S.B. Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation? Cell Cycle. 2007 May 2;6(9):1040-1043.

Riojas, M.A.; Guo, M.; Glockner, S.C.; Machida, E.O.; Baylin, S.B.; Ahuja, N. Methylation-Induced Silencing of ASC/TMS1, a Pro-Apoptotic Gene, is a Late-Stage Event in Colorectal Cancer. Cancer Biol Ther. 2007 Aug 3;6(11):1710-1716.

Schuebel, K.E.; Chen, W.; Cope, L.; Glockner, S.C.; Suzuki, H.; Yi, J.M.; Chan, T.A.; Van Neste, L.; Van Criekinge, W.; van den Bosch, S.; van Engeland, M.; Ting, A.H.; Jair, K.; Yu, W.; Toyota, M.; Imai, K.; Ahuja, N.; Herman, J.G.; Baylin, S.B. Comparing the DNA hypermethylome with gene mutations in human colorectal cancer. PLoS Genet. 2007 Sep;3(9):1709-1723.

Zinn, R.L.; Pruitt, K.; Eguchi, S.; Baylin, S.B.; Herman, J.G. 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. 2007 Jan 1;67(1):194-201.

Briggs, K.J.; Corcoran-Schwartz, I.M.; Zhang, W.; Harcke, T.; Devereux, W.L.; Baylin, S.B.; Eberhart, C.G.; Watkins, D.N. Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma. Genes Dev. 2008 Mar 15;22(6):770-785.

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.; Herman, J.G. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med. 2008 Mar 13;358(11):1118-1128.

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.; Baylin, S.B. Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis. PLoS Med. 2008 May 27;5(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.; Ahuja, N. Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia. J Gastrointest Surg. 2008 Oct;12(10):1745-1753.

Gore, S.D.; Baylin, S.B.; Herman, J.G. Histone Deacetylase Inhibitors and Demethylating Agents. In: Vincent T. DeVita, J.; Lawrence, T.S.; Rosenberg, S.A., editors. 8e ed. Vol. 8e, Section 11, DeVita, Hellman and Rosenberg's Cancer: Principles & Practice of Oncology, 8e. York, PA: Lippincott Williams and Wilkins; 2008.

Jiemjit, A.; Fandy, T.E.; Carraway, H.; Bailey, K.A.; Baylin, S.; Herman, J.G.; Gore, S.D. p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage. Oncogene. 2008 Jun 5;27(25):3615-3623.

Licchesi, J.D.; Westra, W.H.; Hooker, C.M.; Machida, E.O.; Baylin, S.B.; Herman, J.G. Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. Carcinogenesis. 2008 May;29(5):895-904.

McGarvey, K.M.; Van Neste, L.; Cope, L.; Ohm, J.E.; Herman, J.G.; Van Criekinge, W.; Schuebel, K.E.; Baylin, S.B. Defining a chromatin pattern that characterizes DNA-hypermethylated genes in colon cancer cells. Cancer Res. 2008 Jul 15;68(14):5753-5759.

O'Hagan, H.M.; Mohammad, H.P.; Baylin, S.B. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet. 2008;4(8):e1000155.

Suzuki, H.; Toyota, M.; Carraway, H.; Gabrielson, E.; Ohmura, T.; Fujikane, T.; Nishikawa, N.; Sogabe, Y.; Nojima, M.; Sonoda, T.; Mori, M.; Hirata, K.; Imai, K.; Shinomura, Y.; Baylin, S.B.; Tokino, T. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer. Br J Cancer. 2008 Mar 25;98(6):1147-1156.

Tiwari, V.K.; Cope, L.; McGarvey, K.M.; Ohm, J.E.; Baylin, S.B. A novel 6C assay uncovers Polycomb-mediated higher order chromatin conformations. Genome Res. 2008 Jul;18(7):1171-1179.

Tiwari, V.K.; McGarvey, K.M.; Licchesi, J.D.; Ohm, J.E.; Herman, J.G.; Schubeler, D.; Baylin, S.B. PcG proteins, DNA methylation, and gene repression by chromatin looping. PLoS Biol. 2008 Dec 2;6(12):2911-2927.

Winter, J.M.; Ting, A.H.; Vilardell, F.; Gallmeier, E.; Baylin, S.B.; Hruban, R.H.; Kern, S.E.; Iacobuzio-Donahue, C.A. Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin Cancer Res. 2008 Jan 15;14(2):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.; Baylin, S.B. Abnormal DNA methylation of CD133 in colorectal and glioblastoma tumors. Cancer Res. 2008 Oct 1;68(19):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.; Baylin, S.B. Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res. 2008 Apr 15;68(8):2764-2772.

Bailey, V.J.; Easwaran, H.; Zhang, Y.; Griffiths, E.; Belinsky, S.A.; Herman, J.G.; Baylin, S.B.; Carraway, H.E.; Wang, T.H. MS-qFRET: a quantum dot-based method for analysis of DNA methylation. Genome Res. 2009 Aug;19(8):1455-1461.

Glockner, S.C.; Dhir, M.; Yi, J.M.; McGarvey, K.E.; Van Neste, L.; Louwagie, J.; Chan, T.A.; Kleeberger, W.; de Bruine, A.P.; Smits, K.M.; Khalid-de Bakker, C.A.; Jonkers, D.M.; Stockbrugger, R.W.; Meijer, G.A.; Oort, F.A.; Iacobuzio-Donahue, C.; Bierau, K.; Herman, J.G.; Baylin, S.B.; Van Engeland, M.; Schuebel, K.E.; Ahuja, N. Methylation of TFPI2 in stool DNA: a potential novel biomarker for the detection of colorectal cancer. Cancer Res. 2009 Jun 1;69(11):4691-4699.

Huang, Y.; Stewart, T.M.; Wu, Y.; Baylin, S.B.; Marton, L.J.; Perkins, B.; Jones, R.J.; Woster, P.M.; Casero, R.A., Jr. Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clin Cancer Res. 2009 Dec 1;15(23):7217-7228.

Mohammad, H.P.; Cai, Y.; McGarvey, K.M.; Easwaran, H.; Van Neste, L.; Ohm, J.E.; O'Hagan, H.M.; Baylin, S.B. Polycomb CBX7 promotes initiation of heritable repression of genes frequently silenced with cancer-specific DNA hypermethylation. Cancer Res. 2009 Aug 1;69(15):6322-6330.

Zhang, Y.; Bailey, V.; Puleo, C.M.; Easwaran, H.; Griffiths, E.; Herman, J.G.; Baylin, S.B.; Wang, T.H. DNA methylation analysis on a droplet-in-oil PCR array. Lab Chip. 2009 Apr 21;9(8):1059-1064.

Bailey, V.J.; Keeley, B.P.; Zhang, Y.; Ho, Y.P.; Easwaran, H.; Brock, M.V.; Pelosky, K.L.; Carraway, H.E.; Baylin, S.B.; Herman, J.G.; Wang, T.H. Enzymatic incorporation of multiple dyes for increased sensitivity in QD-FRET sensing for DNA methylation detection. Chembiochem. 2010 Jan 4;11(1):71-74.

Bailey, V.J.; Zhang, Y.; Keeley, B.P.; Yin, C.; Pelosky, K.L.; Brock, M.; Baylin, S.B.; Herman, J.G.; Wang, T.H. Single-tube analysis of DNA methylation with silica superparamagnetic beads. Clin Chem. 2010 Jun;56(6):1022-1025.

Belinsky, S.A.; Grimes, M.J.; Picchu, M.A.; Michell, H.D.; Stidley, C.A.; Tesfaigzi, Y.; Channel, M.M.; Liu, Y.; Casero, R.A.; Baylin, S.B.; Reed, M.D.; Tellez, C.S.; March, T.H. Targeting the epigenome for lung cancer therapy. Cancer Research. 2010;In Press.
Dhir, M.; Yachida, S.; Van Neste, L.; Glockner, S.C.; Jeschke, J.; Pappou, E.P.; Montgomery, E.A.; Herman, J.G.; Baylin, S.B.; Iacobuzio-Donahue, C.; Ahuja, N. Sessile serrated adenomas and classical adenomas: An epigenetic perspective on premalignant neoplastic lesions of the gastrointestinal tract. Int J Cancer. 2010 Dec 10.

Easwaran, H.P.; Van Neste, L.; Cope, L.; Sen, S.; Mohammad, H.P.; Pageau, G.J.; Lawrence, J.B.; Herman, J.G.; Schuebel, K.E.; Baylin, S.B. Aberrant silencing of cancer-related genes by CpG hypermethylation occurs independently of their spatial organization in the nucleus. Cancer Res. 2010 Oct 15;70(20):8015-8024 NIHMSID # 263537 PMCID Journal: In process.

Johnstone, S.E.; Baylin, S.B. Stress and the epigenetic landscape: a link to the pathobiology of human diseases? Nat Rev Genet. 2010 Nov;11(11):806-812.

Licchesi, J.D.; Van Neste, L.; Tiwari, V.K.; Cope, L.; Lin, X.; Baylin, S.B.; Herman, J.G. Transcriptional regulation of Wnt inhibitory factor-1 by Miz-1/c-Myc. Oncogene. 2010 Nov 4;29(44):5923-5934.

Mali, P.; Chou, B.K.; Yen, J.; Ye, Z.; Zou, J.; Dowey, S.; Brodsky, R.A.; Ohm, J.E.; Yu, W.; Baylin, S.B.; Yusa, K.; Bradley, A.; Meyers, D.J.; Mukherjee, C.; Cole, P.A.; Cheng, L. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells. 2010 Apr;28(4):713-720.

Mohammad, H.P.; Baylin, S.B. Linking cell signaling and the epigenetic machinery. Nat Biotechnol. 2010 Oct;28(10):1033-1038.

Noushmehr, H.; Weisenberger, D.J.; Diefes, K.; Phillips, H.S.; Pujara, K.; Berman, B.P.; Pan, F.; Pelloski, C.E.; Sulman, E.P.; Bhat, K.P.; Verhaak, R.G.; Hoadley, K.A.; Hayes, D.N.; Perou, C.M.; Schmidt, H.K.; Ding, L.; Wilson, R.K.; Van Den Berg, D.; Shen, H.; Bengtsson, H.; Neuvial, P.; Cope, L.M.; Buckley, J.; Herman, J.G.; Baylin, S.B.; Laird, P.W.; Aldape, K. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010 May 18;17(5):510-522.

Ohm, J.E.; Mali, P.; Van Neste, L.; Berman, D.M.; Liang, L.; Pandiyan, K.; Briggs, K.J.; Zhang, W.; Argani, P.; Simons, B.; Yu, W.; Matsui, W.; Van Criekinge, W.; Rassool, F.V.; Zambidis, E.; Schuebel, K.E.; Cope, L.; Yen, J.; Mohammad, H.P.; Cheng, L.; Baylin, S.B. Cancer-related epigenome changes associated with reprogramming to induced pluripotent stem cells. Cancer Res. 2010 Oct 1;70(19):7662-7673.

Tiwari, V.K.; Baylin, S.B. Mapping networks of protein-mediated physical interactions between chromatin elements. Curr Protoc Mol Biol. 2010 Jan;Chapter 21:Unit 21 16 21-13.

Zahnow, C.A.; Baylin, S.B. Epigenetic networks and miRNAs in stem cells and cancer. Mol Cell. 2010 Sep 10;39(5):661-663.

Zhang, W.; Zeng, X.; Briggs, K.J.; Beaty, R.; Simons, B.; Chiu Yen, R.W.; Tyler, M.A.; Tsai, H.C.; Ye, Y.; Gesell, G.S.; Herman, J.G.; Baylin, S.B.; Watkins, D.N. A potential tumor suppressor role for Hic1 in breast cancer through transcriptional repression of ephrin-A1. Oncogene. 2010 Apr 29;29(17):2467-2476

 

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