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School of Medicine
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William G. Nelson
Department Affiliation: Primary: Oncology; Secondary: Urology; Pharmacology and Molecular Sciences; Medicine; Pathology; Radiation Oncology and Molecular Radiation Sciences
Joint: Environmental Health Sciences
Degree: M.D., Ph.D., Johns Hopkins University
Rank: Professor and Director
Telephone Number: 410-955-8822
Fax Number: 410-955-6787
School of Medicine Address: Suite 1100 Weinberg Building, 401 N. Broadway Street, Baltimore, MD 21231
Cellular defenses against carcinogens; cellular responses to DNA damage; DNA methylation and epigenetic gene silencing; inflammation and prostatic carcinogenesis.
Normal and neoplastic cells respond to genome integrity threats in a variety of different ways. Furthermore, the nature of these responses are critical both for cancer pathogenesis and for cancer treatment. DNA damaging agents activate several signal transduction pathways in damaged cells which trigger cell fate decisions such as proliferation, genomic repair, differentiation, and cell death. For normal cells, failure of a DNA damaging agent (i.e., a carcinogen) to activate processes culminating in DNA repair or in cell death might promote neoplastic transformation. For cancer cells, failure of a DNA damaging agent (i.e., an antineoplastic drug) to promote differentiation or cell death might undermine cancer treatment.
Our laboratory has discovered the most common known somatic genome alteration in human prostatic carcinoma cells. The DNA lesion, hypermethylation of deoxycytidine nucleotides in the promoter of a carcinogen-defense enzyme gene, appears to result in inactivation of the gene and a resultant increased vulnerability of prostatic cells to carcinogens. Studies underway in the laboratory have been directed at characterizing the genomic abnormality further, and at developing methods to restore expression of epigenetically silenced genes and/or to augment expression of other carcinogen-defense enzymes in prostate cells as prostate cancer prevention strategies.
Another major interest pursued in the laboratory is the role of chronic or recurrent inflammation as a cause of prostate cancer. Genetic studies of familial prostate cancer have identified defects in genes regulating host inflammatory responses to infections. A newly described prostate lesion, proliferative inflammatory atrophy (PIA), appears to be an early prostate cancer precursor. Current experimental approaches feature induction of chronic prostate inflammation in laboratory mice and rats, and monitoring the consequences on the development of PIA and prostate cancer.
- Lee, B.H., Yegnasubramanian, S., Lin, X., Nelson, W.G. Procainamide is a specific inhibitor of DNA methyltransferase 1. J. Biol. Chem. 280(49): 40749-40756, 2005. Pub Med Reference
- Yegnasubramanian, S., Lin, X., Haffner, M.C., De Marzo, A.M., Nelson, W.G. Combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes (COMPARE-MS) for the rapid, sensitive and quantitative detection of DNA methylation. Nucl. Acids Res. 34(3): e19, 2006. Pub Med Reference
- Agoston, A.T., Argani, P., Hicks, J.L., De Marzo, A.M., Nelson, W.G. RB pathway dysregulation causes DNA methyltransferase 1 overexpression in cancer via MAD2-mediated inhibition of the anaphase promoting complex. Am. J. Pathol. 170: 1585-93, 2007. Pub Med Reference
- Yegnasubramanian, S., Haffner, M.C., Zhang, Y., Gurel, B., Cornish, T.C., Wu, Z., Irizarry, R.A., Morgan, J., Hicks, J., DeWeese, T.L., Isaacs, W.B., Bova, G.S., De Marzo, A.M., Nelson, W.G. DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity. Cancer Res. 68: 8954-8967, 2008. Pub Med Reference
- Liu, W., Laitinen, S., Khan, S., Vihinen, M., Kowalski, J., Yu, G., Chen, L., Ewing, C.M., Eisenberger, M.A., Carducci, M.A., Nelson, W.G., Yegnasubramanian, S., Luo, J., Wang, Y., Xu, J., Isaacs, W.B., Visakorpi, T., Bova ,G.S. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 15: 559-65, 2009. Pub Med Reference
- Haffner, M.C., Aryee, M.J., Toubaji, A., Esopi, D.M., Albadine, R., Gurel, B., Isaacs, W.B., Bova, G.S., Liu, W., Xu, J., Meeker, A.K., Netto, G., De Marzo, A.M., Nelson, W.G., Yegnasubramanian, S. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat. Genet. 42(8): 668-75, 2010. Pub Med Reference
- Platz, E.A., Yegnasubramanian, S., Liu, J.O., Chong, C.R., Shim, J.S., Kenfield, S.A., Stampfer, M.J., Willett, W.C., Giovannucci, E., Nelson, W.G. A novel two-stage, transdisciplinary study identifies digoxin as a possible drug for prostate cancer treatment. Cancer Discovery E-pub, 2011
- Yegnasubramanian, S., Wu, Z., Haffner, M.C., Esopi, D., Aryee, M.J., Badrinath, R., He, T.L., Morgan, J.D., Carvalho, B., Zheng, Q., De Marzo, A.M., Irizarry, R.A., Nelson, W.G. Chromosome-wide mapping of DNA methylation patterns in normal and malignant prostate cells reveals pervasive methylation of gene-associated and conserved intergenic sequences. BMC Genomics 12: 313, 2011. Pub Med Reference
Other graduate programs in which Dr. Nelson participates:
Cellular and Molecular Medicine Graduate Program