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Graham Casey, Ph.D.
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| Area of general research interest:
Molecular genetic analysis of common human malignancies Current program:
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Brief Description: The overall objectives of the laboratory are to discern molecular genetic mechanisms of cancer development and metastasis. Areas of interest include the identification and characterization of tumor suppressor genes, gene expression profiling, and cancer genetic-epidemiology studies. An important goal of cancer genetics is the identification of individuals at increased risk for developing the disease. Between 5% and 10% of most cancers are hereditary, the result of a genetic predisposition. Whereas some genes for many hereditary cancers such as colon and breast cancers have been identified, gene(s) responsible for the development of hereditary prostate cancer have proven very difficult to identify. We have performed whole genome linkage analyses on over 550 pairs of brothers diagnosed with prostate cancer and have identified several genomic regions linked to prostate cancer incidence. We also identified several regions linked to prostate cancer tumor aggressiveness by also analyzing the similarities in severity of prostate tumors between brothers. We have used complementary molecular approaches and have identified several candidate genes within these regions. Those genes are currently being validated using biochemical and functional analyses. A related prostate cancer project focuses on the identification of high-frequency but low-penetrance gene variants that may more subtly increase cancer risk, rather than the low-frequency, highly penetrant gene mutations described above. In one study, we determined that the presence of a variant of the CYP3A4 gene, a member of the cytochrome P450 family, was associated with the development of more aggressive forms of prostate cancer in African American men. This is particularly significant as African American men are at a higher risk than other ethnic groups for developing not only prostate cancer, but more aggressive forms of the disease. A recent follow up study using a large sib-pair population has shown a similar association with aggressive prostate cancer in Caucasians. This sib-pair population is currently being used to assess the association of genetic variants in a number of candidate genes that may modify prostate cancer risk. The identification of such gene variants should enable us to better predict an individual's risk for developing aggressive forms of prostate cancer and provide insights into treatment. Several genes associated with hereditary forms of colorectal cancer have been identified in recent years, and we are collaborating in a multi-center NIH-supported study of microsatellite instability (MSI) in colon tumors. MSI is a hallmark of hereditary non-polyposis colon cancer (HNPCC) and is associated with mutations in genes involved in DNA mismatch repair. However, MSI also appears to be a feature of approximately 25% of non-familial colorectal cancers that are associated with somatic inactivation of mismatch repair genes by methylation. Importantly, MSI-associated tumors appear to have a different biology and response to chemotherapy and radiation treatment than non-MSI tumors. Goals of this study are to better characterize MSI in colon cancer and determine any association with clinical phenotype. We have initiated a gene discovery program in colorectal cancer, first by subclassifying tumors based upon MSI status, as well as methylation and protein expression of mismatch repair proteins. We are using array-based comparative genomic hybridization (aCGH) approaches to identify genetic changes associated with MSI status, as well as metastatic phenotype. These studies are leading to better approaches to classify colorectal cancer as well as identifying candidate regions containing genes that influence outcome. Metastasis is the spread of the primary tumor to a distant site and is the main cause of death from cancer. The identification of genes involved in cancer metastasis remains a significant challenge. We have been using a model system to identify genes associated with metastasis using Affymetrix GeneChip expression profiling technology. We have used a previously described somatic cell model system of metastasis suppression in which the highly metastatic cancer cell line MDA MB 435 is suppressed for metastatic growth following the introduction of the metastasis suppressor gene BRMS1 (Breast Cancer Metastasis Suppressor 1). A comparison of altered gene expression in metastatic compared with non-metastatic cells has yielded a number of candidate genes that may function as positive (metastasis promoters) or negative (metastasis suppressor) regulators of metastasis. These candidate genes are being rigorously examined to confirm their role in the metastatic process.
Key References: Casey, G., Neville, P.J., Plummer, S.J., Xiang, Z., Krumroy, L.M., Catalona, W.J., Carpten, J.D., Trent, J.M., Silverman, R.H., and Witte, J.S. RNASEL R462Q variant is implicated in up to 13% of prostate cancer cases. Nature Genetics. 32, 581-583, 2002. Neville, P.J. Conti, D.V. Paris, P.L., Levin, H., Catalona, W.J., Suarez, B.K., Witte, J.S., and Casey, G. Prostate cancer aggressiveness locus on chromosome 7q32-q33 identified by linkage and allelic imbalance studies. Neoplasia. 4, 424-431, 2002. Xiang, Y., Wang, Z., Murakami, J., Plummer, S., Klein, E.A., Carpten, J., Trent, J., Isaacs, W., Casey, G., Silverman, R.H. Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2’,5’-oligoadenylates. Cancer Research. 63, 6795-6801, 2003. Casey, G., Lindor, N.M., Papadopoulos, N., Thibodeau, S.N., Moskow, J., et al. Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. JAMA. 293, 799-809, 2005. Lindor N.M., Rabe K, Petersen G, Haile R, Casey G, et al. Lower Cancer Incidence in Amsterdam-I Criteria Families Without Mismatch Repair Deficiency: Familial Colorectal Cancer Type X. JAMA. 293, 1979-1985, 2005. Cicek, M., Fukuyama, R., Sizemore, N., Welch, D.R., and Casey, G. Breast Cancer Metastasis Suppressor 1 (BRMS1) inhibits gene expression by targeting NF-kappaB activity. Cancer Research. 65, 3586-3595, 2005. Casey, G., Neville, P.J., Liu, X., Plummer, S.J., Cicek, M.S., Krumroy, L.M., Curran, A.P., McGreevy, M.R., Catalona W.J., Klein, E.A., and Witte, J.S. Podocalyxin Variants and Risk of Prostate Cancer and Tumor Aggressiveness. Hum. Mol. Genet. 15: 735-741, 2006. Urisman, A., Molinaro, R.J., Fischer, N., Plummer, S.J., Casey, G., et al. Identification of a novel gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathogens. 2: e25, 2006.
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