Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

Graham Casey, Ph.D.THE CASEYLABORATORYPOSTDOCTORAL FELLOWSMine Cicek, Ph.D.Muzaffer Cicek, Ph.D.Anthony Curran, M.S.Phillippa Neville, Ph.D.LEAD TECHNOLOGISTSarah Plummer, B.S.SENIOR RESEARCHTECHNOLOGISTLisa Krumroy, B.S.RESEARCH TECHNOLOGISTAndrea Moreira, B.S.GRADUATE STUDENTFrederick Schumacher, B.S.COLLABORATORSJames M. Church, M.D. 1Robert W. Haile, Ph.D. 2Eric A. Klein, M.D. 3Noralane M. (Laney) Lindor, M.D. 4Sanford D. Markowitz, Ph.D. 5Nywana Sizemore, Ph.D .6Danny R. Welch, Ph.D. 7John S. Witte, Ph.D. 51Dept. of Colorectal Surgery,CCF2Univ. of Southern California,Los Angeles, CA3Urological Inst., CCF4Mayo Clinic, Rochester, MN5Case Western Reserve Univ.,Cleveland, OH6Dept. of Cancer Biol., CCF7Jake Gittlen Cancer Res. Inst.,Coll. of Med., PennsylvaniaState Univ. Hershey, PAThe overall objectives of our laboratoryare to discern molecular genetic mechanisms of cancer development andmetastasis. Areas of interest include theidentification and characterization of tumorsuppressor genes, gene expression profiling, andcancer genetics-epidemiology studies.An important goal of cancer genetics isthe identification of individuals at increasedrisk for developing the disease. We haverecently mapped a hereditary prostate cancergene to chromosomes 16q23 through wholegenomelinkage analyses and loss-of-heterozygositystudies. Furthermore we have determinedthat tumor aggressiveness may also inpart be genetic, as we have identified two loci,on chromosome 19q13.1 and 7q32-q33, thatalso appear to harbor hereditary prostate cancergenes associated with more aggressive cancer atdiagnosis. We are using a range of molecularapproaches to identify and characterize thesegenes.We are also interested in determining therole of low-penetrance gene mutations in risk ofprostate cancer. We recently determined that asingle common variant of the RNASEL genecalled R462Q is associated with up to 13% ofprostate cancers, making it one of the mostfrequent genetic alterations in any of the commoncancers. Nearly 60% of men in the studypossessed at least one copy of the R462Q variant.Men who inherited only one copy of the varianthad a 50% increased risk of prostate cancer,whereas men who inherited two copies had atwo-fold increased risk of prostate cancer. Thismeans that although the effect of carrying theR462Q variant may be relatively small for anindividual, the effect on men’s health overall isThe Department of Cancer BiologyAnalysis IdentifiesGenetic Alterations ofCommon Human Malignanciesvery large due to the frequency of the R462Q variantin the population.We have also found a correlation between somevariants and more aggressive forms of prostate cancer.We have determined that a variant in the cytochromeP450 gene CYP3A4 is associated with more aggressiveprostate cancer in a case-only study of African-American prostate cancer patients. This result hasparticular relevance as African-American men are notonly more prone to prostate cancer but also todeveloping more aggressive forms of the disease.Mutations in the BRCA1 gene are responsiblefor up to 5% of breast cancers. BRCA1 mutationcarriers appear to have a different prognosis fromnon-BRCA1 breast cancer patients. We havedetermined that breast tumorigenesis in BRCA1mutation carriers occurs by a distinct molecularmechanism from that of age-matched nonfamilialcases. Furthermore, our data suggest that age atdiagnosis, possibly related to menopausal status, maybe an important factor in the expression of specificproteins in breast tumors of BRCA1 mutationcarriers. These results may lead to a better understandingof the underlying mechanisms involved inBRCA1-related tumorigenesis.Metastasis, the spread of the primary tumorto a distant site, is the main cause of death fromcancer. We have applied somatic cell approaches toidentify genes associated with metastasis usingAffymetrix GeneChip arrays. We have been usingthe MDA MB 435 metastasis model system. Acomparison of altered gene expression in metastaticand nonmetastatic cells has yielded a number ofcandidate genes that may function as positive(metastatic oncogenes) or negative (metastasissuppressor genes) regulators of metastasis. Thesecandidate genes are being rigorously examined toconfirm their role in the metastatic process.Paris, P.L., Kupelian, P.A., Hall, J.M., Williams, T.L., Levin, H., Klein, E.A., Casey, G., and J.S. Witte(1999) Association between a CYP3A4 genetic variant and clinical presentation in African-Americanprostate cancer patients. Cancer Epidemiol. Biomarkers Prev. 8:901-905.Paris, P.L., Witte, J.S., Kupelian, P.A. Levin, H., Klein, E.A., Catalona, W.J., and G. Casey (2000)Identification and fine mapping of a region showing a high frequency of allelic imbalance on chromosome16q23.2 that corresponds to a prostate cancer susceptibility locus. Cancer Res. 60:3645-3649.Vaziri, S.A., Krumroy, L.M., Elson, P., Budd, G.T., Darlington, G., Myles, J., Tubbs, R.R., and G. Casey(2001) Breast tumor immunophenotype of BRCA1 mutation carriers is influenced by age at diagnosis.Clin. Cancer Res. 7:1937-1945.Neville, P.J. Conti, D.V. Paris, P.L., Levin, H., Catalona, W.J., Suarez, B.K., Witte, J.S., and G. Casey(2002) Prostate cancer aggressiveness locus on chromosome 7q32-q33 identified by linkage and allelicimbalance studies. Neoplasia 4:424-431.Casey, G., Neville, P.J., Plummer, S.J., Xiang, Y., Krumroy, L.M., Klein, E.A., Catalona, W.J., Nupponen,N., Carpten, J.D., Trent, J.M., Silverman, R.H., and J.S. Witte (2002) RNASEL Arg462Glnvariant is implicated in up to 13% of prostate cancer cases. Nature Genet. 32:581-583.50