Dr. William Isaacs
Genetic Mechanisms of Prostate Cancer Susceptibility
Professor of Urology and Oncology
Ph.D., Johns Hopkins School of Medicine
Postdoctoral Fellow, Johns Hopkins University
University of Iowa
To carry out our studies, we have identified 2,500 families with familial prostate cancer, and from the 200 families most likely to have a hereditary form of this disease, we have obtained DNA samples from both affected and unaffected family members. In a subset of these families, we studied multiple markers on each chromosome to scan each chromosome for evidence of genes causing prostate cancer, using an experimental technique called linkage analysis. This approach has allowed us to identify at least three different regions of the human genome that are likely to harbor genes, that, when altered, strongly contribute to the process of prostate cancer formation. In two of these three regions, on the long arm of chromosome 1 (HPC1), and the short arm of chromosome 8, together with our collaborators at NIH and Wake Forest, we have recently identified genes that are mutated in some of our families, and we think these could be some of the susceptibility genes we are searching for. Interestingly, both genes, RNASEL on chromosome 1, and MSR1 on chromosome 8, are involved in innate immunity and thus implicate genetic variability in this process as a determinant of prostate cancer risk.
As complementary approaches to the use of linkage-based, family studies to find prostate cancer genes, we have initiated studies using single nucleotide polymorphism (SNP) genotyping and cDNA microarray gene expression profiling to examine the role of common DNA sequence variation and consistent gene expression changes, respectively, in prostate cancer development. These approaches, which take advantage of the massive amount of information recently generated by the Human Genome Project, have led to the identification of several genes not previously implicated to play a role in prostate cancer. Interestingly, one of these genes is involved in the metabolism of dietary fatty acids (AMACR), and another is involved in repair of oxidative damage to DNA (hOOG1). We feel that our combination of approaches will provide powerful tools to define and understand the complexities of prostate cancer genetics and allow us to begin the transition to use genetic information to more effectively manage prostate cancer in the clinic.
Sfanos, K.S.; Sauvageot, J.; Fedor, H.L.; Dick, J.D.; De Marzo, A.M.; Isaacs, W.B. A molecular analysis of prokaryotic and viral DNA sequences in prostate tissue from patients with prostate cancer indicates the presence of multiple and diverse microorganisms. Prostate. 2008 Feb 15;68(3):306-320.
Aloia, A.L.; Sfanos, K.S.; Isaacs, W.B.; Zheng, Q.; Maldarelli, F.; De Marzo, A.M.; Rein, A. XMRV: a new virus in prostate cancer? Cancer Res. 2010 Dec 15;70(24):10028-10033.
Elliott, K.S.; Zeggini, E.; McCarthy, M.I.; Gudmundsson, J.; Sulem, P.; Stacey, S.N.; Thorlacius, S.; Amundadottir, L.; Gronberg, H.; Xu, J.; Gaborieau, V.; Eeles, R.A.; Neal, D.E.; Donovan, J.L.; Hamdy, F.C.; Muir, K.; Hwang, S.J.; Spitz, M.R.; Zanke, B.; Carvajal-Carmona, L.; Brown, K.M.; Hayward, N.K.; Macgregor, S.; Tomlinson, I.P.; Lemire, M.; Amos, C.I.; Murabito, J.M.; Isaacs, W.B.; Easton, D.F.; Brennan, P.; Barkardottir, R.B.; Gudbjartsson, D.F.; Rafnar, T.; Hunter, D.J.; Chanock, S.J.; Stefansson, K.; Ioannidis, J.P. Evaluation of association of HNF1B variants with diverse cancers: collaborative analysis of data from 19 genome-wide association studies. PLoS One. 2010;5(5):e10858.
Fujita, K.; Ewing, C.M.; Getzenberg, R.H.; Parsons, J.K.; Isaacs, W.B.; Pavlovich, C.P. Monocyte chemotactic protein-1 (MCP-1/CCL2) is associated with prostatic growth dysregulation and benign prostatic hyperplasia. Prostate. 2010 Apr 1;70(5):473-481.
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. 2010 Aug;42(8):668-675.
Hsu, F.C.; Sun, J.; Zhu, Y.; Kim, S.T.; Jin, T.; Zhang, Z.; Wiklund, F.; Kader, A.K.; Zheng, S.L.; Isaacs, W.; Gronberg, H.; Xu, J. Comparison of two methods for estimating absolute risk of prostate cancer based on single nucleotide polymorphisms and family history. Cancer Epidemiol Biomarkers Prev. 2010 Apr;19(4):1083-1088.
Kim, S.T.; Cheng, Y.; Hsu, F.C.; Jin, T.; Kader, A.K.; Zheng, S.L.; Isaacs, W.B.; Xu, J.; Sun, J. Prostate cancer risk-associated variants reported from genome-wide association studies: meta-analysis and their contribution to genetic Variation. Prostate. 2010 Dec 1;70(16):1729-1738.
Prokunina-Olsson, L.; Fu, Y.P.; Tang, W.; Jacobs, K.B.; Hayes, R.B.; Kraft, P.; Berndt, S.I.; Wacholder, S.; Yu, K.; Hutchinson, A.; Spencer Feigelson, H.; Thun, M.J.; Diver, W.R.; Albanes, D.; Virtamo, J.; Weinstein, S.; Schumacher, F.R.; Cancel-Tassin, G.; Cussenot, O.; Valeri, A.; Andriole, G.L.; Crawford, E.D.; Haiman, C.A.; Henderson, B.E.; Kolonel, L.; Le Marchand, L.; Siddiq, A.; Riboli, E.; Travis, R.; Kaaks, R.; Isaacs, W.B.; Isaacs, S.D.; Gronberg, H.; Wiklund, F.; Xu, J.; Vatten, L.J.; Hveem, K.; Kumle, M.; Tucker, M.; Hoover, R.N.; Fraumeni, J.F., Jr.; Hunter, D.J.; Thomas, G.; Chatterjee, N.; Chanock, S.J.; Yeager, M. Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2. Cancer Epidemiol Biomarkers Prev. 2010 May;19(5):1349-1355.
Xu, J.; Zheng, S.L.; Isaacs, S.D.; Wiley, K.E.; Wiklund, F.; Sun, J.; Kader, A.K.; Li, G.; Purcell, L.D.; Kim, S.T.; Hsu, F.C.; Stattin, P.; Hugosson, J.; Adolfsson, J.; Walsh, P.C.; Trent, J.M.; Duggan, D.; Carpten, J.; Gronberg, H.; Isaacs, W.B. Inherited genetic variant predisposes to aggressive but not indolent prostate cancer. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2136-2140.
Sun, J.; Kader, A.K.; Hsu, F.C.; Kim, S.T.; Zhu, Y.; Turner, A.R.; Jin, T.; Zhang, Z.; Adolfsson, J.; Wiklund, F.; Zheng, S.L.; Isaacs, W.B.; Gronberg, H.; Xu, J. Inherited genetic markers discovered to date are able to identify a significant number of men at considerably elevated risk for prostate cancer. Prostate. 2011 Mar 1;71(4):421-430.