1. Possible Loci Linked to Prostate Cancer By Angela Marks Biochemistry/Molecular Biology Seminar

2. The Facts about Prostate Cancer • Most common malignancy among U.S. men • Estimated 179,300 new cases in 1999 • 1 in 5 lifetime probability of diagnosis in U.S. men • African Americans have 34% higher incidence rate and 2 times higher mortality rate than white Americans • Asian men have lowest incidence rate • Estimated 37,000 deaths in 1999 in U.S.

3. The Prostate Gland • Male sex gland • Size of a walnut • Helps control urine flow • Produces fluid component of semen • Produces Prostate Specific Antigen (PSA) and Acid Phosphatase

4. Transition Zone Peripheral Zone Anterior Zone Central Zone Four Areas of the Prostate www.prostatematters.com

5. Factors Increasing Risk of Prostate Cancer • Age • Lifestyle • Hormones • Race • Genetics

6. Germline mutations Methylation changes Genetic mutations in Prostate Cancer? • Loss of GSTp expression • Androgen receptor - short . tandem repeats (Xq11-12) • Chromosome 16q loss • PTEN mutation (10q23) • p53 inactivation (17p)

7. Early event in development of prostate cancer • CpG islands within promoter regions and open reading frames of growth regulatory genes • Small polymorphic CAG repeats (microsatellites) associated with transactivation activity • Inverse relationship between CAG repeats and prostate cancer • Glutathione S transferase -pi (GSTp) scavenges free radicals • Loss may be caused by methylation • GSTp absent in almost every prostate tumor • GSTp may be only thing stopping prostate cancer • 16q is sight of tumor suppressor gene, E-cadherin • Loss of E-cad increases disease progression

8. PTEN phosphatase functions as a tumor suppressor by negatively regulating cell interactions • Acts as a gate to regulate the movement of growth-regulating signals • G:C to A:T transition mutation • Inactivation of p53 results in loss of DNA repair

9. Possible Germline Mutations • Hereditary Prostate Cancer 1 gene (HPC1) on chromosome 1q24-q25 • Predisposing locus for early-onset prostate cancer (PCAP) on 1q42.2-q43 • Hereditary prostate cancer locus (HPCX) on Xq27-q28 • Rare PC-Brain Cancer Susceptibility locus (CAPB) on 1q36

10. Future Research • Comparative Genomic Hybridization (CGH) • Loss of . Heterozygosity . (LOH) • Linkage Analysis Pictures: http://core1.joslab.harvard.edu, http://www.vgl.ucdavis.edu/service/canine/micros.htm, and http://amba.charite.de/cgh

11. Clone those genes to better understand function • Will expand on knowledge of non-hereditary causes of prostate cancer • Allow for more accurate diagnoses and better treatments

12. Genome-wide search for susceptibility loci

13. References • Barry, R. et al. Grant proposal. Mayo Clinic. 1998. • Berthon, P. et al. Predisposing Gene for Early-Onset Prostate Cancer, Localized on Chromosome 1q42.2-43. Am J. Hum Genet 62:1416-1424, 1998. • Capcure. The Association for the Cure of Cancer of the Prostate. Http://www.capcure.org • Dahiya, R., et al. High Frequency of Genetic Instability of Microsatellites in Human Prostatic Adenocarcinoma. Int J. Cancer 72: 762-7, 1997. • Gronberg, H., et al. Early Age at Diagnosis in Families Providing Evidence of Linkage to the Heredita Postate Cancer Locus (HPC1) on Chromosome 1. Cancer Research 57, 4707-9, 11/1/97 • Irvine, RA., et al. The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Research 1;55(9): 1937-40, 1995. • Joslin Diabetes Center, DNA Core Facility. Microsatellites. http://core1.joslab.harvard.edu/core/microsats.html. • Kang, HY., et al. Cloning and Characterization of Human Prostate Coactivator ARA54, a Novel Protein that Associates with the Androgen Receptor. J Biol Chem 274(13): 8570-76, 03/26/99. • Li, L., et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943-46, 1997.

14. References • Navone, NM, et al. p53 mutations in prostate cancer bone metastases suggest that selected p53 mutants in th eprimary site define foci with metastatic potential. J Urol 161(1):304-8, 1/99. • Novahealth@earthlink.net www.prostatematters.com 1998 • Pienta, K., Goodson, J., & Esper, P. Epidemiology of Prostate Cancer: Molecular and Environmental Clues. http://www.cancer.med.umich.edu/prostcan/articles/clues.html • Smith, J, et al. Major Susceptibility Locus for Prostate Cancer on Chromosome 1 Suggested by a Genome-Wide Search. Science 274: 1371-4, 11/22/96. • Veterinary Genetics Laboratory, School of Veterinary Medicine University of California, Davis. Microsatellites. http://www.vgl.ucdavis.edu/service/canine/micros.htm 12/30.97 • Wolf, G. University Hospital Charite Institute of Pathology. http://amba.charite.de/cgh 1/15/99 • Xu, J., et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nature Genet 20: 175-179, 1998.