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Slide 1 - Possible Loci Linked to Prostate Cancer By Angela Marks Biochemistry/Molecular Biology Seminar
Slide 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.
Slide 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
Slide 4 - Four Areas of the Prostate Transition Zone Peripheral Zone Anterior Zone Central Zone www.prostatematters.com
Slide 5 - Factors Increasing Risk of Prostate Cancer Age Lifestyle Hormones Race Genetics
Slide 6 - Genetic mutations in Prostate Cancer? Germline mutations Methylation changes Loss of GSTp expression Androgen receptor - short . tandem repeats (Xq11-12) Chromosome 16q loss PTEN mutation (10q23) p53 inactivation (17p)
Slide 7 - Early event in development of prostate cancer CpG islands within promoter regions and open reading frames of growth regulatory genes 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 Small polymorphic CAG repeats (microsatellites) associated with transactivation activity Inverse relationship between CAG repeats and prostate cancer 16q is sight of tumor suppressor gene, E-cadherin Loss of E-cad increases disease progression
Slide 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
Slide 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
Slide 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
Slide 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
Slide 12 - Genome-wide search for susceptibility loci
Slide 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.
Slide 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.