Possible Loci Linked to Prostate CancerThe Facts about Prostate CancerThe Prostate GlandFour Areas of the ProstateFactors Increasing Risk of Prostate CancerGenetic mutations in Prostate Cancer?Slide 7Slide 8Possible Germline MutationsFuture ResearchSlide 11Slide 12ReferencesSlide 14Possible Loci Linked to Prostate CancerBy Angela MarksBiochemistry/Molecular Biology SeminarThe Facts about Prostate CancerMost common malignancy among U.S. menEstimated 179,300 new cases in 19991 in 5 lifetime probability of diagnosis in U.S. menAfrican Americans have 34% higher incidence rate and 2 times higher mortality rate than white AmericansAsian men have lowest incidence rateEstimated 37,000 deaths in 1999 in U.S.The Prostate GlandMale sex glandSize of a walnutHelps control urine flow Produces fluid component of semenProduces Prostate Specific Antigen (PSA) and Acid PhosphataseClipFour Areas of the ProstateTransition ZonePeripheral ZoneAnterior ZoneCentral Zonewww.prostatematters.comFactors Increasing Risk of Prostate CancerAgeLifestyleHormonesRaceGeneticsGenetic mutations in Prostate Cancer?Germline mutationsMethylation changesLoss of GSTp expressionAndrogen receptor - short . tandem repeats (Xq11-12)Chromosome 16q lossPTEN mutation (10q23)p53 inactivation (17p)•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•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 repairPossible Germline MutationsHereditary Prostate Cancer 1 gene (HPC1) on chromosome 1q24-q25Predisposing locus for early-onset prostate cancer (PCAP) on 1q42.2-q43Hereditary prostate cancer locus (HPCX) on Xq27-q28Rare PC-Brain Cancer Susceptibility locus (CAPB) on 1q36Future ResearchComparative Genomic Hybridization (CGH)Loss of . Heterozygosity . (LOH)Linkage AnalysisPictures: http://core1.joslab.harvard.edu, http://www.vgl.ucdavis.edu/service/canine/micros.htm, and http://amba.charite.de/cghClone those genes to better understand functionWill expand on knowledge of non-hereditary causes of prostate cancerAllow for more accurate diagnoses and better treatmentsGenome-wide search for susceptibility lociReferencesBarry, 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.orgDahiya, 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, 11/1/97Irvine, 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.ReferencesNavone, 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/[email protected] www.prostatematters.com 1998Pienta, K., Goodson, J., & Esper, P. Epidemiology of Prostate Cancer: Molecular and Environmental Clues. http://www.cancer.med.umich.edu/prostcan/articles/clues.htmlSmith, 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 12/30.97Wolf, G. University Hospital Charite Institute of Pathology. http://amba.charite.de/cgh 1/15/99Xu, J., et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nature Genet 20: 175-179,
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