Possible Loci Linked to Prostate Cancer

By Angela MarksBiochemistry/Molecular Biology Seminar

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.

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

Clip

Four Areas of the Prostate

Transition Zone Peripheral Zone

Anterior Zone Central Zone

www.prostatematters.com

Factors Increasing Risk of Prostate Cancer

Age Lifestyle Hormones Race

Genetics

Genetic mutations in Prostate Cancer?

Germline mutations Methylation changesLoss of GSTp expressionAndrogen receptor - short . tandem repeats (Xq11-12)Chromosome 16q loss

PTEN 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 repair

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

Future Research

Comparative 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/cgh

Clone those genes to better understand functionWill expand on knowledge of non-hereditary causes of prostate cancerAllow for more accurate diagnoses and better treatments

Genome-wide search for susceptibility loci

ReferencesBarry, 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.

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, 1/99.

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.