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Possible Loci Linked to Prostate Cancer. By Angela Marks Biochemistry/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

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Possible Loci Linked to Prostate Cancer

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Possible Loci Linked to Prostate Cancer

By Angela Marks

Biochemistry/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


Transition Zone

Peripheral Zone

Anterior Zone

Central Zone

Four Areas of the Prostate

www.prostatematters.com


Factors Increasing Risk of Prostate Cancer

  • Age

  • Lifestyle

  • Hormones

  • Race

  • Genetics


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)


  • 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


  • 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 Analysis

Pictures: 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 function

  • Will expand on knowledge of non-hereditary causes of prostate cancer

  • Allow for more accurate diagnoses and better treatments


Genome-wide search for susceptibility loci


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.


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.

  • [email protected] 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.


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