Transcript Prostate Cancer - University of Wisconsin–Eau Claire

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
Clip
Male sex gland
Size of a walnut
Helps control urine
flow
Produces fluid
component of semen
Produces Prostate
Specific Antigen (PSA)
and Acid Phosphatase
Four Areas of the Prostate
www.prostatematters.com
Transition Zone
Peripheral Zone
Anterior Zone
Central Zone
Factors Increasing Risk of
Prostate Cancer
Age
Lifestyle
Hormones
Race
Genetics
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)
•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, Ecadherin
•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.