Possible Loci Linked to Prostate Cancer

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Possible Loci Linked to Prostate Cancer

• By Angela Marks
• Biochemistry/Molecular Biology Seminar

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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.

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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

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Four Areas of the Prostate
www.prostatematters.com

• Transition Zone
• Peripheral Zone

• Anterior Zone
• Central Zone

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Factors Increasing Risk of Prostate Cancer

• Age
• Lifestyle
• Hormones
• Race
• Genetics

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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)

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• 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

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• PTEN phosphatase functions as a tumor suppressor
  by negatively regulating cell interactions
• Acts as a gate to regulate the movement of
  growth-regulating signals

• GC to AT transition mutation
• Inactivation of p53 results in loss of DNA repair

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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

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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.h
tm, and http//amba.charite.de/cgh
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• 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

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Genome-wide search for susceptibility loci
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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
621416-1424, 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 155(9) 1937-40, 1995.
Joslin Diabetes Center, DNA Core Facility.
Microsatellites. http//core1.joslab.harvard.edu/c
ore/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.
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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_at_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/servi
ce/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.