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Prostate Cancer Association Studies. David Moskowitz. A common variant associated with prostate cancer in European and African populations. Nature Genetics (2006). Allele -8 of microsatellite DG8S737 identified as associated with prostate cancer

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Prostate Cancer Association Studies

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Prostate CancerAssociation Studies

David Moskowitz

A common variant associated with prostate cancer in European and African populations

Nature Genetics (2006)

  • Allele -8 of microsatellite DG8S737 identified as associated with prostate cancer

  • 19% of affected men and 13% overall carry at least one copy

  • In African Americans, 41% of affected men and 30% overall carry at least one copy

  • 600-kb region surrounding DG8S737 was genotyped

  • 53 SNPs and 6 microsatellites identified in relevant LD block

  • 37 of these SNPs were found to be associated with prostate cancer, most significantly allele A of rs1447295

  • Expanded study to new European and European American case, and American control, groups

  • Association replicated for both -8 allele of DG8S737 and A allele of rs1447295, with affected men having much greater frequency of both than controls

  • Risk greatest when individual has both -8 and A alleles

  • Separately, each allele confers significantly increased susceptibility, but are insufficient in fully explaining risk profile

  • Possibly in LD with a third, unidentified risk variant

  • In HapMap YRI sample, aforementioned LD block exhibits more genetic diversity and less overall LD

  • In African Americans, allele -8 was present in 23.4% of men with prostate cancer and in 16.1% of unaffected individuals

  • However, allele A gave a non-significant P-value (.29)

  • Allele -8 is present in even greater frequency in YRI population than in African American sample

  • Population Attributable Risk (PAR) is much higher in African Americans than in Europeans because of greater frequency of -8 allele

  • Study extended to 510 Icelandic men with benign prostatic hyperplasia, but not with prostate cancer, who did not exhibit an increased frequency of either -8 or A alleles

Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men

PNAS (2006)

  • Admixture mapping used since African American population has recent ancestry of both African and European populations

  • 8q24 region identified as having a highly significant association with prostate cancer

  • However, alleles identified in previous study do not fully describe the results of the admixture scan

  • As compared with European chromosomes, African chromosomes are associated with ~1.5-fold increased risk of prostate cancer

  • Almost 50% of all prostate cancer in African Americans is explainable by the presence of at least one African chromosome

  • LOD scores narrow down region in 8q24 containing the disease causing alleles to the 3.8 Mb range between 125.68 and 129.48 Mb

  • This region contains nine genes, but the admixture mapping does not reveal any information as to which may be involved with prostate cancer

  • DG8S737 -8 allele re-tested, given that it might simply have reflected the admixture signal from the surrounding region, resulting in non-significant P-value (.22)

  • Hypothesized that a local rise in African ancestry in 8q24 might have circumstantially associated the -8 allele with prostate cancer

  • Despite A allele of rs1447295 showing statistically significant association with prostate cancer, it does not fully explain the results of the admixture scan

  • Moreover, the relationship between the A allele and Gleason scores was not replicated

Genome-wide association study of prostate cancer identifies a second risk locus at 8q24

Nature Genetics (2007)

  • Genome-wide association study confirmed rs1447295 as a disease causing SNP relevant to prostate cancer

  • New locus at rs6983267 also identified, with an even higher PAR than rs1447295 (21% as opposed to 9%)

  • Overall, the causative allele (G) has a 50% frequency in Europeans

  • No relationship between age and allelic risk was found

  • No relationship between the MYC oncogene and the SNPs was found

  • Although the G allele of rs6983267 confers less risk than does the A allele of rs14417295, it is much more frequent (50% compared to 11%)

  • The alleles investigated do not fully explain the results of the admixture mapping

  • G allele of rs6983267 is present in the YRI population with a frequency of .98

Multiple prostate cancer risk variants on 8q24

Nature Genetics (2007)

  • Region 1 has weak associations in African Americans

  • Risk alleles in region 2 are present with much greater frequency in African American population, which helps to explain the admixture scan

  • Region 2 gives stronger results in younger men

  • Region 3 variants are also much more common in African Americans

  • The three regions independently contribute to risk of prostate cancer

  • Combined, the increase in risk is much greater

  • Still no known effect on any of the surrounding genes

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