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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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a common variant associated with prostate cancer in european and african populations

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

Nature Genetics (2006)

slide3
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
slide5
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
slide8
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
slide10
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
slide11
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)
slide12
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
slide14
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

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

PNAS (2006)

slide16
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
slide19
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
slide20
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
slide21
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
slide23
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

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

Nature Genetics (2007)

slide25
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
slide30
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%)
slide32
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
slide35
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
slide36
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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