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Prostate Cancer Association Studies

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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  1. Prostate CancerAssociation Studies David Moskowitz

  2. A common variant associated with prostate cancer in European and African populations Nature Genetics (2006)

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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)

  8. 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

  9. 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

  10. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men PNAS (2006)

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 Nature Genetics (2007)

  17. 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

  18. 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%)

  19. 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

  20. Multiple prostate cancer risk variants on 8q24 Nature Genetics (2007)

  21. 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

  22. 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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