Prostate Cancer Association Studies

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
(No Transcript)
5

• 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

6
(No Transcript)
7
(No Transcript)
8

• 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

9
(No Transcript)
10

• 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

11

• 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)

12

• 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

13
(No Transcript)
14

• 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

15
Admixture mapping identifies 8q24 as a prostate
cancer risk locus in African-American men

• PNAS (2006)

16

• 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

17
(No Transcript)
18
(No Transcript)
19

• 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

20

• 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

21

• 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

22
(No Transcript)
23

• 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

24
Genome-wide association study of prostate cancer
identifies a second risk locus at 8q24

• Nature Genetics (2007)

25

• 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

26
(No Transcript)
27
(No Transcript)
28
(No Transcript)
29
(No Transcript)
30

• 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)

31
(No Transcript)
32

• 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

33
Multiple prostate cancer risk variants on 8q24

• Nature Genetics (2007)

34
(No Transcript)
35

• 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

36

• 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