Common genetic prostate cancer variant identified

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Jun 19 2006

Prostate cancer (CaP) is a presumed result of both genetic and environmental events.

It is known that a positive family history and African-American ancestry will increase the risk of developing CaP 2-4 fold. This strongly supports a genetic alteration as a significant contributing factor. In the online version of Nature Genetics, the group working under Dr. Kari Stefansson in Iceland has reported a genetic variant on chromosome 8q24.

In the report, 3 genome-wide linkage studies were performed. The first used 1.068 microsatellite markers (repetitive stretches of short DNA sequences that occur in increased numbers in cancer cells) were typed for 871 Icelandic men with CaP that grouped into 323 extended families. This identified a suggestive linkage signal on chromosome 8q24. The researchers genotyped an additional 358 microsatellite markers spanning this region in 869 unrelated men with CaP and 596 population case-controls.

A second group of 422 Icelandic men with CaP and 401 controls was studied and the -8 variant was verified with an OR of 1.72 (p=0.0018). Combining the Icelandic groups demonstrated that the DG8S737 -8 allele variant had a frequency of 13.1% in affected men and 7.8% in controls. This corresponded to a population attributable risk of 11%.

Furthermore, 63 single nucleotide pleomorphisms (SNPs or single nucleotide alterations in a short genetic sequence) were geontyped and 37 were found significantly associated with CaP. Most associated were allele A of SNP rs1447295 (OR=1.72) and this correlated with the DG8S737 -8 allele.

The researchers attempted to replicate the findings in 1.435 unrelated men with CaP and 779 controls from Sweden and 458 European America men with CaP and 247 controls from Chicago. The frequency of the DG8S737 -8 allele variant was greater in affected men than in controls for all groups.

In the final study, 246 African-American men with CaP and 352 controls were genotyped and the frequency of the DG8S737 -8 allele variant was 23.4% in African American men with CaP and 16.1% in controls with an OR of 1.6. Of the SNPs evaluated in this study, rs1447295 gave the lowest, but not significant result suggesting that DG8S737 -8 rather than the SNPs is either itself a functional variant or is tightly associated with a presently unknown risk variant. In African-American men the association for affected individuals was 41% and 30% in the population, with a population attributable risk of 16% that may contribute to the higher incidence of CaP in African-American men.

An analysis of 510 Icelandic men with BPH did not show a significant excess of either the DG8S737 -8 allele or allele A of re1447295.

Reference:

Nat Genet. 2006 Jun;38(6):652-8. Epub 2006 May 7.

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Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA, Sigurdsson A, Benediktsdottir KR, Cazier JB, Sainz J, Jakobsdottir M, Kostic J, Magnusdottir DN, Ghosh S, Agnarsson K, Birgisdottir B, Le Roux L, Olafsdottir A, Blondal T, Andresdottir M, Gretarsdottir OS, Bergthorsson JT, Gudbjartsson D, Gylfason A, Thorleifsson G, Manolescu A, Kristjansson K, Geirsson G, Isaksson H, Douglas J, Johansson JE, Balter K, Wiklund F, Montie JE, Yu X, Suarez BK, Ober C, Cooney KA, Gronberg H, Catalona WJ, Einarsson GV, Barkardottir RB, Gulcher JR, Kong A, Thorsteinsdottir U, Stefansson K