Genetic variation at 8q24 as a susceptibility factor for prostate cancer: definitive results from epidemiologic studies?

In this issue of Cancer Research , two epidemiologic studies investigating the association between genetic variants on chromosome 8q24 and prostate cancer are published. The purpose of this editorial is to comment on the importance and implications of these findings and to explain the rationale of the journal for publishing not just one but two epidemiologic studies on 8q24 and prostate cancer. The long arm of chromosome 8, including 8q24, has been the focus of research in prostate cancer for some time. It consistently shows gains in prostate adenocarcinomas, especially in metastatic cases (1), and some groups report that 8q gains are predictive of poor outcome (2, 3). Last year, the 8q24 locus was first observed to be linked to prostate cancer in a large Icelandic family study in a genome-wide linkage scan conducted by Amundadottir et al. (4) at deCODE genetics. When the same group evaluated a large number of microsatellite and insertion/deletion markers around 8q24, they found that the -8 allele at marker DG8S737, an AC dinucleotide repeat located at 8q24.21, was the one that was most strongly associated with prostate cancer in a set of Icelandic cases and population-based controls. Additional work narrowed the area to a single nucleotide polymorphism (SNP; rs1447295), which was found to be associated with a 50% increased risk of prostate cancer, along with a 60% increased risk for the -8 allele, in pooled casecontrol studies of White men from Sweden and the United States. The work conducted by deCODE genetics was impressive for two reasons: (a) the enormous scope of the undertaking, which encompassed genome-wide linkage scanning, SNP discovery, genotyping of a large number of cases and controls for a large number of markers, and also a search for RNA sequences transcribed from this region in prostate and other tissues; and (b) the logical progression of scientific discovery and testing, extending from a family-based linkage study to a single population-based casecontrol study to a replication case-control study in the same country to "validation" case-control studies in populations of other white ethnicities and finally, to a case-control study in another racial group: African-Americans who are disproportionately affected by the burden of prostate cancer. When investigated in an African-American population, a 60% higher odds for the -8 allele was observed but only a 15% higher for the A allele (4). For both variants, the ORs were only marginally stronger for high-grade prostate cancer (Gleason sum 7+ on biopsy) than for low-grade disease. The results of the work conducted by deCODE genetics are notable for the consistency of the findings from study to study and among racial and ethnic groups. A second collaborative group independently pointed to 8q24 using a whole-genome admixture scan off1,600 African-American men with prostate cancer from seven studies, including the Multiethnic Cohort (5). Ancestral admixture scanning involves comparing regions of the genome that contain more or less than the genome-wide average admixture of ancestral DNA markers within cases. The investigators selected genetic markers for which the prevalences differed most greatly between West Africans and Whites of European ancestry. Carrying 8q24 markers that were common for West African ancestry was associated with a higher risk of prostate cancer, especially at a younger age at onset. The investigators also evaluated the -8 allele at DG8S737 and the A allele at rs1447295 in the African-American prostate cancer cases who were diagnosed when they were younger than 72 years old and age-matched controls sampled from the seven studies. They noted no association for either variant after taking into account possible differences between the cases and controls in the extent of West African ancestry. However, when Freedman et al. (5) conducted a case-control study nested in the prospective Multiethnic Cohort, they noted f40% to 50% higher odds of prostate cancer for the A allele at rs1447295 among Japanese Americans, Latino Americans, and European Americans; the association was stronger in Native Hawaiians. The association for the SNP did not differ statistically significantly by grade (Gleason 8+ versus <8). As in the deCODE study, this work done by Freedman et al. (5) was impressive in the breadth of the research approach, using both admixture mapping and a prospective epidemiologic study, and in the extent of the effort involved. What was particularly notable about their results was again the consistency of findings: (a) in the admixture study, the logarithm of odds stayed high after omitting the cases from each study one by one and (b) in the association studies, the odds ratio (OR) for the SNP was elevated in each non– African-American racial/ethnic group. The consistency of the work published by Amundadottir et al. (4) and Freedman et al. (5) provides some evidence that genetic variation at 8q24 is a risk factor for prostate cancer. However, epidemiologic studies need to be interpreted with caution, as there is always room for selection bias, observation bias, chance, and confounding to explain a finding. We believe that the additional evidence from the National Cancer Institute’s Cohort Consortium’s series of nested case-control studies by Schumacher et al. (6) and the Mayo Clinic’s case-control study by Wang et al. (7) strongly confirms the importance of the 8q24 locus as a susceptibility allele for prostate cancer. Furthermore, these two new studies bring additional information about the nature of the association. Editor’s Note: Dr. Platz has published articles with some of the authors of the Schumacher et al. study but has not been involved in any of the work on 8q24 reported by them. Requests for reprints: Elizabeth A. Platz, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Room E6143, 615 North Wolfe Street, Baltimore, MD 21205. Phone: 410-614-9674; Fax: 410-614-2632; E-mail: [email protected]. I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-0737