Multiple regions within 8q24 independently affect risk for prostate cancer

Abstract

After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 × 10 −19 for the strongest Correspondence should be addressed to D.R. (reich@genetics.med.harvard.edu). COMPETING INTERESTS STATEMENTThe authors declare no competing financial interests. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript association, and P < 1.5 × 10 −4 for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.We recently carried out an admixture scan in African Americans with prostate cancer 1 , highlighting a 3.8-Mb region of chromosome 8 (125.68-129.48 Mb in build 35 of the reference sequence) as containing risk alleles that are highly differentiated in frequency between West Africans and European Americans ( Fig. 1a and Supplementary Table 1 online). Independently, another group 2 localized the same region via linkage analysis and identified specific variants in a region spanning from 128.54-128.62 Mb (denoted 'region 1') that were associated with increased risk of prostate cancer. We replicated the associations after genotyping the same variants in independent samples 1 . However, our data and analyses indicated that the variants in region 1 are insufficient to explain the magnitude of the admixture signal in African Americans with prostate cancer.To search for additional variants that might also contribute to risk at 8q24, we selected SNPs to capture common genetic variation across the admixture peak based on data from the International HapMap Project (see Methods). We genotyped a total of 1,521 variants (including the alleles of microsatellite DG8S737) in 1,175 African American affected individuals with age at diagnosis <72 years and 837 African American controls (Table 1). We genotyped the same variants in 465 European American cases and 446 European American controls.Analysis of these data identified a cluster of genetic variants that we denote 'region 2' in a span of linkage disequilibrium from 128.14-128.28 Mb. These variants are hundreds of kilobases away from the region 1 described in ref. 2 , and the strongest single-SNP association is significant at P = 6.5 × 10 −7 (Fig. 1b and Supplementary Table 2 online). We followed up by genotyping the most associated SNPs in additional cases and controls from five populations: African Americans, Japanese Americans, Native Hawaiians, Latinos and European Americans (for a total sample size of 4,266 individuals with prostate cancer and 3,252 controls) (see Methods and Supplementary Table 3 online). Analysis...

Profiling the expression pattern of GPI transamidase complex subunits in human cancer

“…Recent studies have identified multiple regions within 8q24 independently affecting the risk for prostate cancer. 18,19 In this study, we observed that GPAA1, at 8q24, is overexpressed in 41% of prostate cancer tissues. It will be interesting to explore whether the SNPs discovered in 8q24 18,19 affect regulation or transcription of GPAA1.…”

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

“…This may have excluded a genuine second linkage signal, lying nearby, although it is doubtful that signals in such close proximity can be adequately resolved in most studies. However, it is possible that the wide clusters represent multiple co-located genes, as seen in prostate cancer (8q24) [113] and several other diseases. For the moment, we invoke Occam's razor in assuming that, generally, a single cluster represents a single underlying gene, with the linkage signal picked up over a substantial length of the genome.…”

Variants in circadian genes and prostate cancer risk: a population-based study in China

“…Interestingly, the human MYC gene resides close to the 8q24 region that was found to be strongly associated with prostate cancer risk in recent genomewide association studies of prostate cancer. [25][26][27][28] Although no in vivo studies directly assessed the relationship between CRY2 and cancer, it is plausible that variations or mutations of CRY genes may alter cancer risk in a manner similar to that of PER2 because both are negative regulators of the circadian pathway. Since animal studies also suggest that circadian genes may be tumor suppressors, disruptions to human circadian genes might increase cancer risk by interfering with or inhibiting their tumor suppression activity.…”