Comprehensive resequence analysis of a 136 kb region of human chromosome 8q24 associated with prostate and colon cancers

Abstract

Recently, genome-wide association studies have identified loci across a segment of chromosome 8q24 (128,100,000-128,700,000) associated with the risk of breast, colon and prostate cancers. At least three regions of 8q24 have been independently associated with prostate cancer risk; the most centromeric of which appears to be population specific. Haplotypes in two contiguous but independent loci, marked by rs6983267 and rs1447295, have been identified in the Cancer Genetic Markers of Susceptibility project ( http://cgems.cancer.gov ), which genotyped more than 5,000 prostate cancer cases and 5,000 controls of European origin. The rs6983267 locus is also strongly associated with colorectal cancer. To ascertain a comprehensive catalog of common single-nucleotide polymorphisms (SNPs) across the two regions, we conducted a resequence analysis of 136 kb (chr8: 128,473,000-128,609,802) using the Roche/454 next-generation sequencing technology in 39 prostate cancer cases and 40 controls of European origin. We have characterized a comprehensive catalog of common (MAF > 1%) SNPs within this region, including 442 novel SNPs and have determined the pattern of linkage disequilibrium across the region. Our study has generated a detailed map of genetic variation across the region, which should be useful for choosing SNPs for fine mapping of association signals in 8q24 and investigations of the functional consequences of select common variants.

Fig. 1

Coverage distribution within the target region (chr8: 128,473,000–128,609,802). The depth of coverage is calculated based on number of reads that mapped to that position. The X-axis is the relative position from the start of the target region. The colored horizontal bars at lower portion of the plot indicate the position of the amplicons from long range PCR (Supplementary Table 1)

Fig. 2

Distribution of minor allele frequencies for newly discovered and previously reported SNPs

Fig. 3

Minor allele frequency estimations for 442 polymorphic novel SNPs and 562 SNPs that had previously been reported in dbSNP across the 8q24 region

Fig. 4

Completion rates per locus and per sample

Fig. 5

Refinement of linkage disequilibrium among SNPs > 0.05 MAF across the 8q24 region, with approximate positions of SNPs that have been implicated in prostate cancer risk: rs6983267, rs1447295, and rs4242382 are denoted by arrows (from left to right, respectively)

Fig. 6

Best SNP from centromeric region (rs6983267), conservation, regulatory potential, and enhancer element probabilities. Vista enhancer tracks are shown on the UCSC browser. The level of conservation is displayed on the vertical axis. Scores for regulatory potential compare frequencies of short alignment patterns between known regulatory elements and neutral DNA. They are computed from human, chimp, macaque, mouse, rat, dog, and cow alignments (King et al. 2005). The location of rs6983267 is indicated with a red line