Genome-wide association study identifies new prostate cancer susceptibility loci

Abstract

Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P < 0.02) in two published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 × 10(-8)). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 × 10(-9)). The estimated per-allele odds ratios for these loci (1.14 for rs2292884 and 1.17 for rs902774) did not differ between advanced and non-advanced PrCa (case-only test for heterogeneity P= 0.72 and P= 0.61, respectively). Further studies will be needed to assess whether these or other loci are differentially associated with PrCa subtypes.

Figure 1.

Regional association plots of two PrCa loci. (A and B) Plots show the genomic regions of association with overall PrCa risk on chromosome 2q37 (A) and 12q13 (B). Shown are the –log₁₀ association P-values of genotyped (square) and imputed (circle) SNPs in 2782 advanced PrCa cases and 4458 controls in Stage 1. The –log₁₀ association P-values for the index SNP in Stage 1, Stage 2 and combined is shown (diamond). The intensity of red shading indicates the strength of LD with the index SNP. Also shown are the SNP build 36 coordinates in kilobases (kb), recombination rates in centimorgans (cM) per megabase (Mb) (in blue) and genes in the region (in green).

Figure 2.

Comparison of the observed per-allele odds ratio in the BPC3 advanced PrCa GWAS (Stage 1) versus previously reported per-allele odds ratios for 51 of the 57 markers in Supplementary Material, Table S2. (For six markers, a per-allele odds ratio for overall PrCa could not be calculated from published information.) The reference/risk alleles are defined as in Supplementary Material, Table S2. The radius of the plotted point is proportional to the −log₁₀ P-value in the BPC3 GWAS and the center of each point is marked by the region number (Supplementary Material, Table S2). The red highlighted SNPs were originally published as advanced PrCa markers; the blue highlighted SNPs were published in a GWAS conducted among Japanese men (22).