A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21

Abstract

Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.

Low penetrance breast cancer predisposition SNPs are site specific

“…Only one SNP (rs6983267 on 8q24, P \ 5 9 10 -4 ) conferred risk to cancer in two tissue types (CRC and prostate cancer), as previously published [15,16]. Of the remaining 31 SNPs analysed (5 associated with CRC risk, 13 with breast cancer, 13 with prostate cancer), none were significantly associated with cancer risk in another tumour type, either on its own or in combination of those tissue types in which the SNP was not discovered (Supplementary Table 1).…”

“…cancer.gov/: breast study-1,183 postmenopausal cases and 1,185 controls; prostate study-1,177 cases and 1,105 controls) and SNP data from the first phase of our colorectal cancer GWAS (930 familial colorectal tumour cases and 960 controls) [15]. Data from these breast, prostate and colorectal cancer samples were combined with the West of Ireland cohort to derive an overall estimate of cancer risk using a fixed effects model with inverse variance weighting of individual studies.…”

“…A second independent locus within 8q24 conferring prostate cancer risk, rs16901979 (chr8:128,194,098), has been identified [11,12]. Another nearby SNP, rs6983267 (chr8:128,482,237), confers an increased risk of colorectal cancer [15,16] and also confers some independent prostate cancer risk and ovarian cancer risk [17]. The association with prostate cancer is weaker than that with rs1447295 [18], but again independent of both rs1447295 and rs16901979.…”

Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

“…However, recent association studies have shown that common genetic variation in the 8q24 (refs. [4][5][6] ) and 18q21 (SMAD7) 7 regions also contribute to CRC risk. To explore the role of common genetic variation in CRC etiology, we undertook a comprehensive, phased-design genome-wide association scan (GWAS), capitalizing on Scottish population characteristics.…”

The pursuit of genome-wide association studies: where are we now?

“…55,56 Both studies did not identify other SNP associations for colorectal cancer except the 8q24 locus, which was found earlier for prostate cancer. 57,58 In fact, subsequent studies have shown the association of 8q24 with multiple cancers.…”