Genome-wide association study for germline prognostic markers in colorectal cancer.

Abstract

3514 Background: Individual variation in colorectal cancer (CRC) survival may in part be explained by germline determinants. To date, the literature investigating such effects is sparse, and the few associations described weak. We performed a genome-wide association study (GWAS) to determine the impact of germline variation on CRC survival. Methods: 947 patients in the VICTOR trial with stage 2 or 3 CRC were typed at autosomal 309,200 SNPs on Illumina Hap300 BeadChips (Illumina Inc., San Diego). Survival analysis was performed using Cox regression. After excluding noninformative SNPs and those with a minor allele frequency (MAF) <0.12, 25 SNPs with the lowest p value (range 9.19e-08 to 1.46e-05) and 15 SNPs with p<1e-04 and a suggestive functional relevance based on the nearest gene were typed in 3 further patients sets: 561 Scottish population-based patients (S, 33 SNPs) and 1,251 patients enrolled in PETACC 2 (P, 33 SNPs), 401 Danish population-based patients (D, 10 SNPs); all had stage 2 and 3 CRC. The replication HR were stage adjusted and meta-analyzed using a fixed effects model. The significance threshold was p<0.01. This study had 80% power to detect HR=1.5. Results: One SNP reached statistical significance at the prespecified level in meta-analysis of the replication sets with p = 8.54e-03, HR = 1.46 (95% CI 1.10-1.94), and no evidence of statistical heterogeneity (I2 = 0%, p=0.856). This SNP was not significant in any of the individual replication sets, but effect size and direction was similar in all three cohorts: HR = 1.27 (S), HR = 1.55 (P), HR = 1.41 (D). The data are most consistent with a multiplicative model with a detrimental interaction in the minor allele homozygotes (MAF = 25.9%). It lies on chromosome 2, near ACTR2 involved in cell shape and motility, and the process of invasion. No previously described germline determinants were replicated. Conclusions: This GWAS for prognosis in stage II and III CRC is the first in CRC and largest in any tumour type. It supports an effect of germline genetic variation on prognosis in this setting, but very large effects (HR ≥ 2.0) seem unlikely. The study was underpowered to detect lesser effects and further work will explore these in larger cohorts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer