Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.

Author(s): Phipps AI,  Passarelli MN,  Chan AT,  Harrison TA,  Jeon J,  Hutter CM,  Berndt SI,  Brenner H,  Caan BJ,  Campbell PT,  Chang-Claude J,  Chanock SJ,  Cheadle JP,  Curtis KR,  Duggan D,  Fisher D,  Fuchs CS,  Gala M,  Giovannucci EL,  Hayes RB,  Hoffmeister M,  Hsu L,  Jacobs EJ,  Jansen L,  Kaplan R,  Kap EJ,  Maughan TS,  Potter JD,  Schoen RE,  Seminara D,  Slattery ML,  West H,  White E,  Peters U,  Newcomb PA

Journal: Carcinogenesis

Date: 2016 Jan

Major Program(s) or Research Group(s): PLCO

PubMed ID: 26586795

PMC ID: PMC4715234

Abstract: Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest.