A Genome‐Wide Association Study of Colorectal Cancer Mortality Outcomes Among Individuals of African and Admixture Ancestry

TL;DR

This study identifies genetic variants linked to colorectal cancer mortality in African Americans, highlighting potential targets for improving outcomes.

Contribution

The first GWAS of CRC mortality in African Americans reveals novel loci associated with mortality risk.

Findings

Two novel LTBP1 loci are associated with higher CRC-specific mortality risk.

A variant in a noncoding RNA gene is linked to lower CRC-specific mortality risk.

A MCTP2 locus is associated with reduced overall mortality risk.

Abstract

African Americans have the highest colorectal cancer (CRC) mortality rates in the United States. We performed the first genome‐wide association study (GWAS) of overall and CRC‐specific mortality among African Americans with incident CRC to identify genetic contributors to CRC outcomes. Participants enrolled in the Southern Community Cohort Study in 2002–2009; incident CRC and mortality were identified via state cancer registries and the National Death Index. SNPs were genotyped across the genome via Illumina platforms and imputed using the Michigan Imputation Server with Minimac4. Associations with mortality were estimated as hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox proportional hazards models, adjusted for age, sex, stage, and five principal components for ancestry. In total, 500 Black‐identifying participants were analyzed, including 316 deaths and 184 CRC‐specific deaths. Two novel loci in linkage disequilibrium (r
2 = 1) within LTBP1 were associated with higher CRC‐specific mortality risk: rs34071846 and rs12712337 (per allele HR: 2.74, CI: 1.91–3.92, p = 3.78 × 10−8). An additional variant mapped to a gene for a noncoding RNA was associated with CRC‐specific mortality: rs10103953 (per allele HR: 0.52, CI: 0.42–0.66, p = 2.03 × 10−8). One loci mapping to MCTP2 was associated with lower overall mortality risk: rs7171579 (per allele HR: 0.59, CI: 0.50–0.71, p = 2.13 × 10−8). In conclusion, evidence from the present study supports LTBP1 and MCTP2 as important to CRC mortality.

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