Germline Genetic Variants and Lung Cancer Survival in African Americans

Abstract

Background: African Americans have the highest lung cancer mortality in the United States. Genome-wide association studies (GWASs) of germline variants influencing lung cancer survival have not yet been conducted with African Americans. We examined five previously reported GWAS catalog variants and explored additional genome-wide associations among African American lung cancer cases.Methods: Incident non-small cell lung cancer cases (N = 286) in the Southern Community Cohort Study were genotyped on the Illumina HumanExome BeadChip. We used Cox proportional hazards models to estimate HRs and 95% confidence intervals (CIs) for overall mortality. Two independent African American studies (N = 316 and 298) were used for replication.Results: One previously reported variant, rs1878022 on 12q23.3, was significantly associated with mortality (HR = 0.70; 95% CI: 0.54-0.92). Replication findings were in the same direction, although attenuated (HR = 0.87 and 0.94). Meta-analysis had a HR of 0.83 (95% CI, 0.71-0.97). Analysis of common variants identified an association between chromosome 6q21.33 and mortality (HR = 0.46; 95% CI, 0.33-0.66).Conclusions: We identified an association between rs1878022 in CMKLR1 and lung cancer survival. However, our results in African Americans have a different direction of effect compared with a prior study in European Americans, suggesting a different genetic architecture or presence of gene-environment interactions. We also identified variants on chromosome 6 within the gene-rich HLA region, which has been previously implicated in lung cancer risk and survival.Impact: We found evidence that inherited genetic risk factors influence lung cancer survival in African Americans. Replication in additional populations is necessary to confirm potential genetic differences in lung cancer survival across populations. Cancer Epidemiol Biomarkers Prev; 26(8); 1288-95. ©2017 AACR.

FIGURE 1

Meta-analysis of Cox proportional hazard results for rs1878022 in the discovery (SCCS, N=275) and replication (KCI/WSU and UCSF, N=312 and 284, respectively) African American studies of non-small cell lung cancer. I² = 0.30; measure of heterogeneity

FIGURE 2

Multivariable Cox proportional hazards results for common SNPs assayed on the Illumina HumanExome BeadChip v1.1 and lung cancer survival among African Americans with NSCLC in the SCCS (N=275). Models are adjusted for age, sex, treatment, stage, and percent African ancestry. Solid black line represents our suggestive significance threshold (p value < 1.0x10⁻⁴). Dashed black line represents a Bonferroni corrected significance threshold (p value < 1.78x10⁻⁶)