Exome-Wide Association Study Identifies Low-Frequency Coding Variants in 2p23.2 and 7p11.2 Associated with Survival of Non–Small Cell Lung Cancer Patients

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A growing body of evidence has suggested that low-frequency or rare coding variants might have strong effects on the development and prognosis of cancer. Here, we aim to assess the role of low-frequency and rare coding variants in the survival of NSCLC in Chinese populations.


We performed an exome-wide scan of 247,870 variants in 1008 patients with NSCLC and replicated the promising variants by using imputed genotype data of The Cancer Genome Atlas (TCGA) with a Cox regression model. Gene-based and pathway-based analysis were also performed for nonsynonymous or splice site variants. Additionally, analysis of gene expression data in the TCGA was used to increase the reliability of candidate loci and genes.


A low-frequency missense variant in chaperonin containing TCP1 subunit 6A gene (CCT6A) (rs33922584: adjusted hazard ratio [HRadjusted] = 1.75, p = 6.06 × 10-4) was significantly related to the survival of patients with NSCLC, which was further replicated by the TCGA samples (HRadjusted = 4.19, p = 0.015). Interestingly, the G allele of rs33922584 was significantly associated with high expression of CCT6A (p = 0.019) that might induce the worse survival in the TCGA samples (HRadjusted = 1.15, p = 0.047). Besides, rs117512489 in gene phospholipase B1 gene (PLB1) (HR = 2.02, p = 7.28 × 10-4) was also associated with survival of the patients with NSCLC in our samples, but it was supported only by gene expression analysis in the TCGA (HRadjusted = 1.15, p = 0.023). Gene-based and pathway-based analysis revealed a total of 32 genes, including CCT6A and 34 potential pathways might account for the survival of NSCLC, respectively.


These results provided more evidence for the important role of low-frequency or rare variants in the survival of patients with NSCLC.

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