A Novel apaQTL-SNP for the Modification of Non-Small-Cell Lung Cancer Susceptibility across Histological Subtypes

SIMPLE SUMMARY: Lung cancer is one of the major public health problems in the world. Genetic variation plays an important role in the development of lung cancer. In this study, we screened apaQTL-SNPs that may influence lung cancer development based on a publicly available database. Then we performed a two-stage case-control population susceptibility study. We found a novel apaQTL-SNP, rs10138506, which might affect lung adenocarcinoma (LUAD) risk by modulating the 3′UTR length of CHURC1. At the same time, CHURC1 could function as a suppressor gene in LUAD with APA regulation. Further experiments indicated that CHURC1 has two poly(A) sites (proximal and distal) and different genotypes of rs1127968 which in perfect LD with rs10138506 can mediate changes in the lengths of the 3′UTR of the CHURC1 isoforms by choosing different poly(A) sites. The results of this study may be helpful in providing more genetic basis data for the screening of high-risk populations of lung cancer. ABSTRACT: Background: Alternative polyadenylation (APA) events may be modulated by single nucleotide polymorphisms (SNPs). Therefore, this study aims to evaluate the association between APA quantitative trait loci (apaQTLs)-related SNPs (apaQTL-SNPs) and non-small-cell lung cancer (NSCLC) risk. Methods: APA-related genes associated with NSCLC (LUAD and LUSC) were first identified, and the respective apaQTL-SNPs of those genes were selected. Then, a two-phase case-control study was performed to evaluate the association between candidate apaQTL-SNPs and NSCLC risk. Results: A total of 7 LUAD- and 21 LUSC-associated apaQTL-SNPs were selected. In the first phase, the apaQTL-SNP rs10138506 was significantly associated with LUAD risk (p < 0.05), whereas the other two apaQTL-SNPs (rs1130698 and rs1130719) were significantly associated with LUSC risk (p < 0.05). In the second phase, the variant G allele of rs10138506 was still significantly associated with an increased risk of LUAD (OR = 1.42, 95%CI = 1.02–1.98, p = 0.038). Functional annotation indicated that the variant G allele of rs10138506 was significantly associated with a higher PDUI value of CHURC1. Meanwhile, 3′RACE experiments verified the presence of two poly(A) sites (proximal and distal) in CHURC1, while qRT-PCR results indicated that different genotypes of rs1127968 which, in perfect LD with rs10138506, can mediate changes in the lengths of the 3′UTR of CHURC1 isoforms. Conclusion: The variant G allele of rs10138506 in CHURC1 was correlated with a longer 3′UTR of CHURC1 mRNA and an increased LUAD risk. Further studies should evaluate the interaction between rs10138506 and different 3′UTR lengths of CHURC1 that regulate LUAD development.