Shared susceptibility loci at 2q33 region for lung and esophageal cancers in high-incidence areas of esophageal cancer in northern China

Abstract

BackgroundCancers from lung and esophagus are the leading causes of cancer-related deaths in China and share many similarities in terms of histological type, risk factors and genetic variants. Recent genome-wide association studies (GWAS) in Chinese esophageal cancer patients have demonstrated six high-risk candidate single nucleotide polymorphisms (SNPs). Thus, the present study aimed to determine the risk of these SNPs predisposing to lung cancer in Chinese population.MethodsA total of 1170 lung cancer patients and 1530 normal subjects were enrolled in this study from high-incidence areas for esophageal cancer in Henan, northern China. Five milliliters of blood were collected from all subjects for genotyping. Genotyping of 20 high-risk SNP loci identified from genome-wide association studies (GWAS) on esophageal, lung and gastric cancers was performed using TaqMan allelic discrimination assays. Polymorphisms were examined for deviation from Hardy-Weinberg equilibrium (HWE) using Х2 test. Bonferroni correction was performed to correct the statistical significance of 20 SNPs with the risk of lung cancer. The Pearson’s Х2 test was used to compare the distributions of gender, TNM stage, histopathological type, smoking and family history by lung susceptibility genotypes. Kaplan-Meier and Cox regression analyses were carried out to evaluate the associations between genetic variants and overall survival.ResultsFour of the 20 SNPs identified as high-risk SNPs in Chinese esophageal cancer showed increased risk for Chinese lung cancer, which included rs3769823 (OR = 1.26; 95% CI = 1.107–1.509; P = 0.02), rs10931936 (OR = 1.283; 95% CI = 1.100–1.495; P = 0.04), rs2244438 (OR = 1.294; 95% CI = 1.098–1.525; P = 0.04) and rs13016963 (OR = 1.268; 95% CI = 1.089–1.447; P = 0.04). All these SNPs were located at 2q33 region harboringgenes of CASP8, ALS2CR12 and TRAK2. However, none of these susceptibility SNPs was observed to be significantly associated with gender, TNM stage, histopathological type, smoking, family history and overall survival.ConclusionsThe present study identified four high-risk SNPs at 2q33 locus for Chinese lung cancer and demonstrated the shared susceptibility loci at 2q33 region for Chinese lung and esophageal cancers.

The Relationship Between Environmental Exposure and Genetic Architecture of the 2q33 Locus With Esophageal Cancer in South Africa

“…This is the first study to report that SNPs mapping to TRAK2 were significantly associated with ESCC risk in African populations and support previous findings of an association between rs2244438 and ESCC and lung cancer risk in the Chinese (Zhao et al, 2017). The trafficking kinesin-binding protein 2 ( TRAK2 , also known as GRIF-1 ) is a member of a coiled-coil family of proteins with a role in regulating protein and organelle transport in cells (Brickley and Stephenson, 2011).…”

“…In addition, these associations were not strengthened when the analysis was restricted to ever-smokers or alcohol drinkers relative to the full sample. Our findings are suggestive of no gene-environment interactions at the 2q33 locus, which is in line with the lack of interaction with smoking for Chinese lung cancer risk (Zhao et al, 2017). However, the proportion of never-smokers and non-drinkers in the Mixed Ancestry sample was very small, with low power to detect associations in these subgroups.…”

“…This study investigated the association between common genetic polymorphisms at 2q33 and 6p21 and the risk of ESCC in two South African populations. These variants were previously reported to be associated with higher risk for both ESCC and other cancer types in the Chinese population (Shen et al, 2014; Zhang et al, 2017; Zhao et al, 2017). Our analysis revealed three SNPs at 2q33 (rs10931936, rs7578456, rs2244438) that conferred an increased risk of ESCC in the Mixed Ancestry population, thus replicating the association signals identified in the Chinese study (Zhao et al, 2017).…”

“…For the 2q33 locus, we selected five SNPs (rs3769823, rs10931936, rs13016963, rs7578456, and rs2244438) that were significantly associated (p < 0.05) with both esophageal and lung cancer risk in a northern Chinese population (Zhao et al, 2017). For the 6p21 locus, the selected SNPs were those with strongest evidence of association from published studies of ESCC in northern China (Shen et al, 2014; Zhang et al, 2017).…”

“…A recent GWAS in a northern Chinese population identified common genetic variants on chromosome 2q33 that increased the risk for both ESCC and lung cancer (Zhao et al, 2017). These variants are therefore strong candidates for the study of pivotal biological mechanisms and pleiotropic effects associated with carcinogenesis.…”