Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies

Abstract

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia

“…1. Specifically, for the VTI1A regional plot, genotypes of 70 SNPs spanning chr10: 114,362,000 - 114,593,000 (UCSC Genome Build hg18) were phased using PHASE v2.1 53 to calculate background recombination rates. The PHASE outcome was used as direct input for the SequenceLDhot program and LD was estimated as r 2 for 70 SNPs within a ∼230 kb region, and a heat map was drawn using the snp.plotter program 54 .…”

PLCE1 mRNA and Protein Expression and Survival of Patients with Esophageal Squamous Cell Carcinoma and Gastric Adenocarcinoma

“…In one study, the rs2274223 G allele (the risk allele from GWAS (6-8,12)) was associated with increased PLCE1 mRNA and protein expression in ESCC tumor tissues and cancer cell lines(26). However, in a second study, the same rs2274223 G allele (the risk allele) showed reduced gene expression (n=39) in ESCC (24).…”

“…A handful of genetic loci associated with risk of ESCC or GC have been identified from genome-wide association studies (6-14). Among them, genetic variants at 10q23 in the phospholipase C epsilon ( PLCE1 ) gene have demonstrated the most consistent and strongest associations with risk of ESCC for Chinese (6-8,12), and also conveyed significant associations with risk of GCA, surpassing genome-wide significance6, offering promise in the further exploration of molecular events of PLCE1 in the development and progression of these cancers.…”

A fast and powerful tree-based association test for detecting complex joint effects in case–control studies

“…The other six tests failed to detect them. Among the three known ESCC-associated regions at 10q23.33, 22q12.1 (Abnet et al, 2010) and 2q33.1 (Abnet et al, 2012), TREAT identified gene HSCB (P ¼ 2:1 Â 10 À6 ) at 22q12.1. In general, the ARTP and AdaJoint tests, each of which found five associated genes that exceeded the genome-wide threshold, appear to have the most success in these three established regions.…”