Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies

Abstract

Objective Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer. Design We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages. Results The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 ( per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21×10 −11 ). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC_004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (P wilcoxon signed-rank =7.20×10 −4). We also identified a new signal at the 1q22 locus, rs80142782 ( per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71×10 ), which was independent of the previously reported SNP at the same locus, rs4072037 ( per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28×10 −17 ). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (P conditional =3.47×10 −8). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations. Conclusion These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.

Long noncoding RNA CASC2 predicts the prognosis of glioma patients and functions as a suppressor for gliomas by suppressing Wnt/β-catenin signaling pathway

“…They are involved in the regulation of gene expression at different levels, affecting multiple cellular processes including cell differentiation, stem cell maintenance, and epithelial–mesenchymal transition 3–5. Accumulating evidence has strongly suggested that many lncRNAs function as oncogenes and/or tumor suppressors in tumor initiation and development 6. These findings make those lncRNAs potential diagnostic and therapeutic targets in tumor management.…”

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

“…Gastric cancer risk SNPs were extracted from the original gastric cancer GWAS studies in GWAS Catalog 5, 6, 7, 8, 9, 10, 27. Only 1 SNP was remained when multiple variants were in linkage disequilibrium (LD, r 2  ≥ .8), and the minor‐allele frequency (MAF) should be greater or equal than .05.…”

“…Many genetic variations, most of which are single nucleotide polymorphisms (SNPs), have been detected over the past years by the genome‐wide association studies (GWAS) of gastric cancer 4. These common susceptibility loci included 1q22 ( MUC1 ), 3q13.32 ( ZBTB20 ), 5p13.1 ( PRKAA1 ), 5q14.3 ( lnc‐POLR3G‐4 ), 6p21.1 ( UNC5CL ), 8q24 ( PSCA ), and 10q23 ( PLCE1 ) 5, 6, 7, 8, 9, 10…”

Tipping the Scale Towards Gastric Disease: a Host-Pathogen Genomic Mismatch?

“…Analyzed independently of the colonizing H. pylori , these explain a small proportion of estimated heritability of gastric disease [49]. Based on candidate gene studies, host risk factors for gastric cancer include genes encoding cytokines and cytokine receptors like the interleukin-1 (IL-1) family of cytokines (including IL-1β, IL1RN, IL8 and IL-10), TNF-α, stromal remodeling proteins like matrix metalloproteinases, the MUC1 , PRKAA1 and PTGER4 genes and prostate stem cell antigen (PSCA) that acts as a tumor suppressor gene in gastric pathology [50–55]. In a seminal study by El Omar, et al, specific pro-inflammatory cytokine genotypes were associated with gastric cancer risk, in the setting of H. pylori infection [56].…”