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^-19), 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.

Keywords: EPIDEMIOLOGY; GASTRIC CANCER; GENETIC POLYMORPHISMS.

Figure 1

Regional plots of association results (A) 5q14.3:88 400 000–89 400 000; (B) 1q22:152 940 379–153 897 376. Association results are based on a trend test in which –log10 p values (y axis, left) were plotted against the chromosomal positions based on hg19 (x axis). All p values were based on the discovery meta-analysis stage 1 data except for three index single-nucleotide polymorphisms (SNPs) (rs7712641 in 1a; rs80142782 and rs4072037 in (B) which were based on all data (stages 1, 2A and 2B). The line graph shows recombination rate (y axis, right). The linkage disequilibrium (LD) (r²) is colour-coded (figure legend) based on estimates from the 1000 Genomes Mar 2012 release Asian (ASN) population. The plots were generated using LocusZoom online version (URLs).

Figure 2

Differential expression of lnc-POLR3G-4 between non-cardia gastric tumour and normal tissue based on a quantitative real-time PCR analysis. X axis is the log₂ of tumour:normal fold change. All 75 pairs were sorted in increasing order of fold change and plotted along the Y axis. Two-thirds of pairs show lower expression in tumour compared with normal, while expression is higher in normal compared with tumour in one-third of pairs. Highlighted in the middle are 15 pairs with fold changes between 0.5 and 2 (or −1 to 1 in log₂ scale). Based on all 75 pairs, the Wilcoxon signed-rank test was P=7.2×10⁻⁴ and the median tumour:normal fold change is 0.3.