Novel Risk Associations between microRNA Polymorphisms and Gastric Cancer in a Chilean Population

Abstract

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis.

Keywords: Helicobacter pylori; cag pathogenicity island; gastric cancer; miRNA; polymorphism.

Figure 1

Flowchart of the comparisons among subsets. Dashed lines represent the stratified analysis.

Figure 2

Secondary structure modeling of genetic variants in the pre-miRNAs. The predicted structures of pre-miRNAs with common allele (left) and the variant (right) are shown. A red arrow indicates the position of the allele. The free energies of both alleles are also shown.

Figure 3

Secondary structure modeling of genetic variants in mature miRNAs. (A) The predicted structures of pre-miRNAs with common allele (left) and the variant (right) are shown. A red arrow indicates the position of the allele. The free energies of both alleles are also shown. (B) The sequence of the mature miRNA is shown in bold, and the seed region is underlined.

Figure 4

A heatmap of the most enriched pathways of the eight miRNAs analyzed is shown. A total of 41 pathways were targeted by at least half (50%) of the studied miRNAs. Remarkably, the “gastric cancer” pathway was targeted by six miRNAs. This pathway involved other displayed pathways (***) demonstrating the redundancy of these findings. Adjusted p-value after Bonferroni correction for multiple comparisons.