rs12416605:C>T in MIR938 associates with gastric cancer through affecting the regulation of the CXCL12 chemokine gene

Background: MicroRNAs are small regulatory RNAs with important roles in carcinogenesis. Genetic variants in these regulatory molecules may contribute to disease. We aim to identify allelic variants in microRNAs as susceptibility factors to gastric cancer using association studies and functional approaches. Methods: Twenty-one single nucleotide variants potentially functional, because of their location in either the seed, mature or precursor region of 22 microRNAs, were selected for association studies. Genetic association with gastric cancer in 365 cases and 1,284 matched controls (European Prospective Investigation into Cancer and Nutrition Cohort) was analysed using logistic regression. MicroRNA overexpression, transcriptome analysis, and target gene validation experiments were performed for functional studies. Results: rs3746444:T>C, in the seed of MIR499A and mature MIR499B, associated with the cardia adenocarcinoma location; rs12416605:C>T, in the seed of MIR938, associated with the diffuse subtype; and rs2114358:T>C, in the precursor MIR1206, associated with the noncardia phenotype. In all cases, the association was inverse, indicating a protective affect against gastric cancer of the three minor allelic variants. MIR499 rs3746444:T>C and MIR1206 rs2114358:T>C are reported to affect the expression of these miRNAs, but the effect of MIR938 rs12416605:C>T is unknown yet. Functional approaches showed that the expression of MIR938 is affected by rs12416605:C>T and revealed that MIR938 could regulate a subset of cancer-related genes in an allele-specific fashion. Furthermore, we demonstrated that CXCL12, a chemokine participating in gastric cancer metastasis, is specifically regulated by only one of the rs12416605:C>T alleles. Conclusion: rs12416605 appears to be involved in gastric cancer by affecting the regulatory function of MIR938 on genes related to this cancer type, particularly on CXCL12 posttranscriptional regulation.This work was funded by the “Ministerio de Educación, Gobierno de Chile, Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) ‐ Fondo de Fomento al Desarrollo Científico y Tecnológico (FONDECYT regular)” [grant Nº 1170446]; the Spanish “Ministerio de Ciencia e Innovación” [grant BFU2010‐18477]; “the Spanish Ministerio de Economía y Competitividad ‐ Instituto de Salud Carlos III”; the European Regional Development Funds (ERDF/FEDER) ‘A way to build Europe' [grants PI070130 and PI12/01187] and “LaCaixa” Foundation [grant BM06‐130‐0]. We also thank CERCA Program / Generalitat de Catalunya for their institutional support. MRV and DZC were employed by the Fondecyt regular grant 1170446