Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 135, Issue 9, Pages 2065-2076Publisher
WILEY
DOI: 10.1002/ijc.28850
Keywords
gastric adenocarcinoma; miRNA; miRNA cluster; cancer genetic susceptibility; polymorphisms; tagSNP; posttranscriptional regulation; prospective cohort
Categories
Funding
- Health Research Fund of the Spanish Ministry of Health [PI070130, PI081420, PI12/01187]
- Spanish Ministry of Science and Innovation [BFU2010-18477]
- Fundacio LaCaixa [BM06-130-0]
- European Commission FP5 [QLG1-CT-2001-01049]
- European Comission FP6 (ECNIS Network of Excellence) [FOOD-CT-2005-513 943]
- European Comission FP7 [PIOF-GA-2009-236836]
- Spanish Ministry of Health Network RTICCC [ISCIII RD06/0020/0091]
- AGAUR, Generalitat de Catalunya [2009SGR939]
- Instituto de Salud Carlos III of the National Health System [CA06/0200]
- Spanish Ministry of Science and Innovation (MICINN) [JCI 2010-0836]
- MRC [MC_UU_12015/1] Funding Source: UKRI
- Cancer Research UK [16491, 14136] Funding Source: researchfish
- Medical Research Council [G0401527, G1000143, MC_UU_12015/1, MC_U106179471] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10114, NF-SI-0512-10135] Funding Source: researchfish
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MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value=1.7 x 10(-4); odds ratio, OR=1.72; 95% confidence interval, CI=1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value=5.38 x 10(-3); OR=0.56, 95% CI=0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value=5.40 x 10(-3); OR=1.41, 95% CI=1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.
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