Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: Results from the EPIC-EURGAST study

Yolanda Espinosa-Parrilla, Xavier Muñoz, Catalina Bonet, Nadia Garcia, Adoraciõn Venceslá, Nikos Yiannakouris, Alessio Naccarati, Sabina Sieri, Salvatore Panico, José M. Huerta, Aurelio Barricarte, Virginia Menéndez, Emilio Sánchez-Cantalejo, Miren Dorronsoro, Paul Brennan, Talita Duarte-Salles, H. B. Bueno-De-Mesquita, Elisabete Weiderpass, Eiliv Lund, Françoise Clavel-ChapelonMarie Christine Boutron-Ruault, Antoine Racine, Mattijs E. Numans, Rosario Tumino, Federico Canzian, Daniele Campa, Malin Sund, Mattias Johansson, Bodil Ohlsson, Björn Lindkvist, Kim Overvad, Anne Tjønneland, Domenico Palli, Ruth C. Travis, Kay Tee Khaw, Nick Wareham, Heiner Boeing, Gabriella Nesi, Elio Riboli, Carlos A. Gonzalez, Núria Sala

Research output: Contribution to journalArticlepeer-review

Abstract

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 × 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 × 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 × 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. What's New? Even though deregulation of miRNA expression has been associated with human cancers, the contribution of miRNAs to cancer genetic susceptibility is unclear. Here the authors designed a panel of 133 SNPs tagging 104 candidate miRNA genes and analysed their association with gastric cancer (GC). They describe an unreported significant genetic association of GC with miRNA clusters in chromosomes 7 and X including miR-29, miR-25, miR-93, and miR-106. These miRNAs have been previously involved in the pathophysiology of GC and have functionally validated target genes implicated in cancer-related processes. The data suggest these miRNAs as novel genetic susceptibility factors for GC.

Original languageEnglish
Pages (from-to)2065-2076
Number of pages12
JournalInternational Journal of Cancer
Volume135
Issue number9
DOIs
Publication statusPublished - Nov 1 2014

Keywords

  • cancer genetic susceptibility
  • gastric adenocarcinoma
  • miRNA
  • miRNA cluster
  • polymorphisms
  • posttranscriptional regulation
  • prospective cohort
  • tagSNP

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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