| Literature DB >> 24643999 |
Yolanda Espinosa-Parrilla1, Xavier Muñoz, Catalina Bonet, Nadia Garcia, Adoración 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 As Bueno-de-Mesquita, Elisabete Weiderpass, Eiliv Lund, Françoise Clavel-Chapelon, Marie-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.
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.Entities:
Keywords: cancer genetic susceptibility; gastric adenocarcinoma; miRNA; miRNA cluster; polymorphisms; posttranscriptional regulation; prospective cohort; tagSNP
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Year: 2014 PMID： 24643999 DOI： 10.1002/ijc.28850
Source DB: PubMed Journal: Int J Cancer ISSN： 0020-7136 Impact factor: 7.396