Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study.
СтатьяМногоцентровое исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Espinosa-Parrilla Yolanda, Muñoz Xavier, Bonet Catalina, Garcia Nadia, Venceslá Adoración, Yiannakouris Nikos, Naccarati Alessio, Sieri Sabina, Panico Salvatore, Huerta José M, Barricarte Aurelio, Menéndez Virginia, Sánchez-Cantalejo Emilio, Dorronsoro Miren, Brennan Paul, Duarte-Salles Talita, B As Bueno-de-Mesquita H, Weiderpass Elisabete, Lund Eiliv, Clavel-Chapelon Françoise, Boutron-Ruault Marie-Christine, Racine Antoine, Numans Mattijs E, Tumino Rosario, Canzian Federico, Campa Daniele, Sund Malin, Johansson Mattias, Ohlsson Bodil, Lindkvist Björn, Overvad Kim, Tjønneland Anne, Palli Domenico, Travis Ruth C, Khaw Kay-Tee, Wareham Nick, Boeing Heiner, Nesi Gabriella, Riboli Elio, Gonzalez Carlos A, Sala Núria
Аннотация
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.