title: Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study.
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.
authors.affiliation: Institut de Biologia Evolutiva, CSIC-Universitat Pompeu Fabra, Departament de Ciències Experimentals i de la Salut, UPF, Barcelona, Spain; Programa de Genética Humana, ICBM, Facultad de Medicina, Universidad de Chile, Santiago de Chile, Chile.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Espinosa-Parrilla
authors.forename: Xavier
authors.initials: X
authors.lastname: Muñoz
authors.forename: Catalina
authors.initials: C
authors.lastname: Bonet
authors.forename: Nadia
authors.initials: N
authors.lastname: Garcia
authors.forename: Adoración
authors.initials: A
authors.lastname: Venceslá
authors.forename: Nikos
authors.initials: N
authors.lastname: Yiannakouris
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.forename: Sabina
authors.initials: S
authors.lastname: Sieri
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: José M
authors.initials: JM
authors.lastname: Huerta
authors.forename: Aurelio
authors.initials: A
authors.lastname: Barricarte
authors.forename: Virginia
authors.initials: V
authors.lastname: Menéndez
authors.forename: Emilio
authors.initials: E
authors.lastname: Sánchez-Cantalejo
authors.forename: Miren
authors.initials: M
authors.lastname: Dorronsoro
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Talita
authors.initials: T
authors.lastname: Duarte-Salles
authors.forename: H
authors.initials: H
authors.lastname: B As Bueno-de-Mesquita
authors.forename: Elisabete
authors.initials: E
authors.lastname: Weiderpass
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Boutron-Ruault
authors.forename: Antoine
authors.initials: A
authors.lastname: Racine
authors.forename: Mattijs E
authors.initials: ME
authors.lastname: Numans
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Daniele
authors.initials: D
authors.lastname: Campa
authors.forename: Malin
authors.initials: M
authors.lastname: Sund
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.forename: Bodil
authors.initials: B
authors.lastname: Ohlsson
authors.forename: Björn
authors.initials: B
authors.lastname: Lindkvist
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Nick
authors.initials: N
authors.lastname: Wareham
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nesi
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Gonzalez
authors.forename: Núria
authors.initials: N
authors.lastname: Sala
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000235:genetics*; D044465:White People
chemical_list: D014408:Biomarkers, Tumor; C542541:MIRN106 microRNA, human; C543351:MIRN25 microRNA, human; C532045:MIRN29a microRNA, human; C543350:MIRN93 microRNA, human; D035683:MicroRNAs
keywords: cancer genetic susceptibility; gastric adenocarcinoma; miRNA; miRNA cluster; polymorphisms; posttranscriptional regulation; prospective cohort; tagSNP