TY - JOUR
T1 - Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: Results from the EPIC-EURGAST study
AU - Espinosa-Parrilla, Yolanda
AU - Munoz, Xavier
AU - Bonet, Catalina
AU - Garcia, Nadia
AU - Vencesla, Adoracion
AU - Yiannakouris, Nikos
AU - Naccarati, Alessio
AU - Sieri, Sabina
AU - Panico, Salvatore
AU - Huerta, Jose M.
AU - Barricarte, Aurelio
AU - Menendez, Virginia
AU - Sanchez-Cantalejo, Emilio
AU - Dorronsoro, Miren
AU - Brennan, Paul
AU - Duarte-Salles, Talita
AU - Bueno-de-Mesquita, H. B. (As)
AU - Weiderpass, Elisabete
AU - Lund, Eiliv
AU - Clavel-Chapelon, Francoise
AU - Boutron-Ruault, Marie-Christine
AU - Racine, Antoine
AU - Numans, Mattijs E.
AU - Tumino, Rosario
AU - Canzian, Federico
AU - Campa, Daniele
AU - Sund, Malin
AU - Johansson, Mattias
AU - Ohlsson, Bodil
AU - Lindkvist, Bjorn
AU - Overvad, Kim
AU - Tjonneland, Anne
AU - Palli, Domenico
AU - Travis, Ruth C.
AU - Khaw, Kay-Tee
AU - Wareham, Nick
AU - Boeing, Heiner
AU - Nesi, Gabriella
AU - Riboli, Elio
AU - Gonzalez, Carlos A.
AU - Sala, Nuria
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - gastric adenocarcinoma
KW - miRNA
KW - miRNA cluster
KW - cancer genetic
KW - susceptibility
KW - polymorphisms
KW - tagSNP
KW - posttranscriptional regulation
KW - prospective cohort
U2 - 10.1002/ijc.28850
DO - 10.1002/ijc.28850
M3 - Article
C2 - 24643999
SN - 0020-7136
VL - 135
SP - 2065
EP - 2076
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 9
ER -
