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.

Genetic association of gastric cancer with miRNA clusters including the cancer-related genesMIR29, MIR25, MIR93andMIR106: Results from the EPIC-EURGAST study / Yolanda Espinosa-Parrilla;Xavier Mu?oz;Catalina Bonet;Nadia Garcia;Adoraci?n Vencesl?;Nikos Yiannakouris;Alessio Naccarati;Sabina Sieri;Salvatore Panico;Jos? M. Huerta;Aurelio Barricarte;Virginia Men?ndez;Emilio S?nchez-Cantalejo;Miren Dorronsoro;Paul Brennan;Talita Duarte-Salles;H. Bas Bueno-de-Mesquita;Elisabete Weiderpass;Eiliv Lund;Fran?oise Clavel-Chapelon;Marie-Christine Boutron-Ruault;Antoine Racine;Mattijs E. Numans;Rosario Tumino;Federico Canzian;Daniele Campa;Malin Sund;Mattias Johansson;Bodil Ohlsson;Bj?rn Lindkvist;Kim Overvad;Anne Tj?nneland;Domenico Palli;Ruth C. Travis;Kay-Tee Khaw;Nick Wareham;Heiner Boeing;Gabriella Nesi;Elio Riboli;Carlos A. Gonzalez;N?ria Sala. - In: INTERNATIONAL JOURNAL OF CANCER. - ISSN 0020-7136. - ELETTRONICO. - (2014), pp. n/a-n/a. [10.1002/ijc.28850]

Genetic association of gastric cancer with miRNA clusters including the cancer-related genesMIR29, MIR25, MIR93andMIR106: Results from the EPIC-EURGAST study

NESI, GABRIELLA;
2014

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.
2014
n/a
n/a
Yolanda Espinosa-Parrilla;Xavier Mu?oz;Catalina Bonet;Nadia Garcia;Adoraci?n Vencesl?;Nikos Yiannakouris;Alessio Naccarati;Sabina Sieri;Salvatore Panico;Jos? M. Huerta;Aurelio Barricarte;Virginia Men?ndez;Emilio S?nchez-Cantalejo;Miren Dorronsoro;Paul Brennan;Talita Duarte-Salles;H. Bas Bueno-de-Mesquita;Elisabete Weiderpass;Eiliv Lund;Fran?oise Clavel-Chapelon;Marie-Christine Boutron-Ruault;Antoine Racine;Mattijs E. Numans;Rosario Tumino;Federico Canzian;Daniele Campa;Malin Sund;Mattias Johansson;Bodil Ohlsson;Bj?rn Lindkvist;Kim Overvad;Anne Tj?nneland;Domenico Palli;Ruth C. Travis;Kay-Tee Khaw;Nick Wareham;Heiner Boeing;Gabriella Nesi;Elio Riboli;Carlos A. Gonzalez;N?ria Sala
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/866801
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