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Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: Results from the EPIC-EURGAST study

Espinosa-Parrilla, Yolanda; Munoz, Xavier; Bonet, Catalina; Garcia, Nadia; Vencesla, Adoracion; Yiannakouris, Nikos; Naccarati, Alessio; Sieri, Sabina; Panico, Salvatore and Huerta, Jose M., et al. (2014) In International Journal of Cancer 135(9). p.2065-2076
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... (More)
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. (Less)
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keywords
gastric adenocarcinoma, miRNA, miRNA cluster, cancer genetic, susceptibility, polymorphisms, tagSNP, posttranscriptional regulation, prospective cohort
in
International Journal of Cancer
volume
135
issue
9
pages
2065 - 2076
publisher
John Wiley & Sons
external identifiers
  • wos:000341983700012
  • scopus:84906270676
ISSN
0020-7136
DOI
10.1002/ijc.28850
language
English
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yes
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8a32c273-6119-4a3b-a942-4aab487109ca (old id 4699621)
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2014-11-03 07:21:12
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2017-10-22 03:19:28
@article{8a32c273-6119-4a3b-a942-4aab487109ca,
  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 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.},
  author       = {Espinosa-Parrilla, Yolanda and Munoz, Xavier and Bonet, Catalina and Garcia, Nadia and Vencesla, Adoracion and Yiannakouris, Nikos and Naccarati, Alessio and Sieri, Sabina and Panico, Salvatore and Huerta, Jose M. and Barricarte, Aurelio and Menendez, Virginia and Sanchez-Cantalejo, Emilio and Dorronsoro, Miren and Brennan, Paul and Duarte-Salles, Talita and Bueno-de-Mesquita, H. B. (As) and Weiderpass, Elisabete and Lund, Eiliv and Clavel-Chapelon, Francoise and Boutron-Ruault, Marie-Christine and Racine, Antoine and Numans, Mattijs E. and Tumino, Rosario and Canzian, Federico and Campa, Daniele and Sund, Malin and Johansson, Mattias and Ohlsson, Bodil and Lindkvist, Bjorn and Overvad, Kim and Tjonneland, Anne and Palli, Domenico and Travis, Ruth C. and Khaw, Kay-Tee and Wareham, Nick and Boeing, Heiner and Nesi, Gabriella and Riboli, Elio and Gonzalez, Carlos A. and Sala, Nuria},
  issn         = {0020-7136},
  keyword      = {gastric adenocarcinoma,miRNA,miRNA cluster,cancer genetic,susceptibility,polymorphisms,tagSNP,posttranscriptional regulation,prospective cohort},
  language     = {eng},
  number       = {9},
  pages        = {2065--2076},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Cancer},
  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},
  url          = {http://dx.doi.org/10.1002/ijc.28850},
  volume       = {135},
  year         = {2014},
}