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. What's New? Even though deregulation of miRNA expression has been associated with human cancers, the contribution of miRNAs to cancer genetic susceptibility is unclear. Here the authors designed a panel of 133 SNPs tagging 104 candidate miRNA genes and analysed their association with gastric cancer (GC). They describe an unreported significant genetic association of GC with miRNA clusters in chromosomes 7 and X including miR-29, miR-25, miR-93, and miR-106. These miRNAs have been previously involved in the pathophysiology of GC and have functionally validated target genes implicated in cancer-related processes. The data suggest these miRNAs as novel genetic susceptibility factors for GC

Molecular mechanism of myofibroblast formation and strategies for clinical drugs treatments in hypertrophic scars

“…The miR‐29 expression was significantly decreased in skin biopsy samples or the biopsy sample derived fibroblasts cultured in vitro of patients with scleroderma (Tatmatsu‐Rocha et al, ). At the same time, knockdown or downregulation expression of miR‐29 in lung fibroblasts could activate fibrosis‐related genes in vitro (Espinosa‐Parrilla et al, ; Qu, Zhu, Tao, & Zhao, ). More evidence showed that downregulation of miR‐29 in cardiac fibroblasts could induce the expression of fibrosis related genes both in vivo and in vitro, while high expression could inhibit fibrosis (Gao, Qiao, Lu, & Hou, ; Qu et al, ).…”

The correlation of circulating pro‐angiogenic miRNAs’ expressions with disease risk, clinicopathological features, and survival profiles in gastric cancer

“…It is also revealed that miR‐126 facilitates angiogenesis of GC through regulating vascular endothelial growth factor (VEGF) level, which is an important regulator in vasculogenesis 18. These studies indicate that miRNAs are involved in angiogenesis, and aberrant expressions of these miRNAs are associated with etiology and progression in cancers 24, 25, 26, 27, 28. However, the predictive value of angiogenesis‐related miRNAs in GC is rarely reported.…”

aCGH Analysis of Predictive Biomarkers for Response to Bevacizumab plus Oxaliplatin- or Irinotecan-Based Chemotherapy in Patients with Metastatic Colorectal Cancer

“…Overlapping genes found commonly in CNGs of 7q31.2–q32 regions were KCND2 , MIR29A , MIR29B1 , FJ43663 , and MKLN1. MIR29A and MIR29B1 are known as tumor suppressor miRNAs that inhibit the progression of several cancer types and may potentially serve as candidate positive prognostic factors . The intrinsic genes in 8q11.1 are less characterized but may also include unknown prognostic factors (genes) for mCRC .…”