MicroRNA-binding site polymorphisms in genes involved in colorectal cancer etiopathogenesis and their impact on disease prognosis
Language English Country England, Great Britain Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29048575
DOI
10.1093/mutage/gex026
PII: 4555222
Knihovny.cz E-resources
- MeSH
- 3' Untranslated Regions * MeSH
- Ataxia Telangiectasia Mutated Proteins genetics MeSH
- Fluorouracil therapeutic use MeSH
- Genetic Predisposition to Disease * MeSH
- Polymorphism, Single Nucleotide * MeSH
- Colorectal Neoplasms drug therapy genetics metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- RNA, Messenger metabolism MeSH
- MicroRNAs metabolism MeSH
- Poly (ADP-Ribose) Polymerase-1 genetics metabolism MeSH
- Prognosis MeSH
- Adenomatous Polyposis Coli Protein genetics MeSH
- Smad7 Protein genetics MeSH
- Antimetabolites, Antineoplastic therapeutic use MeSH
- Proto-Oncogene Proteins p21(ras) genetics MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Binding Sites MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3' Untranslated Regions * MeSH
- APC protein, human MeSH Browser
- ATM protein, human MeSH Browser
- Ataxia Telangiectasia Mutated Proteins MeSH
- Fluorouracil MeSH
- KRAS protein, human MeSH Browser
- RNA, Messenger MeSH
- MicroRNAs MeSH
- PARP1 protein, human MeSH Browser
- Poly (ADP-Ribose) Polymerase-1 MeSH
- Adenomatous Polyposis Coli Protein MeSH
- Smad7 Protein MeSH
- Antimetabolites, Antineoplastic MeSH
- Proto-Oncogene Proteins p21(ras) MeSH
- SMAD7 protein, human MeSH Browser
According to the Vogelstein's model of colorectal carcinogenesis, genetic variations in highly penetrant genes may be involved in the colorectal cancer (CRC) pathogenesis. Similarly, aberrant function and/or altered expression of microRNAs (miRNAs) often occur in CRC. In this context, polymorphisms in miRNA-binding sites (miRSNPs) may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and increased susceptibility to common diseases. To explore this phenomenon, we have mined the 3' untranslated regions (3'UTRs) of genes known to be frequently mutated in CRC to search for miRSNPs and tested their association with CRC risk and clinical outcome. Eight miRSNPs (rs1804191, rs397768, rs41116 in APC; rs1137918, s227091, rs4585 in ATM; rs712, rs1137282, rs61764370 in KRAS; rs8674 in PARP1 and rs16950113 in SMAD7) were tested for their association with CRC risk in a case-control study (1111 cases and 1469 healthy controls). The role of these miRSNPs was also investigated in relation to clinical outcome on a subset of patients with complete follow-up. rs8679 within PARP1 was associated with CRC risk and patients' survival. In the dominant model, carriers of at least one C allele were at a decreased risk of cancer (P = 0.05). The CC genotype in rs8679 was also associated with an increased risk of recurrence/progression in patients that received 5-FU-based chemotherapy (log-rank test P = 0.03). Carriers of the homozygous variant genotype TT for rs712 in KRAS gene were associated with a decreased risk of rectal cancer (odds ratio (OR) = 0.65, 95% confidence intervals (CI) 0.43-1.00, P = 0.05) while individuals with colon cancer carrying the heterozygous GT genotype showed a longer overall survival (OS) (P = 0.04). We provide the first evidence that variations in potential miRNA-binding target sites in the 3' UTR of PARP1 gene may modulate CRC risk and prognosis after therapy. Further studies are needed to replicate our finding and assess miRSNPs as predictive biomarkers in independent populations.
Department of Biology University of Pisa Via Derna 1 56126 Pisa Italy
Department of Medical Sciences University of Turin Via Verdi 8 10124 Turin Italy
Department of Surgery General University Hospital Prague Prague 12800 Czech Republic
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