Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma
Jazyk angličtina Země Velká Británie, Anglie Médium electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
27733154
PubMed Central
PMC5062913
DOI
10.1186/s12885-016-2826-8
PII: 10.1186/s12885-016-2826-8
Knihovny.cz E-zdroje
- Klíčová slova
- 5-fluorouracil, Colorectal carcinoma, Expression, Methylation, Prognosis,
- MeSH
- antimetabolity antitumorózní farmakologie MeSH
- CpG ostrůvky MeSH
- fluorouracil farmakologie MeSH
- kolorektální nádory genetika metabolismus mortalita patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metylace DNA MeSH
- promotorové oblasti (genetika) MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- ribonukleosiddifosfátreduktasa genetika metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- signální transdukce účinky léků MeSH
- staging nádorů MeSH
- stanovení celkové genové exprese * MeSH
- stupeň nádoru MeSH
- transkriptom * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antimetabolity antitumorózní MeSH
- fluorouracil MeSH
- ribonucleotide reductase M2 MeSH Prohlížeč
- ribonukleosiddifosfátreduktasa MeSH
BACKGROUND: This study addresses involvement of major 5-fluorouracil (5-FU) pathway genes in the prognosis of colorectal carcinoma patients. METHODS: Testing set and two validation sets comprising paired tumor and adjacent mucosa tissue samples from 151 patients were used for transcript profiling of 15 5-FU pathway genes by quantitative real-time PCR and DNA methylation profiling by high resolution melting analysis. Intratumoral molecular profiles were correlated with clinical data of patients. Protein levels of two most relevant candidate markers were assessed by immunoblotting. RESULTS: Downregulation of DPYD and upregulation of PPAT, UMPS, RRM2, and SLC29A1 transcripts were found in tumors compared to adjacent mucosa in testing and validation sets of patients. Low RRM2 transcript level significantly associated with poor response to the first-line palliative 5-FU-based chemotherapy in the testing set and with poor disease-free interval of patients in the validation set irrespective of 5-FU treatment. UPP2 was strongly methylated while its transcript absent in both tumors and adjacent mucosa. DPYS methylation level was significantly higher in tumor tissues compared to adjacent mucosa samples. Low intratumoral level of UPB1 methylation was prognostic for poor disease-free interval of the patients (P = 0.0002). The rest of the studied 5-FU genes were not methylated in tumors or adjacent mucosa. CONCLUSIONS: The observed overexpression of several 5-FU activating genes and DPYD downregulation deduce that chemotherapy naïve colorectal tumors share favorable gene expression profile for 5-FU therapy. Low RRM2 transcript and UPB1 methylation levels present separate poor prognosis factors for colorectal carcinoma patients and should be further investigated.
3rd Faculty of Medicine Charles University Prague Czech Republic
Biomedical Centre Medical School Pilsen Charles University Prague Pilsen Czech Republic
Department of Toxicogenomics National Institute of Public Health Prague Czech Republic
Toxicogenomics Unit National Institute of Public Health Srobarova 48 100 42 Prague 10 Czech Republic
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