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Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma
T. Kunicka, P. Prochazka, I. Krus, P. Bendova, M. Protivova, S. Susova, V. Hlavac, V. Liska, P. Novak, M. Schneiderova, P. Pitule, J. Bruha, O. Vycital, P. Vodicka, P. Soucek,
Language English Country England, Great Britain
Document type Journal Article
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BioMedCentral
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- MeSH
- CpG Islands MeSH
- Fluorouracil pharmacology MeSH
- Colorectal Neoplasms genetics metabolism mortality pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- DNA Methylation MeSH
- Promoter Regions, Genetic MeSH
- Antimetabolites, Antineoplastic pharmacology MeSH
- Gene Expression Regulation, Neoplastic drug effects MeSH
- Ribonucleoside Diphosphate Reductase genetics metabolism MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Signal Transduction drug effects MeSH
- Neoplasm Staging MeSH
- Gene Expression Profiling * MeSH
- Neoplasm Grading MeSH
- Transcriptome * MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article 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.
Biomedical Centre Medical School Pilsen Charles University Prague Pilsen Czech Republic
Department of Toxicogenomics National Institute of Public Health Prague Czech Republic
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- $a 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.
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