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Updated: Aug 10, 2026
Multiomics Analysis of TMEM200A as a Pan-Cancer Biomarker
Published on: September 15, 2023
Expression of thymidylate synthase in primary colorectal adenocarcinoma
Jan Lindebjerg1, Jens Nederby Nielsen, Lone Damkier Hoeffding
1Danish Colorectal Cancer Group South, Vejle Hospital, Vejle, Denmark. janlin@vs.vejleamt.dk
Abstract:
Thymidylate synthase (TS) is a key regulatory enzyme in the cellular pathway of de novo pyrimidine synthesis and a target enzyme for 5-fluorouracil (5-FU). Most clinical studies have shown that high levels of TS in tumors are associated with decreased sensitivity to 5-FU treatment. In this study TS expression was assessed at DNA, RNA, and protein levels. The study included 69 tumors from patients with primary colorectal adenocarcinoma. At the DNA level TS enhancer polymorphism was measured on whole blood by PCR. At the RNA level TS mRNA expression was measured on formalin-fixed paraffin-embedded tumor tissue and on fresh-frozen tumor tissue by real-time RT-PCR. Protein expression was assessed by IHC. Correlation was found between TS mRNA expression in fresh-frozen tumor tissue and formalin-fixed paraffin-embedded tissue (R=0.71). TS enhancer 3/3 had significantly higher protein levels as assessed by IHC than the TS enhancer 2/2 (P=0.02), although there was no statistically significant correlation between TS enhancer polymorphism and TS mRNA expression. An interesting observation not previously reported is that the predominant IHC reaction pattern in tumors from patients with the TS enhancer genotype 3/3 is different in tumors from patients with genotypes 2/2 and 2/3. The results indicate that clinical studies of the significance of TS with regard to 5-FU-based chemotherapy should be based on assessment of TS activity at DNA, RNA, and protein levels.
Insights
Assessing thymidylate synthase (TS) at DNA, RNA, and protein levels is crucial for predicting 5-fluorouracil (5-FU) chemotherapy response in colorectal cancer patients. High TS levels often indicate reduced sensitivity to 5-FU.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Thymidylate synthase (TS) is a critical enzyme in pyrimidine synthesis.
- TS is a primary target for 5-fluorouracil (5-FU) chemotherapy.
- Elevated TS expression in tumors typically correlates with diminished 5-FU sensitivity.
Purpose of the Study:
- To investigate thymidylate synthase (TS) expression at DNA, RNA, and protein levels in colorectal adenocarcinoma.
- To explore the correlation between TS enhancer polymorphism and TS expression across different molecular levels.
- To evaluate the clinical significance of multi-level TS assessment for 5-FU chemotherapy response.
Main Methods:
- DNA analysis: Polymerase Chain Reaction (PCR) for TS enhancer polymorphism.
- RNA analysis: Real-time RT-PCR for TS mRNA expression in fresh-frozen and formalin-fixed paraffin-embedded tissues.
- Protein analysis: Immunohistochemistry (IHC) for TS protein expression.
Main Results:
- A strong correlation (R=0.71) was observed between TS mRNA levels in fresh-frozen and formalin-fixed paraffin-embedded tissues.
- TS enhancer genotype 3/3 showed significantly higher protein levels (P=0.02) compared to genotype 2/2 via IHC.
- No significant correlation was found between TS enhancer polymorphism and TS mRNA expression. A novel observation was the distinct IHC reaction pattern based on TS enhancer genotype.
Conclusions:
- Multi-level assessment of thymidylate synthase (TS) at DNA, RNA, and protein levels is recommended for clinical studies evaluating 5-FU chemotherapy.
- TS enhancer polymorphism may influence protein expression and cellular localization, but its direct correlation with mRNA levels needs further investigation.
- Understanding TS expression across molecular levels provides a more comprehensive approach to predicting 5-FU efficacy in colorectal cancer.
