Prognostic and Predictive Value of Thymidylate Synthase Expression in Colon Cancer

Second Department of Propedeutic Surgery, Medical School, University of Athens, Athens, Greece.
Digestive Diseases and Sciences (Impact Factor: 2.61). 06/2008; 53(5):1289-96. DOI: 10.1007/s10620-007-0008-x
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Thymidylate synthase (TS) is an enzyme responsible for DNA synthesis. Its competitive inhibition constitutes the major mechanism of the antitumor effect of 5-fluorouracil (5-FU) therapy, which significantly improves the survival rate of colon cancer patients. The aim of our study was to examine the clinical importance of TS expression in colon cancer patients and to correlate its expression with various clinicopathological parameters, tumor proliferative capacity, cell cycle-related molecules' expression and patients' survival. Of the 71 colon cancer patients studied, 51 (71.8%) tested positive for TS, with the positive result being statistically significantly correlated with patients' gender (P = 0.012), tumor histological grade (P = 0.032), vascular invasion (P = 0.017) and the expression of cyclin E, pRb and p16 (P = 0.042, P = 0.001 and P = 0.001, respectively). The overall 5-year survival rate was 40% for TS-positive patients and 68.6% for TS-negative ones (P = 0.0134); in patients aged >70 years, this was 30 and 77.8%, respectively (P = 0.0008). In a multivariate analysis of survival, TS expression proved to be of prognostic significance (P = 0.0174). Our findings support evidence for the clinical importance of TS expression in colon cancer patients and define it as an independent prognostic risk factor.

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    • "In spite of the fact that clinicopathological staging separates patients with CRC into groups with distinct outcomes, it provides little information about response to treatment in individual patients (Walther et al, 2009). In an attempt to refine prognostication and predict the benefit derived from systemic treatment, several protein and genetic markers have been evaluated in patients with CRC, including allelic loss of chromosome 18q (Jen et al, 1994; Martinez-Lopez et al, 1998; Ogunbiyi et al, 1998; Popat and Houlston, 2005), absence of the deleted in colorectal carcinoma (DCC) protein (Shibata et al, 1996; Reymond et al, 1998; Popat and Houlston, 2005), decreased SMAD4 mRNA expression (Boulay et al, 2002; Alazzouzi et al, 2005), expression and/or abnormalities of cytoplasmic oncoprotein p53 (TP53) (Sun et al, 1992; Munro et al, 2005; Russo et al, 2005), protein levels and/or gene haplotype of thymidylate synthetase (TYMS) (Popat et al, 2004; Suh et al, 2005; Tsourouflis et al, 2008), microsatellite instability (MSI) (Gryfe et al, 2000; Popat et al, 2005), and chromosomal instability (CIN) (Walther et al, 2008). Nevertheless, none of these biomarkers has been prospectively validated and established so far in clinical practice. "
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    ABSTRACT: L-DOPA decarboxylase (DDC) is an enzyme that catalyses, mainly, the decarboxylation of L-DOPA to dopamine and was found to be involved in many malignancies. The aim of this study was to investigate the mRNA expression levels of the DDC gene and to evaluate its clinical utility in tissues with colorectal adenocarcinoma. Total RNA was isolated from colorectal adenocarcinoma tissues of 95 patients. After having tested RNA quality, we prepared cDNA by reverse transcription. Highly sensitive quantitative real-time PCR method for DDC mRNA quantification was developed using the SYBR Green chemistry. GAPDH served as a housekeeping gene. Relative quantification analysis was performed using the comparative C(T) method (2(-DeltaDeltaC(T))). DDC mRNA expression varied remarkably among colorectal tumours examined in this study. High DDC mRNA expression levels were found in well-differentiated and Dukes' stage A and B tumours. Kaplan-Meier survival curves showed that patients with DDC-positive tumours have significantly longer disease-free survival (P=0.009) and overall survival (P=0.027). In Cox regression analysis of the entire cohort of patients, negative DDC proved to be a significant predictor of reduced disease-free (P=0.021) and overall survival (P=0.047). The results of the study suggest that DDC mRNA expression may be regarded as a novel potential tissue biomarker in colorectal adenocarcinoma.
    British Journal of Cancer 04/2010; 102(9):1384-90. DOI:10.1038/sj.bjc.6605654 · 4.84 Impact Factor
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    • "At the present time, the principal investigations are about TS gene and its protein expression. Although diVerent clinical studies indicate an inverse correlation between the intratumoral TS protein or mRNA expression and patients' survival (Ciaparrone et al. 2006; TsourouXis et al. 2008), in other studies, opposite results have been observed (Inoue et al. 2005). The DPD levels have also been shown to correlate with possible response to 5-FU (Jensen et al. 2007; Tsuji et al. 2004). "
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    ABSTRACT: 5-Fluorouracil (5-FU) is the most commonly used therapeutic agent for colon cancer treatment. Several studies have evaluated in patients with colon cancer, either the role of genes involved in the 5-FU pathway, such as thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) or the role of microsatellite instability (MSI) as prognostic or predictive markers for adjuvant chemotherapy efficacy, with discordant results. In this study we investigated the combined effect of TS, TP, DPD mRNA expression and MSI status in primary tumors of patients with colon cancer, all treated with 5-FU adjuvant therapy. TS, TP and DPD expression levels were investigated by real-time quantitative RT-PCR on RNA extracts from formalin-fixed and paraffin-embedded tissues of 55 patients with colon adenocarcinoma. In the same case study MSI status was assessed on DNA extracts. A higher TS expression was significantly associated with a longer survival for patients with cancers of stage II (P < 0.01), but not for those with stage III (P = 0.68). In addition, in multivariate analysis, a higher TS expression was significantly associated with a decreased risk of death (HR 0.13, 95% CI 0.03-0.59, P < 0.01), while the MSI status did not have effects on patients' survival. This retrospective investigation suggests that TS gene expression at mRNA level can be a useful marker of better survival in patients (especially of those with cancers of stage II) receiving 5-FU adjuvant chemotherapy, independently of the MSI status.
    Journal of Cancer Research and Clinical Oncology 04/2010; 137(2):201-10. DOI:10.1007/s00432-010-0872-1 · 3.08 Impact Factor
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    • "Moreover, the mRNA ratio of microtubule-associated protein 7 (MAP7)/B2M has been suggested as a valuable prognostic marker in patients with stage II colon cancer and as a potential guide for better therapeutic decision-making (Blum et al., 2008). Thymidylate synthase, an enzyme responsible for DNA synthesis , is also a promising tissue biomarker for therapy response, since it is the molecular target of 5-fluorouracil, a chemotherapeutic drug that significantly improves the survival rate of colon cancer patients (Gosens et al., 2008; Tsourouflis et al., 2008). Nevertheless, no established tissue molecular markers for colon cancer have been used so far in clinical practice. "
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    ABSTRACT: Apoptosis is a tightly regulated process that plays a critical role in many biological events. Members of the BCL2 (Bcl-2) family of apoptosis-related genes have been found to be differentially expressed in various malignancies and have been proposed as prognostic tumor biomarkers. We have recently discovered and cloned a new member of the BCL2 gene family, BCL2L12, expressed in colon tissues. Here we have investigated expression of the BCL2L12 gene in colon cancer tissues and assessed its prognostic value. Total RNA was isolated from 96 specimens of malignant colon tissue. After testing the RNA quality, cDNA was prepared by reverse transcription. A highly sensitive real-time PCR method for BCL2L12 mRNA quantification was developed using SYBR Green chemistry. GAPDH served as a housekeeping gene. Relative quantification analysis was performed using the comparative C(T) method (2(-DeltaDeltaCT)). High BCL2L12 expression levels were found in smaller (< or =5 cm, p=0.027) and well-differentiated tumors (p=0.034), as well as in early-stage tumors (p=0.039). Survival analysis demonstrated that patients with BCL2L12-positive colon tumors have significantly longer disease-free survival and overall survival (p=0.015 and p=0.027, respectively). Our results suggest that BCL2L12 gene expression may represent a potential new biomarker for colon cancer.
    Biological Chemistry 10/2008; 389(12):1467-75. DOI:10.1515/BC.2008.173 · 3.27 Impact Factor
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