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
Source: PubMed


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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    • "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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    • "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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