Prognostic significance of thymidylate synthase polymorphisms in rectal cancer patients treated with neoadjuvant chemoradiotherapy

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Abstract

Aim

There is a lack of prognostic factors of preoperative chemoradiation for locally advanced rectal cancer. Thymidylate synthase (TS) is the most important target of 5-fluorouracil; three main genetic polymorphisms of TS have been described. We analysed the prognostic value of these in patients with locally advanced rectal cancer treated with fluoropyrimidine-based chemoradiation.

Method

Ninety-nine patients treated between November 2001 and March 2009 were included. All were treated by radiotherapy (5040 cGy) and concomitant fluoropyrimidine-based chemotherapy. Three polymorphisms were analysed: (i) a double (2R) or triple (3R) repeat of a 28 base pair (bp) tandem sequence upstream of the ATG codon initiation site in the 5′-terminal regulatory region, (ii) a functional G > C single nucleotide polymorphism present in the second repeat of the 3R alleles and (iii) a 6 bp deletion at nucleotide 1494 in the 3′-untranslated region. DNA was extracted from paraffin-embedded core biopsies taken from the tumour and the genotype was analysed using polymerase chain reaction restriction fragment length polymorphism.

Results

The 6 bp polymorphism was significantly associated with disease-free survival (+ 6 bp/+ 6 bp vs−6 bp/−6 bp, P=>0.032 logistic regression). No differences were found in disease-free survival according to the other polymorphisms studied. No relationship was observed between the different TS genotypes and pathological regression.

Conclusion

The study suggests that the TS 6 bp polymorphism may be a predictor of disease-free survival in patients with locally advanced rectal cancer treated with fluoropyrimidine-based chemoradiation.

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