Thymidylate Synthase Gene Polymorphism Predicts Disease Free Survival in Stage II–III Rectal Adenocarcinoma Patients Receiving Adjuvant 5-FU-based Chemotherapy

Xiaona Su; Songlin Li; Hui Zhang; He Xiao; Chuan Chen; Ge Wang

Disclosures

Chin Clin Oncol. 2019;8(3) 

In This Article

Abstract and Introduction

Abstract

Background: The objective is to investigate whether thymidylate synthase gene TS 5'-UTR polymorphism of peripheral blood mononuclear cells are associated with clinical outcomes of patients with stage II–III rectal adenocarcinoma treated with adjuvant 5-fluorouracil (5-FU) chemotherapy in Chinese population.

Methods: One hundred and seventeen pathologically diagnosed colorectal adenocarcinoma patients with stage II–III, who underwent curative resection and received 5-fluoropyrimidine-based adjuvant chemotherapy were enrolled to this study. The 5'-TSER polymorphisms determined from the peripheral blood mononuclear cells were measured by Direct Sequencing. Kaplan–Meier curves and log-rank tests were used for survival analysis. The independent prognostic factors influencing DFS and OS were estimated by Cox proportional hazards model.

Results: The distribution of TS 5'-UTR polymorphisms ware 2.6% 2R/2R, 31.6% 2R/3R and 65.8% 3R/3R respectively, which was fitted with Hard-Weinberg equilibrium (χ 2=0.345, P=0.558). Stage, N stage, number of mesenteric lymph node metastasis, KPS, and 5'-UTR polymorphisms (2R/2R/2R/3R vs. 3R/3R, P<0.001) were significantly associated with DFS. Meanwhile, gender (female vs. male, P=0.025) and adjuvant radiotherapy (yes vs. no, P=0.025) were significantly associated with OS. Multivariate Cox regression showed that KPS score (HR =0.947, P=0.007), TS 5'-UTR polymorphism (HR =0.455, P=0.004) were independent prognostic factors for DFS. Whereas, KPS score was the only independent prognostic factors for OS (HR =0.910, P=0.005).

Conclusions: TS 5'-UTR tandem repeat polymorphisms had potential utilization for personalized therapy in Chinese population.

Introduction

Colorectal cancer (CRC) is the fifth most common cancer with an estimated 376.3 thousand new diagnosed cases in China and approximately 191.0 thousand deaths during 2015.[1]

The 5-fluorouracil (5-FU)-based adjuvant chemotherapy is the standard treatment for operable CRC patients.[2] Although adjuvant chemotherapy greatly improves disease-free survival (DFS) and overall survival (OS) in the subpopulation of stage II patients with high risk and stage III patients underwent resection and consequent adjuvant chemotherapy, local recurrence or distant metastasis occurs in about 30–50% patients during the course of the disease.[2] Prognostic factor for such patients is a prerequisite for realizing individual therapeutics as to adjuvant chemotherapy. A large number of researches have reported a variety of prognostic factors for DFS and OS in stage II–III CRC such as defective mismatch repair (dMMR),[3] gene expression signature,[4] and histological index.[5]

Besides, pharmacogenetic polymorphism has been attracting attention during the past decade. Thymidylate synthase (TS) is a key rate-limiting enzyme in folate metabolism, participates in DNA synthesis and also serves as the primary molecular target of fluorouracil. Mechanically, TS catalyses the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) to promote DNA synthesis and repair.[6] TS has a 28-bp repeat polymorphism in the 5'-untranslated promoter region (5'-UTR) that has been associated with TS expression.[7] Several studies have shown that TS protein expression and its activity are higher with the increase of number of repeats (from double repeate-2R to triple repeate-3R or higher) in vitro and in vivo.[8–10] However, there were controversies about the prognostic value of TS 5'-UTR tandem repeat polymorphisms for operable CRC patients receiving 5-FU based adjuvant chemotherapy.[11–13]

The present study was undertaken to investigate whether the TS 5'-UTR tandem repeat polymorphisms detected from the peripheral blood mononuclear cells have any prognostic value for DFS and OS in rectal adenocarcinoma patients treated with 5-FU-based adjuvant chemotherapy.

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