Cancer Chemother Pharmacol (2009) 63:911–918
DOI 10.1007/s00280-008-0815-6
123
ORIGINAL ARTICLE
The polymorphisms of TS and MTHFR predict survival
of gastric cancer patients treated with Xuorouracil-based
adjuvant chemotherapy in Chinese population
Zhao-Hui Huang · Dong Hua · Li-Hua Li
Received: 22 May 2008 / Accepted: 28 July 2008 / Published online: 15 August 2008
© Springer-Verlag 2008
Abstract
Purpose The aim of this study was to investigate the
association of the thymidylate synthase (TS) and methyl-
enetetrahydrofolate reductase (MTHFR) polymorphisms
with the clinical outcomes of gastric cancer patients treated
with 5-FU-based adjuvant chemotherapy.
Methods One-hundred and sixteen patients with gastric
cancer were treated with 5-FU-based adjuvant chemother-
apy. The TS (a 28-bp tandem repeat polymorphism in the
TS enhancer region (TSER) and a 6 bp deletion/insertion
polymorphism in the 3Ј-untranslated region) and MTHFR
C677T polymorphisms were determined in blood samples
from those patients using PCR and PCR-LDR (ligation
detection reaction) method, respectively.
Results The overall survival (OS) in patients with the TS
ins6/ins6 genotype was signiWcantly shorter than those in
patients with the del6/del6 (P = 0.017) and ins6/del6
(P = 0.022) genotype. The relapse-free survival (RFS) and
OS in patients with the MTHFR C/C genotype were signiW-
cantly worse than those in patients with the T/T or C/T
genotype (P = 0.043 and 0.040, respectively). Cox multi-
variate analysis also showed that patients with the TS ins6/
ins6 genotype have worse OS than patients with the T/T or
C/T genotype (HR = 2.437, P = 0.041), and the MTHFR C/
C genotype was associated with shorter RFS (HR = 1.723,
P = 0.031) and OS (HR = 1.681, P =0.056). No signiWcant
association was found between the TSER polymorphism
and the clinical outcomes (P >0.05).
Conclusion The polymorphisms of TS 3Ј-UTR ins6/del6
and MTHFR C677T appear to be potential prognostic fac-
tors in gastric cancer patients treated with 5-FU-based adju-
vant chemotherapy, which may allow identiWcation of
gastric cancer patients who will beneWt from 5-FU chemo-
therapy.
Keywords Gastric cancer · Adjuvant chemotherapy ·
Polymorphism · 5-Fluorouracil · Thymidylate synthase ·
Methylenetetrahydrofolate reductase
Introduction
Gastric cancer is the fourth most common cancer and the
second most frequent cause of cancer deaths worldwide.
Surgery is the primary modality for managing early-stage
disease. However, even after radical surgery, the majority
of gastric cancer patients develop local or distant recur-
rence [1]. Meta-analyses of adjuvant chemotherapy clinical
trials have conWrmed a survival beneWt in favor of the sys-
temic medical treatment [
2–4]. Despite the development of
new agents, 5-Xuorouracil (5-FU) remains a cornerstone in
the treatment of gastric cancer. However, the response rate
is only approximately 25%, even if supplemented by leuco-
vorin (CF), which improves the eVect of 5-FU. Despite
numerous eVorts on identifying suitable predictive markers,
there is still a lack of accurate markers to discriminate
between the patients who are likely to beneWt from 5-FU
chemotherapy and those who are not [5–8].
As a pyrimidine analog, 5-FU exerts its anti-tumor
eVects through anabolism, which is determined by the rate
Electronic supplementary material The online version of this
article (doi:10.1007/s00280-008-0815-6) contains supplementary
material, which is available to authorized users.
Z.-H. Huang (&) · D. Hua · L.-H. Li
Wuxi Oncology Institute,
The Fourth AYliated Hospital of Suzhou University,
200 Huihe Road, 214062 Wuxi, Jiangsu Province, China
e-mail: hzhwxsy@yahoo.com.cn