Thymidylate synthase haplotype is associated with tumor recurrence in stage II and stage III colon cancer.
BACKGROUND
Tumor recurrence after curative resection is a major problem in the management of colon cancer therapy. Identifying molecular markers for tumor recurrence is critical for successfully selecting patients who are more likely to benefit from adjuvant chemotherapy. We analyzed the value of thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms as a prognostic marker in stage II and stage III colon cancer patients treated with 5-fluorouracil-based adjuvant chemotherapy.


METHODS
Between 1987 and 2007, blood samples were obtained from 197 patients with stage II or stage III colon cancer at medical facilities at the University of Southern California. DNA was extracted from peripheral blood, and the genotypes were analyzed using PCR-restriction fragment length polymorphism technique.


RESULTS
Patients harboring the TS 3RG/+6-bp haplotype were at greatest risk to develop tumor recurrence [relative risk (RR): 2.25; 95% confidence interval (CI): 1.04-4.85; adjusted P value=0.032]. TS enhancer region 3RG alone (RR: 3.48 years; 95% CI: 1.61-7.54; adjusted P value=0.013) or in combination with TS 1494del6 bp (RR: 3.41 years; 95% CI: 1.33-8.75; adjusted P value=0.044) proved to be adverse prognostic markers in both univariate and multivariable analysis.


CONCLUSIONS
'High-expression' variants of TS 2R/3R repeat, TS enhancer region 3R G/C, TS 1494del6 bp, and TS haplotype analysis might help to identify stage II and stage III colon cancer patients who are at great risk of developing tumor recurrence, and also those who are more likely to benefit from 5-fluorouracil-based adjuvant chemotherapy. Larger, independent, prospective studies are, however, needed to confirm and validate our preliminary findings.
Lurje
Georg
G
Division of Medical Oncology, Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California 90033, USA.
Zhang
Wu
W
Yang
Dongyun
D
Groshen
Susan
S
Hendifar
Andrew E
AE
Husain
Hatim
H
Nagashima
Fumio
F
Chang
Heung M
HM
Fazzone
William
W
Ladner
Robert D
RD
Pohl
Alexandra
A
Ning
Yan
Y
Iqbal
Syma
S
El-Khoueiry
Anthony
A
Lenz
Heinz-Josef
HJ
D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D006239:Haplotypes; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D012008:Recurrence; D013940:Thymidylate Synthase / Q000235:genetics*
D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase