Lurje Georg, Zhang Wu, Yang Dongyun, Groshen Susan, Hendifar Andrew E, Husain Hatim, Nagashima Fumio, Chang Heung M, Fazzone William, Ladner Robert D, Pohl Alexandra, Ning Yan, Iqbal Syma, El-Khoueiry Anthony, Lenz Heinz-Josef
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.
Pharmacogenet Genomics. 2008 Feb;18(2):161-8. doi: 10.1097/FPC.0b013e3282f4aea6.
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.
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.
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.
'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.
根治性切除术后肿瘤复发是结肠癌治疗管理中的一个主要问题。识别肿瘤复发的分子标志物对于成功选择更可能从辅助化疗中获益的患者至关重要。我们分析了胸苷酸合成酶（TS）和亚甲基四氢叶酸还原酶（MTHFR）基因多态性作为接受基于5-氟尿嘧啶的辅助化疗治疗的II期和III期结肠癌患者预后标志物的价值。
1987年至,2007年间，从南加州大学医学机构的197例II期或III期结肠癌患者中采集血样。从外周血中提取DNA，并使用聚合酶链反应-限制性片段长度多态性技术分析基因型。
携带TS 3RG/+6-bp单倍型的患者发生肿瘤复发的风险最高[相对风险（RR）：2.25；95%置信区间（CI）：1.04-4.85；校正P值=,0.032]。单独的TS增强子区域3RG（RR：3.48年；95%CI：1.61-7.54；校正P值=,0.013）或与TS 1494del6 bp联合（RR：3.41年；95%CI：1.33-8.75；校正P值=,0.044）在单变量和多变量分析中均被证明是不良预后标志物。
TS 2R/3R重复、TS增强子区域3R G/C、TS 1494del6 bp的“高表达”变体以及TS单倍型分析可能有助于识别有高肿瘤复发风险的II期和III期结肠癌患者，以及更可能从基于5-氟尿嘧啶的辅助化疗中获益的患者。然而，需要更大规模、独立的前瞻性研究来证实和验证我们的初步发现。
