Terrazzino Salvatore, Agostini Marco, Pucciarelli Salvatore, Pasetto Lara Maria, Friso Maria Luisa, Ambrosi Alessandro, Lisi Veronica, Leon Alberta, Lise Mario, Nitti Donato
Research & Innovation (R&I) Company, University of Padua, Padua, Italy.
Pharmacogenet Genomics. 2006 Nov;16(11):817-24. doi: 10.1097/01.fpc.0000230412.89973.c0.
The objective of the present study was to evaluate whether germline methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms as well as polymorphisms in the thymidylate synthase gene promoter, namely the variable number tandem repeat polymorphism (TS VNTR) and the intrarepeat G to C single nucleotide polymorphism (TS SNP), are predictive markers of tumor regression in rectal cancer patients following preoperative chemoradiotherapy.
Blood samples from 125 patients with primary adenocarcinoma of the mid-low rectum who received 5-fluorouracil-based chemotherapy and external beam radiotherapy (median dose 48.4 Gy), 125 patients (women n=45, men n=80; median age 60 years, range 31-79 years) were genotyped. Response to preoperative treatment was evaluated employing the Tumor Regression Grade criteria. On the basis of the pathologic response, patients were classified as responders (TRG 1-2, n=48) and non-responders (TRG 3-5, n=74). Three patients were excluded because of insufficient data.
Among the polymorphic variants examined, the MTHFR 677T-1298A haplotype was, upon univariate analysis, the only variable found associated with tumor regression (P=0.004). Moreover, at multivariate analysis, the MTHFR 677T-1298A haplotype was an independent predictor of tumor regression. Patients not carrying the MTHFR 677T-1298A haplotype (odds ratio 0.29, 95% confidence interval 0.13-0.64, P=0.002) displayed a higher response rate than patients with the MTHFR 677T-1298A haplotype.
Unlike TS VNTR and SNP polymorphisms, MTHFR 677T-1298A haplotype in genomic DNA has the potential to be a predictive marker of tumor response in rectal cancer patients submitted to preoperative chemoradiotherapy.
本研究的目的是评估生殖系亚甲基四氢叶酸还原酶（MTHFR）C677T和A1298C多态性以及胸苷酸合成酶基因启动子中的多态性，即可变数目串联重复多态性（TS VNTR）和重复序列内G到C单核苷酸多态性（TS SNP），是否为直肠癌患者术前放化疗后肿瘤消退的预测标志物。
对125例接受以5-氟尿嘧啶为基础的化疗和外照射放疗（中位剂量48.4 Gy）的中低位直肠原发性腺癌患者的血样进行基因分型，这125例患者（女性45例，男性80例；中位年龄60岁，范围31 - 79岁）。采用肿瘤消退分级标准评估术前治疗反应。根据病理反应，将患者分为反应者（TRG 1 - 2，48例）和无反应者（TRG 3 - 5，74例）。3例患者因数据不足被排除。
在检测的多态性变体中，单因素分析显示，MTHFR 677T - 1298A单倍型是唯一与肿瘤消退相关的变量（P = 0.004）。此外，多因素分析显示，MTHFR 677T - 1298A单倍型是肿瘤消退的独立预测因子。未携带MTHFR 677T - 1298A单倍型的患者（比值比0.29，95%置信区间0.13 - 0.64，P = 0.002）的反应率高于携带MTHFR 677T - 1298A单倍型的患者。
与TS VNTR和SNP多态性不同，基因组DNA中的MTHFR 677T - 1298A单倍型有可能成为接受术前放化疗的直肠癌患者肿瘤反应的预测标志物。
