亚甲基四氢叶酸还原酶（MTHFR）基因多态性与结直肠癌患者 FOLFOX 反应的关系。
Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients.
机构信息
Centre Antoine Lacassagne, Oncopharmacology Unit, EA 3836, Nice, France.
出版信息
Br J Clin Pharmacol. 2010 Jan;69(1):58-66. doi: 10.1111/j.1365-2125.2009.03556.x.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
- Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.
WHAT THIS STUDY ADDS
- This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival. * These results corroborate the observation that response was related to the cumulative FU dose, whereas progression-free survival was related to the cumulative oxaliplatin dose.
AIMS
To test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy.
METHODS
Advanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G-->C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C-->T, 1298A-->C), dihydropyrimidine deshydrogenase (IVS14+1G-->A) and Oxa: glutathione S-transferase (GST) pi (105Ile-->Val, 114Ala-->Val), excision repair cross-complementing group 1 (ERCC1) (118AAT-->AAC), ERCC2 (XPD, 751Lys-->Gln) and XRCC1 (399Arg-->Gln)] were determined (blood mononuclear cells).
RESULTS
None of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C-->T (P= 0.042) and 1298A-->C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GSTpi 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054).
CONCLUSIONS
These results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.
已知关于该主题的内容
- 多项临床研究，包括一些前瞻性研究，报告了与氟尿嘧啶（FU）和奥沙利铂药代动力学相关的基因多态性对影响的相互矛盾的结果。
本研究的新发现
- 这项前瞻性研究首次报告，奥沙利铂药代动力学相关的亚甲基四氢叶酸还原酶（MTHFR）基因多态性（677C--->T 和 1298A--->C）与 FOLFOX 临床反应显著相关，分别在没有、一个、两个或三个有利 MTHFR 等位基因的患者中，其反应率为 37%、53%、63%和 80%。* 只有与奥沙利铂药代动力学相关的基因多态性（GSTpi 105Ile--->Val 和 XPD 751Ly--->Gln）影响无进展生存期。* 这些结果证实了观察结果，即反应与累积 FU 剂量有关，而无进展生存期与累积奥沙利铂剂量有关。
目的
前瞻性检测与氟尿嘧啶（FU）和奥沙利铂（Oxa）药代动力学相关的生殖基因多态性对接受 FOLFOX 治疗的结直肠癌（CRC）患者毒性和反应的预测价值。
方法
招募接受 FOLFOX 7 治疗的晚期 CRC 患者（n=117）。与 FU 相关的基因多态性（TYMS，28 bp 重复包括 3'UTR 中的 G--->C 突变+6 bp 缺失，MTHFR，677C--->T，1298A--->C，二氢嘧啶脱氢酶（IVS14+1G--->A）和 Oxa：谷胱甘肽 S-转移酶（GST）pi（105Ile--->Val，114Ala--->Val）、切除修复交叉互补组 1（ERCC1）（118AAT--->AAC）、ERCC2（XPD，751Lys--->Gln）和 XRCC1（399Arg--->Gln））在血液单核细胞中确定（血液单核细胞）。
结果
没有一种基因型具有毒性预测性。反应率（完全缓解+部分缓解 54.7%）与 FU 药代遗传学有关，677C--->T（P=0.042）和 1298A--->C（P=0.004）MTHFR 基因型均与临床反应相关。重要的是，有利 MTHFR 等位基因（677T 和 1298C）评分与反应呈正相关，无有利等位基因的患者反应率分别为 37.1%、53.3%、62.5%和 80.0%（P=0.040）。与奥沙利铂药代动力学相关的基因多态性显示对无进展生存期的影响，GSTpi 105 Val/Val 基因型或 XPD 751Lys 基因型的患者预后较好（P=0.054）。
结论
这些结果表明，CRC 患者接受 FOLFOX 治疗的反应可能由 MTHFR 生殖基因突变驱动。
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