Polymorphisms of GSTP1, ERCC2 and TS-3'UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients.
Polymorphisms of GSTP1, ERCC2 and TS-3'UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients.
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DOI：
10.3892/ol.2013.1467
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发表时间：
2013-09
期刊：
影响因子：
2.9
通讯作者：
Ishida H
中科院分区：
文献类型：
--
作者：
Kumamoto K;Ishibashi K;Okada N;Tajima Y;Kuwabara K;Kumagai Y;Baba H;Haga N;Ishida H
本研究的目的是研究药物代谢基因多态性是否对接受5-氟尿嘧啶(FU)/奥沙利铂治疗转移性结直肠癌（MCRC）的患者有任何临床影响。总共招募了63名MCRC患者，并使用改良的FOLFOX6 （mFOLFOX6）治疗作为一线化疗。采用聚合酶链反应（PCR）、PCR限制性片段长度多态性（PCR- rflp）技术或入侵技术对这些患者的5个药物代谢基因和2个dna修复基因的多态性进行了评估。其中包括在5 ' -非翻译区（UTR）有28个bp的串联重复，在3 ' -UTR中有6个bp的缺失，这些缺失包括：thymidylate合成酶（TS）、亚甲基四氢叶酸还原酶（MTHFR; Ala677Val）、谷胱甘肽s-转移酶π (GSTP1; IIe105Val)、GST θ1 （GSTT1；缺失）和GST μ1 （GSTM1；缺失）以及两个dna修复基因，即切除修复交叉互补-1 （ERCC1; Asp118Asn）和ERCC2 （Lys751Gln）。评估这些多态性与临床结果的相关性，包括药物反应、无进展生存期（PFS）、总生存期（OS）和周围神经病变的发生率。GSTP1-105 A/A基因型患者与GSTP1-105 A/G和G/G基因型患者相比，对mFOLFOX6治疗的反应较差（P=0.01）。ERCC2-751 A/A基因型患者的中位PFS比ERCC2-751 A/C基因型患者的中位PFS更长（P=0.05）。TS-3′-UTR−6/−6基因型患者的生存期明显长于其他基因型患者（P=0.003）。多因素logistic回归分析发现，2级以上周围神经病变的发生率与GSTP1-105基因型（P=0.03）和GSTM1基因型（P=0.02）有统计学意义。结果表明，GSTP1-105、ERCC2-751和TS的3 ' -UTR多态性可能是临床预后的有统计学意义的预测因子。GSTP1-105和GSTM1基因型可能是5-FU/奥沙利铂作为一线化疗的MCRC患者严重周围神经病变的有用标志物。
The aim of the current study was to examine whether polymorphisms in drug metabolism genes have any clinical impact on patients treated with 5-fluorouracil (FU)/oxaliplatin for metastatic colorectal cancer (MCRC). In total, 63 patients with MCRC were recruited and treated with a modified FOLFOX6 (mFOLFOX6) treatment as a first-line chemotherapy. Polymorphisms in five drug metabolism genes and two DNA-repair genes were assessed in these patients using polymerase chain reaction (PCR), a PCR restriction fragment length polymorphism (PCR-RFLP) technique or invader techniques. These included a 28-bp tandem repeat in the 5′-untranslated region (UTR) and 6-bp deletions in the 3′-UTR of thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR; Ala677Val), glutathione S-transferase π (GSTP1; IIe105Val), GST θ1 (GSTT1; deletion) and GST μ1 (GSTM1; deletion) and the two DNA-repair genes, excision repair cross-complementing-1 (ERCC1; Asp118Asn) and ERCC2 (Lys751Gln). The correlation between these polymorphisms and the clinical outcome, including drug response, progression-free survival (PFS), overall survival (OS) and the incidence of peripheral neuropathy, were evaluated. Patients with the GSTP1-105 A/A genotype had poor responses to mFOLFOX6 treatment compared with those with the GSTP1-105 A/G and G/G genotypes (P=0.01). The median PFS of patients with the ERCC2-751 A/A genotype tended to be longer than that of patients with the ERCC2-751 A/C genotype (P=0.05). Patients with the TS-3′-UTR −6/−6 genotype had a significantly longer OS compared with patients with other genotypes (P=0.003). A statistically significant association between the incidence of peripheral neuropathy higher than grade 2 and the GSTP1-105 (P=0.03) and GSTM1 genotypes (P=0.02) was identified by multivariate logistic regression analyses. Results demonstrated that polymorphisms in GSTP1-105, ERCC2-751 and the 3′-UTR of TS may be a statistically significant predictors of clinical outcome. GSTP1-105 and GSTM1 genotypes may be useful markers of severe peripheral neuropathy in MCRC patients treated with 5-FU/oxaliplatin as first-line chemotherapy.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
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影响因子：
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作者：
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DOI：
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影响因子：
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影响因子：
45.3
作者：
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通讯作者：
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影响因子：
45.3
作者：
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通讯作者：
de Gramont, A