GNAS1 T393C polymorphism and survival in patients with sporadic colorecta cancer
GNAS1 T393C polymorphism and survival in patients with sporadic colorecta cancer
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DOI：
10.1158/1078-0432.ccr-05-0472
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发表时间：
2005-07-15
影响因子：
11.5
通讯作者：
Schmid, KW
中科院分区：
文献类型：
--
作者：
Frey, UH;Alakus, H;Schmid, KW
目的：通过G蛋白G α s通路的信号传导与癌细胞系中的促凋亡过程有关。我们最近发现，与C等位基因携带者相比，具有纯合TT基因型的膀胱癌患者GNAS 1 T393 C多态性与疾病进展之间存在相关性，表现出Gas转录增加和更有利的临床病程。在本研究中，对151例散发性结直肠癌患者进行回顾性基因分型，以检查T393 C基因型与生存率之间的潜在关联。此外，还研究了GNAS 1基因常见单倍型区块中的另外两个单核苷酸多态性及其与T393 C多态性的交互作用。Kaplan-Meier总生存率曲线（平均随访43个月）显示，在国际抗癌联合会（UICC）I至11期中，TT基因型（87.8%）的5年生存率显著高于TC（71.0%）和CC基因型（50.0%; P = 0.009），而在UICC III至IV期中未观察到基因型效应。在多变量考克斯比例分析中，T393 C多态性是生存的独立预后因素。与TT基因型相比，纯合子CC患者的死亡风险最高（风险比，12.1; P = 0.006）。杂合子患者有一个中等风险与基因剂量效应相一致。两个单倍型块的调查与临床outcome.Conclusions：结果支持的作用，T393 C多态性作为一个标志物的生存期结直肠癌I期至11日，并在识别患者谁可能受益于辅助化疗。
Purpose: Signaling via the G protein G alpha s pathway is linked to proapoptotic processes in cancer cell lines. We have recently shown an association between the GNAS1 T393C polymorphism and disease progression in patients with bladder cancer with homozygous TT genotypes displaying increased transcription of Gas and a more favorable clinical course compared with C-allele carriers.Experimental Design: In the present study, 151 patients with sporadic colorectal cancer were retrospectively genotyped to examine a potential association between T393C genotypes and survival. Moreover, two other single-nucleoticle polymorphisms in common haplotype blocks within the gene GNAS1 and their interaction with the T393C polymorphism were investigated.Results: The allele frequency in the patients group was not significantly different from that of healthy blood donors. Kaplan-Meier curves for overall survival (mean follow-up, 43 months) showed that in International Union Against Cancer (UICC) stages I to 11, the 5-year survival rate was significantly higher in TT genotypes (87.8%) compared with TC (71.0%) and CC genotypes (50.0%; P = 0.009), whereas no genotype effect could be observed for UICC stages III to IV. In multivariate Cox proportional analysis the T393C polymorphism was an independent prognostic factor for survival. Homozygous CC patients were at highest risk for death (hazard ratio, 12.1; P = 0.006) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. The two haplotype blocks investigated were not associated with clinical outcome.Conclusions: The results support the role of the T393C polymorphism as a marker for survival in patients with colorectal cancer stages I to 11 and in the identification of patients who may benefit from adjuvant chemotherapy.