Lung Cancer：rs2269577加重晚期NSCLC患者铂类药胃肠毒性

X-box结合蛋白1（XBP1）是内质网应激反应过程中的一个关键转录因子，也是维持细胞稳态的基本要素。为了调查晚期非小细胞肺癌（NSCLC）患者在接受以铂类为基础的化疗方案治疗时，XBP1基因的调控变量rs2269577对患者预后的影响，来自上海复旦大学生命科学学院遗传学研究所、基因工程国家重点实验室的彭军及其同事进行了一项研究，研究结果发表在2013年3月16日的出版的《Lung Cancer》杂志上。研究显示：rs2269577的G/G基因型与患者严重的胃肠道毒性反应显著相关。

该研究共招募了我国663例晚期NSCLC患者，而且这些患者均接受了以铂类为基础的化疗方案。研究者评估了rs2269577与患者的临床转归之间的关系；并使用包括实时定量PCR和双荧光素酶检测等在内的后续功能分析方法，探索了其中可能的分子机制。

该研究结果显示：与纯合子C/C基因型相比，rs2269577的G/G基因型与患者严重的胃肠道毒性反应显著相关（P=0.012，比值比=2.755），而且，这种相关性在女性、体力状态评分为0-1分、以及腺癌亚组患者中更加明显。但rs2269577与患者的治疗效果之间无显著相关。此外，对胃上皮细胞进行的体外分子分析表明，在接受了顺铂治疗后的胃上皮细胞中，其XBP1 mRNA的表达水平出现降低，其rs2269577 G等位基因也减弱了XBP1启动子的转录活性。

研究者认为，对于接受铂类治疗的晚期NSCLC患者而言，这是首个使用药物基因组学和功能分子分析2种方法，来评估XBP1基因多态性对化疗相关严重不良后果影响的研究。

原文链接：

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XBP1 promoter polymorphism modulates platinum-based chemotherapy gastrointestinal toxicity for advanced non-small cell lung cancer patients.

BACKGROUND
The X-box binding protein 1 (XBP1) is a critical transcription factor in the endoplasmic reticulum stress response, which is essential for the maintenance of cellular homeostasis. Here, we investigated whether the regulatory variant rs2269577 of the XBP1 gene influences clinical outcome in advanced non-small cell lung cancer (NSCLC) patients undergoing platinum-based chemotherapy.
PATIENTS AND METHODS
We recruited 663 Chinese patients with advanced NSCLC treated with platinum-based regimens and assessed the association between rs2269577 and clinical outcome. Subsequent functional analyses, including real-time quantitative PCR and dual-luciferase assays, were performed to explore possible molecular mechanisms.
RESULTS
The G/G genotype of rs2269577 was significantly associated with severe gastrointestinal toxicity compared with the homozygous C/C genotype (P=0.012, odds ratio=2.755), particularly in the female, performance status 0-1, and adenocarcinoma subgroups. No significant relevance was found between rs2269577 and treatment efficacy. In gastric epithelial cells, in vitro molecular analyses demonstrated that XBP1 mRNA expression levels decreased after treatment with cisplatin and the G allele of rs2269577 weakened the transcriptional activity of the XBP1 promoter.
CONCLUSION
This is the first study to evaluate the effect of XBP1 polymorphism on severe chemotherapy-related adverse outcomes in platinum-treated advanced NSCLC patients using both pharmacogenomics and functional molecular analyses.

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来源：丁香园