单核苷酸多态性预测直肠癌术后同步放化疗毒副反应和疗效的研究

Postoperative concomitant chemoradiotherapy is the standard of care for stage II and III rectal cancer patients, which can improve the local control rate and long-term survival rate. Oral 5-fluorouracil (capecitabine) is recommended as the standard concurrent chemotherapy regimen. Clinical studies found variations of benefits and side effects in patients of this treatment option. Hence, identi?cation of biomarkers that distinguish patients who respond to chemoradiotherapy and those who bene?t from more aggressive treatments is required. Genetic variations are likely to be the molecular basis of individual response to treatment. SNP is one of the important genetic variation. SNPs have been widely reported on significant correlation to efficacy and toxicities of concurrent chemoradiotherapy in malignant tumors, such as lung cancer, esophageal cancer, breast cancer and prostate cancer, et al..In this cohort study, patients with stage II / III rectal cancer were treated with postoperative concomitant chemoradiotherapy (radiotherapy + capecitabine), acute adverse reactions and efficacy were recorded during the treatment. SNPs genotyping from the peripheral blood were studied to find frequency difference between serious adverse reactions and non-serious adverse reactions. We hope to establish correlations of SNPs to treatment side effects and patient outcomes as well. This study might be helpful to clarify the effects of genetic variants on the individual's variation of the efficacy of chemoradiotherapy, which in turn might provide evidence for future studies on individualized chemoradiotherapy of rectal cancer.

II/III期直肠癌术后同步放化疗可提高患者的局部控制率和长期生存率,是标准的辅助治疗手段。口服5-氟尿嘧啶（卡培他滨）为标准同步化疗药物。临床研究发现，该治疗方案中患者的获益及毒副作用各不相同。遗传变异很可能是个体间治疗反应不同的分子生物学基础。单核苷酸多态性（SNP）是其中一种重要的遗传变异。已有大量的研究报道SNPs与肺癌、食管癌、乳腺癌和前列腺癌等多种恶性肿瘤的治疗效果和放化疗毒副作用有明显相关性。.本研究采用标准的卡培他滨术后同步放化疗方案治疗II/III期直肠癌，观察其急性不良反应和疗效，同时采取外周血中进行SNPs研究，寻找严重不良反应和非严重不良反应患者SNPs频率的差异，期望建立SNPs与治疗毒副作用和疗效之间的关系。目的是阐明基因遗传变异对直肠癌放化疗疗效个体差异的影响及作用机制，发现可用于预测疗效的标志，为进一步研究直肠癌的个体化放化疗提供基础。

目的：探索基因遗传变异对局部晚期直肠癌术后同期放化疗疗效和治疗相关不良反应的差异的影响。 .方法：至2013-2016年，共纳入II/III期直肠癌接受全直肠系膜切除术联合术后同期放化疗患者共计468例，随诊患者治疗相关毒副反应分级以及预后状况，分析患者外周血内DNA代谢通路相关基因候选SNP位点和miRNA基因候选SNP位点的变异与治疗相关毒副反应和生存状况的关联。.结果：1个位于CHEK1基因的遗传变异rs11220165，2个位于CHEK2基因的遗传变异rs2236142及rs2236141，与2-4级放射性肠炎的发生相关（P<0.05）；1个位于TP基因的遗传变异rs11479与2-4级血液学毒性的发生风险相关（P=0.027），hsa-miR-3117-3p种子区的遗传变异（rs12402181）与2-4级放射性肠炎的发生相关。3个位于miRNA种子区的遗传变异（rs2273626，rs202127912，rs62376935）与2-4级血液学毒性的发生风险相关。位于hsa-miR-4274基因的rs202195689与总生存率、无病生存率、无远地转移生存率均相关。.结论：利用单核苷酸多态性的分析能够预测局部晚期直肠癌患者术后同期放化疗的治疗相关反应以及生存状况。能够为局部晚期直肠癌患者的个体化治疗提供理论基础。