XRCC1基因多态性与局部晚期直肠癌术前新辅助放化疗敏感性的相关性研究

发布时间：2017-12-28 12:27

本文关键词：XRCC1基因多态性与局部晚期直肠癌术前新辅助放化疗敏感性的相关性研究　出处：《济南大学》2015年硕士论文　论文类型：学位论文

【摘要】：背景新辅助放化疗可以使局部晚期直肠癌患者的肿瘤体积缩小、提高根治性切除率及保留肛门的几率,有效降低术后局部复发率,延长生存期。然而并非所有患者都能从新辅助放化疗中受益。部分患者可能对新辅助放化疗缺乏敏感性,不仅失去最佳手术机会,而且增加了经济负担。因此,准确地预测直肠癌患者对同步放化疗的敏感性,不仅可以准确地选择局部晚期直肠癌患者的治疗方案,而且可以减少患者的痛苦与经济负担。人类x线交错互补修复基因1(X-ray repair cross complementing gene1,XRCC1)的Arg399Gln多态性在涉及肺癌、食管癌的多项研究中显示其与放化疗敏感性的显著性关系,可能是预测新辅助治疗疗效的生物学指标。本研究中通过检测XRCC1的Arg399Gln多态性在局部晚期直肠癌患者中的表达情况,分析其与新辅助放化疗的敏感性之间有无显著性关系,从而认识和了解其在局部晚期直肠癌患者新辅助放化疗疗效预测中的意义。方法收集64例局部晚期直肠癌患者的一般临床病理资料,并检测XRCC1的Arg399Gln多态性。患者在接受新辅助放化疗后行手术治疗,通过CT疗效评价及术后Dworak’s肿瘤退缩分级(Tumor Regression Grading,TRG)对患者的新辅助放化疗敏感性进行评价,单因素分析XRCC1 399位点多态性、患者临床病理资料分别与新辅助放化疗敏感性之间有无显著性关联,并通过多因素logistic回归分析找出其中的独立影响因素,寻找可以预测直肠癌新辅助放化疗疗效的指标,以指导不同敏感性的局部晚期直肠癌患者进行个体化治疗。结果研究中共收集到局部晚期直肠癌患者(ct3-4n0m0或任何tn+m0)病例64例,其中男性患者38例,女性患者26例。所有64例患者采集外周血通过pcr-rflp技术获得相应基因型。其中纯合子gg型患者33例,杂合子ga型患者24例,aa型患者7例。基因型分布经hardy-weinberg平衡检验发现存在群体基因遗传平衡(p=0.42)。新辅助治疗后ct疗效评价显示获得cr的患者数为10例;pr患者数为16例;sd患者数为24例;获得pd患者数为14例。术后病理按照dworak’s肿瘤退缩分级,其中trg4(pcr)者12例;trg3者17例;trg2患者15例;trg1者12例;trg0者8例。在以dworak’s肿瘤退缩分级为评价标准的新辅助治疗敏感性研究中,通过单因素分析我们发现:术前ct分期、cn分期以及患者的术前cea水平均与新辅助放化疗的敏感性及疗效显著相关,p值分别为0.002、0.016、0.047。xrcc1基因arg399gln多态性与局部晚期直肠癌患者的新辅助放化疗敏感性显著相关(p=0.011),携带野生型基因gg的患者对新辅助治疗的敏感性显著优于携带ga和aa型患者。在ct为主的resist评价标准中,术前ct分期、cn分期、术前cea水平及xrcc1399位点多态性也均与新辅助治疗敏感性显著相关。在多因素logistic回归分析中,我们发现,患者术前ct分期(p=0.005)是影响直肠癌患者新辅助治疗疗效的独立因素。在局部晚期直肠癌术前ct分期较低的情况下,xrcc1基因arg399gln位点无突变(gg型)的直肠癌患者经新辅助治疗后可以获得更好的疗效。结论术前ct分期、cn分期以及患者的术前cea水平与新辅助放化疗的敏感性及疗效显著相关。xrcc1基因arg399gln多态性与局部晚期直肠癌患者的新辅助放化疗敏感性显著相关,携带野生型基因gg的患者对新辅助治疗的敏感性显著优于携带ga和aa型患者。术前ct分期为直肠癌患者新辅助治疗疗效的独立影响因素。在局部晚期直肠癌术前ct分期较低的情况下,xrcc1基因arg399gln位点无突变(gg型)的直肠癌患者经新辅助治疗后可以获得更好的疗效。
[Abstract]:Background neoadjuvant chemoradiotherapy can reduce the volume of tumor in locally advanced rectal cancer, increase the rate of radical resection and preserve the anus, effectively reduce the local recurrence rate and prolong the survival time. Not all patients, however, can benefit from neoadjuvant chemoradiotherapy. Some patients may not be sensitive to neoadjuvant chemoradiotherapy, not only lose the best operation opportunity, but also increase the economic burden. Therefore, accurately predicting the sensitivity of rectal cancer patients to concurrent chemoradiotherapy can not only accurately select the treatment plan for locally advanced rectal cancer, but also reduce the pain and economic burden of patients. The human X-ray repair cross complementing gene 1 (X-ray repair cross complementing gene1, XRCC1) Arg399Gln polymorphism showed significant relationship with chemotherapy sensitivity in a number of studies involving lung cancer and esophageal cancer, may predict biological response to neoadjuvant therapy index. Expression of Arg399Gln polymorphisms detected by XRCC1 in this study in patients with locally advanced rectal cancer, there is no significant relationship between the analysis and the sensitivity of neoadjuvant chemotherapy, so as to know and understand the local advanced rectal cancer patients with neoadjuvant chemotherapy efficacy prediction of significance. Methods the general clinicopathological data of 64 patients with locally advanced rectal cancer were collected and the Arg399Gln polymorphism of XRCC1 was detected. In patients receiving neoadjuvant treatment chemotherapy followed by surgery, and postoperative curative effect evaluation by CT Dworak s (Tumor Regression Grading tumor regression grading, TRG) of patients treated with neoadjuvant chemoradiotherapy sensitivity evaluation, single factor analysis there is no significant correlation between XRCC1 399 polymorphism and clinical pathological data and the new adjuvant chemotherapy sensitivity, and by multivariate logistic regression analysis to identify independent factors which can predict for neoadjuvant chemoradiotherapy for rectal cancer curative effect, individualized treatment is to guide the different sensitivity of patients with locally advanced rectal cancer. Results a total of 64 cases of locally advanced rectal cancer (ct3-4n0m0 or any tn+m0) were collected, including 38 male patients and 26 female patients. The peripheral blood was collected from all 64 patients and the corresponding genotypes were obtained by PCR-RFLP technique. Among them, there were 33 patients with homozygote type GG, 24 heterozygote GA patients and 7 patients with type AA. Genetic balance (p=0.42) was found in the genotype distribution by Hardy-Weinberg balance test. After the new adjuvant treatment, the CT efficacy evaluation showed that the number of patients received CR was 10 cases, the number of PR patients was 16 cases, the number of SD patients was 24 cases, and the number of PD patients was 14 cases. The postoperative pathology was based on Dworak 's tumor regression classification, of which 12 cases were trg4 (PCR), 17 of trg3, 15 in trg2, 12 in TRG1 and 8 in trg0. In Dworak s' tumor regression as the evaluation criteria for the classification of neoadjuvant treatment sensitivity study, through single factor analysis we found that: there is a significant correlation between sensitivity and efficacy of preoperative CT staging, CN staging and preoperative CEA level were associated with neoadjuvant chemotherapy, P values were 0.002, 0.016, 0.047. The Arg399Gln polymorphism of XRCC1 gene is significantly correlated with the sensitivity of neoadjuvant chemoradiotherapy in locally advanced rectal cancer (p=0.011). The patients with wild type GG are more sensitive to neoadjuvant therapy than those with GA and AA. Among the CT based resist evaluation criteria, preoperative CT staging, CN stage, preoperative CEA level and xrcc1399 site polymorphism were also significantly associated with the sensitivity of neoadjuvant therapy. In the multifactor logistic regression analysis, we found that preoperative CT staging (p=0.005) was an independent factor affecting the efficacy of neoadjuvant therapy for rectal cancer. In patients with locally advanced rectal cancer with low CT stage before operation, the XRCC1 gene Arg399Gln site without mutation (GG type) of rectal cancer can get better results after neoadjuvant therapy. Conclusion the preoperative CT staging, CN staging and preoperative CEA levels of the patients were significantly related to the sensitivity and efficacy of neoadjuvant radiochemotherapy. The Arg399Gln polymorphism of XRCC1 gene is significantly correlated with the sensitivity of neoadjuvant chemoradiotherapy in locally advanced rectal cancer. The patients with wild type GG are more sensitive to neoadjuvant therapy than those carrying GA and AA. Preoperative CT staging is an independent factor in the efficacy of neoadjuvant therapy for rectal cancer. In patients with locally advanced rectal cancer with low CT stage before operation, the XRCC1 gene Arg399Gln site without mutation (GG type) of rectal cancer can get better results after neoadjuvant therapy.
【学位授予单位】：济南大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R735.37

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