遗传变异与小细胞肺癌铂类药物化疗疗效及生存的关联研究

发布时间：2018-05-07 09:18

本文选题：遗传变异 + 小细胞肺癌　；参考：《北京协和医学院》2016年硕士论文

【摘要】：背景和目的：小细胞肺癌(small cell lung cancer,SCLC)是一种恶性度极高的神经内分泌肿瘤,具有易发生早期转移,预后差的临床特点。以铂类药物为主的化疗是小细胞肺癌的一线治疗方案,然而具有相同临床背景的患者接受化疗后疗效和生存不同。大量研究表明,遗传变异是造成个体间治疗疗效及生存差异的重要影响因素。近来研究发现非编码区作为基因组中的重要组成成分并非“荒漠区”,在肿瘤的发生发展中发挥了重要的功能。此外,人们近来发现RAD52基因作为DNA双链断裂损伤修复过程中的关键分子在保持基因组稳定性及阻止DNA损伤细胞发生癌变方面发挥重要作用。本研究采用高通量方法探讨非编码区基因遗传变异与小细胞肺癌铂类药物化疗疗效及生存的关联,同时采用候选基因策略研究RAD52基因遗传变异与小细胞肺癌铂类药物化疗疗效及生存的关联,寻找具有潜在应用价值的可用于小细胞肺癌精准治疗的生物标志物。方法：本研究入组1997年3月到2013年5月于中国医学科学院肿瘤医院确诊并接受铂类药物化疗的生存资料完整的SCLC患者进行非编码区基因遗传变异的关联研究。研究采用全基因组关联研究的策略,首先对475例患者外周血DNA非编码区基因遗传变异与患者化疗疗效、总生存及无进展生存进行发现阶段关联分析,然后对发现的相关SNP在432例样本的独立队列中进行验证。此外,我们还采用候选基因策略对募集的939例有完整疗效评价资料的SCLC患者进行RAD52基因遗传变异与化疗疗效、总生存及无进展生存的关联研究。此部分研究采用Sequenom Mass ARRAY平台检测患者外周血RAD52基因上9个标签SNP位点的基因型。化疗疗效关联分析和生存分析采用目前标准通用的Logistic和Cox多因素回归模型等统计方法。结果：我们发现位于LINC01006基因内含子区的rs6968202 GC遗传变异增加患者铂类药物化疗疗效。与携带G等位基因的患者相比,携带C等位基因患者化疗敏感性增强,化疗无效的风险降低(OR=0.53,95%CI=0.41-0.69,P=1.59×10-6)。.Cox回归分析发现rs17129504.rs17574506和rs10916317位点遗传变异与患者总生存相关。rs17129504 AC和CC基因型的死亡风险分别是AA基因型的1.27倍(95%CI=1.08-1.50,P=0.0038)和1.76倍(95%CI=1.33-2.33,P:8.49×10-5)。rs17574506CT和TT基因型的死亡风险分别是CC基因型的1.51倍(95% CI=1.26-1.81,P=9.85×10-6)和1.66倍(95%CI=1.33-2.09.P=9.85×10-6)。rs10916317 GA和AA基因型的死亡风险分别是GG基因型的1.36倍(95% CI=1.15-1.60,P=2.68×10-4)和1.45倍(95% CI=1.13-1.87,P=0.0042)。同时我们发现rs77910142 AT遗传变异患者无进展生存时间和总生存时间缩短(HR=1.51,95%CI=1.21-1.89,P= 2.80×10-4；HR=1.38,95%CI=1.09-1.74,P=0.0072).此外,我们发现RAD52基因rs10774474 TA遗传变异降低患者铂类药物化疗敏感性,与携带TT基因型患者相比,携带TA或AA基因型的患者化疗疗效显著降低,化疗无效风险增高(OR=1.59, 95%CI=1.16-2.19.P=0.0041)。结论：本研究发现非编码区基因相关遗传变异与小细胞肺癌铂类药物化疗疗效及生存相关,DNA修复通路中编码基因RAD52上的rs10774474遗传变异与患者化疗疗效相关。本研究有助于全面深入了解遗传变异与小细胞肺癌个体治疗疗效及预后的相关性,为后续的分子机制研究提供一定数据支持。这些遗传变异可能成为小细胞肺癌疗效及预后的生物标志物,具有潜在应用价值。
[Abstract]:Background and purpose: small cell lung cancer (SCLC) is a highly malignant neuroendocrine tumor, which has the clinical characteristics of early metastasis and poor prognosis. Chemotherapy based on platinum is a first-line treatment for small cell lung cancer. However, patients with the same clinical background receive chemotherapy and after chemotherapy. A large number of studies have shown that genetic variation is an important factor affecting the therapeutic effect and survival difference between individuals. Recent studies have found that the non coded region is not a "desert area" as an important component of the genome, and has played an important role in the development of the tumor. In addition, the RAD52 gene has recently been found to be a DNA gene. Key molecules in the repair of double strand breaks play an important role in maintaining genomic stability and preventing DNA damaged cells from carcinogenesis. This study uses high throughput methods to explore the association between genetic variation of non coding region genes and chemotherapeutic efficacy and survival of small cell lung cancer, and the study of candidate gene strategies. The association of RAD52 gene mutation with chemotherapeutic efficacy and survival of small cell lung cancer in order to find potential biomarkers for precise treatment of small cell lung cancer. Methods: This study was admitted to the Cancer Hospital of the Chinese Academy of Medical Sciences from March 1997 to May 2013 and accepted the survival of platinum group chemotherapy. The study of genetic variation in the non coding region of the complete data of the SCLC patients. The study adopted the strategy of full genome association study. First, the genetic variation in the DNA non coding region of the peripheral blood of 475 patients was correlated with the patients' chemotherapy effect, the total survival and the progression free survival, and then the related SNP was found in 432. In addition, we also used a candidate gene strategy to study the association between RAD52 gene mutation and chemotherapy, total survival and progression free survival in 939 SCLC patients with complete efficacy evaluation data. This part studies the detection of peripheral blood RAD52 in patients with Sequenom Mass ARRAY platform. Genotypes of 9 gene tagging SNP loci. Chemotherapeutic effect association analysis and survival analysis using current standard general Logistic and Cox multivariate regression models. Results: we found that the rs6968202 GC genetic variation in the intron of the LINC01006 gene increased the chemotherapy efficacy of the platinum group and the G allele. The patients with C allele were more sensitive to chemotherapy, and the risk of chemotherapy was reduced (OR=0.53,95%CI=0.41-0.69, P=1.59 x 10-6)..Cox regression analysis found that the genetic variation of rs17129504.rs17574506 and rs10916317 sites and the mortality risk of.Rs17129504 AC and CC genotypes of patients with total survival were 1.27 of the AA genotypes, respectively. The mortality risk of 95%CI=1.08-1.50, P=0.0038, and 1.76 times (95%CI=1.33-2.33, P:8.49 x 10-5).Rs17574506CT and TT genotypes were 1.51 times of the CC genotype (95% CI=1.26-1.81, P=9.85 x 10-6) and 1.66 times (95%CI=1.33-2.09.P=9.85 x 10-6).Rs10916317 GA and the death risk of the genotype were 1.36 times (95%) respectively. .60, P=2.68 x 10-4) and 1.45 times (95% CI=1.13-1.87, P=0.0042). At the same time, we found that the time of progression free survival and total survival time shortened (HR=1.51,95%CI=1.21-1.89, P= 2.80 x 10-4; HR=1.38,95%CI=1.09-1.74, P=0.0072) in patients with rs77910142 AT genetic variation. The chemotherapeutic sensitivity of the patients with TT genotype was significantly lower in patients carrying TA or AA genotypes, and the risk of chemotherapy was higher (OR=1.59, 95%CI=1.16-2.19.P=0.0041). Conclusion: This study found that the genetic variation of non coding region gene was related to the chemotherapy efficacy and survival of small cell lung cancer with platinum drugs, DNA repair The genetic variation of the rs10774474 gene RAD52 in the pathway is related to the efficacy of chemotherapy in patients. This study helps to understand the correlation between genetic variation and the individual therapeutic effect and prognosis of small cell lung cancer, and provide some data support for subsequent molecular mechanism research. These mutations may be the therapeutic effect of small cell lung cancer. The biomarker of the prognosis is of potential application value.

【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R734.2

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