TGF-β1相关信号通路的基因多态性与鼻咽癌患者远处转移风险的关联性研究
发布时间：2018-07-31 05:29
【摘要】：背景:随着影像诊断技术和放射治疗技术的进步,鼻咽癌的局部区域控制率得到很大提高,远处转移成为治疗失败的主要原因。如何在治疗前识别具有高转移风险的患者成为提高疗效的关键问题。虽然临床分期在指导治疗及预后判断上发挥了重要作用,然而相同临床分期的患者在经过同样的治疗手段后,其治疗效果及病情转归可能存在很大的差异,越来越多的研究表明,个体遗传因素在这种预后差异中扮演了重要的角色。转化生长因子β(transforming growth factor-beta,TGF-β)信号转导通路的异常与鼻咽癌的发生发展密切相关,本研究拟在496例中国汉族鼻咽癌患者中探讨该通路Smad依赖的经典途径,即TGF-β1/Smad途径中关键基因的单核苷酸多态性(Single Nucleotide Polymorphism,SNP)与鼻咽癌远处转移风险的关联。方法:研究共纳入496例2012.01-2013.05期间于我院就诊的初治无远处转移的鼻咽癌患者,均接受调强放射治疗且治疗前均留有全血标本。选取TGF-β1/Smad通路中关键基因的12个标签SNP(Tag SNP),采用基质辅助激光解吸附电离飞行时间质谱和Taq Man探针的方法行SNP分型。利用Kaplan-Meier及Cox比例风险模型评估各SNP与鼻咽癌远处转移风险的关联。此外,本研究还利用ELISA方法检测了147例相对应患者的血浆TGF-β1含量,评估TGF-β1不同基因型对血浆TGF-β1水平的影响。结果:全组患者中位随访时间40个月(范围4~51个月),3年总生存及3年无远处转移生存时间分别为91.8%和85.1%。TGF-β1/Smad通路中共有12个Tag SNP纳入分型,我们发现仅TGF-β1:rs1800469和TGF-β1:rs1800470对远处转移风险具有独立预测价值。TGF-β1:rs1800469 CC基因型携带者具有更高的远处转移风险(HR0.560,95%CI 0.335-0.936,P=0.027),且主要体现在晚期患者;TGF-β1:rs1800470TT基因型携带者也表现出更高的远处转移风险(HR 0.499,95%CI 0.301-0.827,P=0.007),在早晚期患者中均具有预测价值。进一步分析发现具有两个风险基因型的患者远处转移风险最高,具备一个风险基因型的次之,而不具备风险基因型的远处转移风险最低,这说明两个位点具有叠加效应,随着携带风险基因数量增加,转移风险逐渐增加(P=0.012)。利用ELISA检测血浆中TGF-β1的含量,发现两个位点的基因多态性与血浆中TGF-β1的含量无明显关联(P0.05)。结论:我们发现TGF-β1/Smad信号通路中的TGF-β1:rs1800469和TGF-β1:rs1800470与鼻咽癌患者远处转移的风险相关联,两个位点在评估转移风险上还具有叠加效应,随着携带风险基因数量增加,转移风险逐渐增加。这两个位点对转移风险的影响可能不是通过调控血浆中TGF-β1的含量发挥作用,具体机制有待于进一步研究阐明。我们的发现若能在其它中心进行独立样本的验证,将有助于在治疗前筛选鼻咽癌高转移风险的亚组人群,进一步完善个体化治疗的进行。背景:远处转移是目前鼻咽癌治疗失败的主要原因,如何在治疗前识别具有高转移风险的患者成为提高疗效的关键问题。虽然临床分期在指导治疗及预后判断上发挥了重要作用,然而相同临床分期的患者在经过同样的治疗手段后,其治疗效果及病情转归可能存在很大的差异,越来越多的研究表明,个体遗传因素在这种预后差异中扮演了重要的角色。转化生长因子β(transforming growth factor-beta,TGF-β)信号转导通路的异常与鼻咽癌的发生发展密切相关。本研究的第一部分已对Smad依赖经典途径,即TGF-β1/Smad途径中的12个单核苷酸多态性(Single Nucleotide Polymorphism,SNP)位点进行基因分型,发现该通路的遗传变异与鼻咽癌的远处转移风险相关联,本部分的内容拟针对该通路中非Smad依赖的途径,即PI3K/PTEN/AKT/m TOR信号传导通路中关键基因的标签SNP(Tag SNP)位点进行分型,探讨该途径遗传变异是否与鼻咽癌远处转移有关联。方法:研究共纳入496例2012.01-2013.05期间于我院就诊的初治无远处转移的鼻咽癌患者,均接受调强放射治疗且治疗前均留有全血标本。选取PI3K/PTEN/AKT/m TOR通路中关键基因的16个标签SNP(Tag SNP),采用基质辅助激光解吸附电离飞行时间质谱和Taq Man探针的方法行SNP分型。利用Kaplan-Meier及Cox比例风险模型评估各SNP与鼻咽癌远处转移风险的关联。此外,我们利用递归分割(recursive partitioning analysis,RPA)的分析方法,整合风险基因型与解剖学因素建立RPA模型,并利用赤池信息量准则(Akaike information criterion,AIC)和哈勒尔一致性指数(Harrell’s concordance index,C指数)比较N分期、临床分期和RPA模型对转移风险的预测能力。结果:全组患者中位随访时间40个月(范围4~51个月),3年总生存及3年无远处转移生存时间分别为91.8%和85.1%。在16个纳入分型的Tag SNP中仅AKT1:rs3803300和AKT1:rs2494738对患者的远处转移风险具有显著预测价值。AKT1:rs3803300 GG基因型与AKT1:rs2494738 GA/AA基因型具有更高的远处转移风险(AKT1:rs3803300 HR 0.536,95%CI 0.292-0.986,P=0.045;AKT1:rs2494738 HR 0.530,95%CI 0.302-0.929,P=0.027)。联合分析显示携带风险基因者无远处转移生存显著低于不携带者(HR 0.443,95%CI 0.264-0.744,P=0.002)。RPA方法将患者分为四个不同风险组:RPA1为低危组(N0-1但无携带风险基因型),RPA2为中危组(N0-1且携带风险基因型),RPA3为高危组(N2-3但无携带风险基因型)和RPA4为极高危组(N2-3且携带风险基因型)。该RPA模型对远处转移生存也具有显著预后预测价值(HR1.846,95%CI 1.443-2.361,P0.001)。与N分期及临床分期相比,RPA模型具有更低的AIC值以及更高的C指数,说明RPA模型拟合程度最好,评估远处转移风险的能力最强。结论:我们发现PI3K/PTEN/AKT/m TOR信号通路中的AKT1:rs3803300和AKT1:rs2494738与鼻咽癌患者远处转移的风险相关联,且这两个位点组合的风险基因型与N分期组成的RPA模型对远处转移风险的评估能力优于N分期及临床分期,可能可以作为解剖学分期的有效补充用于筛选鼻咽癌高转移风险的亚组人群,进一步完善个体化治疗的进行。我们的发现有待于在其他中心进行独立样本的验证,且该通路遗传变异影响转移潜能的具体机制也需要后续进一步的功能验证阐明。
[Abstract]:Background: with the progress of imaging diagnosis and radiotherapy technology, the local regional control rate of nasopharyngeal carcinoma has been greatly improved. Distant metastasis has become the main cause of treatment failure. How to identify patients with high metastasis risk before treatment is the key problem to improve the efficacy. Although clinical stages are guiding the treatment and prognosis judgment However, more and more studies have shown that individual genetic factors play an important role in this difference in prognosis. Transforming growth factor-beta, TGF- The abnormal signal transduction pathway is closely related to the occurrence and development of nasopharyngeal carcinoma. This study intends to explore the classical pathway of Smad dependence in 496 cases of Chinese Han nasopharyngeal carcinoma, that is, the association of the single nucleotide polymorphisms of the key genes (Single Nucleotide Polymorphism, SNP) to the distant metastasis risk of nasopharyngeal carcinoma in the TGF- beta 1/Smad pathway. Methods: a total of 496 patients with nasopharyngeal carcinoma without distant metastasis were enrolled in our hospital during the period of 2012.01-2013.05. All the patients were treated with intensity modulated radiation therapy and all blood samples were left before treatment. 12 label SNP (Tag SNP) of the key genes in the TGF- beta 1/Smad pathway were selected, and the base assisted laser desorption ionization time of flight mass spectrometry and Taq M were used. The an probe method was used for SNP typing. The correlation between SNP and distant metastasis risk of nasopharyngeal carcinoma was evaluated using the Kaplan-Meier and Cox proportional hazard model. In addition, the plasma TGF- beta 1 content was detected by ELISA method in 147 cases of corresponding patients, and the effect of TGF- beta 1 genotypes on the level of TGF- beta 1 was evaluated. The follow-up time of 40 months (range 4~51 months), 3 years of total survival and 3 years of non distant metastasis survival time were 91.8% and 85.1%.TGF- beta 1/Smad pathway included 12 Tag SNP types. We found that only TGF- beta 1:rs1800469 and TGF- beta 1:rs1800470 have independent predictive value for the distant metastasis risk of.TGF- beta 1:rs1800469 CC genotypes. Higher distant metastasis risk (HR0.560,95%CI 0.335-0.936, P=0.027) and mainly in advanced patients; TGF- beta 1:rs1800470TT genotype carriers also showed a higher risk of distant metastasis (HR 0.499,95%CI 0.301-0.827, P=0.007), which had predictive value in early and late patients. Further analysis found that there were two risk groups. The risk of distant metastasis was the highest, and the risk genotypes had the lowest risk of distant metastasis, which indicated that the two loci had the superposition effect. With the increase in the number of risk genes, the transfer risk increased gradually (P=0.012). The content of TGF- beta 1 in plasma was detected by ELISA, and two were found. There is no significant association between the polymorphism of the loci and the content of TGF- beta 1 in plasma (P0.05). Conclusion: we found that the TGF- beta 1:rs1800469 and TGF- beta 1:rs1800470 in the TGF- beta 1/Smad signaling pathway are associated with the risk of distant metastasis in patients with nasopharyngeal carcinoma. The two loci also have a superposition effect in assessing the risk of metastasis, with the number of carrying risk genes. The risk of transfer increases gradually. The two sites may affect the risk of metastasis not by regulating the levels of TGF- beta 1 in the plasma, and the specific mechanism remains to be further clarified. Our findings will help to screen the risk of high metastasis of nasopharyngeal carcinoma before treatment. Background: distant metastasis is the main reason for the failure of nasopharyngeal carcinoma treatment, and how to identify patients with high risk of metastasis before treatment is the key problem to improve the curative effect. Although clinical staging plays an important role in guiding the treatment and prognosis, it is the same clinical practice. After the same treatment, the therapeutic effects and prognosis may vary greatly. More and more studies have shown that individual genetic factors play an important role in this prognostic difference. The abnormalities of the transforming growth factor-beta (TGF- beta) signal transduction pathway and nasopharynx The first part of this study has identified the genetic variation of the 12 single nucleotide polymorphisms (Single Nucleotide Polymorphism, SNP) loci in the Smad dependent TGF- beta 1/Smad pathway, and found that the genetic variation of the pathway is associated with the risk of distant metastasis of nasopharyngeal carcinoma. The content of this part is intended to be targeted. The non Smad dependent pathway in this pathway, the label SNP (Tag SNP) site of the key gene in the PI3K/PTEN/AKT/m TOR signal transduction pathway, is typed to investigate whether the genetic variation of this pathway is associated with distant metastasis of nasopharyngeal carcinoma. Methods: a total of 496 cases of nasopharyngeal carcinoma without distant metastasis in our hospital during 2012.01-2013.05 period were included. All the patients were treated with intensity modulated radiation therapy and all blood samples were left before treatment. 16 label SNP (Tag SNP) of the key genes in the PI3K/PTEN/AKT/m TOR pathway were selected. The matrix assisted laser desorption ionization time of flight mass spectrometry and Taq Man probe were used for SNP typing. Kaplan-Meier and Cox proportional hazard model was used to evaluate the SNP and nasopharynx. In addition, we use the recursive partitioning analysis (RPA) analysis method to integrate the risk genotypes and anatomical factors to establish the RPA model, and use the Chi Chi information criterion (Akaike information criterion, AIC) and the Harar consensus index (Harrell 's concordance) index. Comparison of N staging, clinical staging and RPA model's predictive ability to transfer risk. Results: the median follow-up time was 40 months (4~51 months), 3 years of total survival and 3 years without distant metastasis were 91.8% and 85.1%. in 16 subtypes of Tag SNP only AKT1:rs3803300 and AKT1:rs2494738 against patients' distant metastasis wind. Risk has a significant predictive value,.AKT1:rs3803300 GG genotype and AKT1:rs2494738 GA/AA genotype have higher distant metastasis risk (AKT1:rs3803300 HR 0.536,95%CI 0.292-0.986, P=0.045; AKT1:rs2494738 HR 0.530,95%CI). The HR 0.443,95%CI 0.264-0.744 (P=0.002).RPA method was used to divide the patients into four different risk groups: RPA1 was a low risk group (N0-1 but without risk genotypes), RPA2 was a medium risk group (N0-1 and carrying risk genotypes), RPA3 was a high-risk group (N2-3 but without risk genotypes) and RPA4 was a high-risk group. It also has a significant prognostic value (HR1.846,95%CI 1.443-2.361, P0.001) for distant metastasis (P0.001). Compared with N staging and clinical staging, the RPA model has a lower AIC value and a higher C index, indicating the best fitting degree of the RPA model and the strongest ability to assess the risk of distant metastases. Conclusion: we found PI3K/PTEN/AKT/m TOR signaling. AKT1:rs3803300 and AKT1:rs2494738 in the road are associated with the risk of distant metastasis in nasopharyngeal carcinoma, and the risk genotypes composed of the two sites and the RPA model of N staging are superior to N staging and clinical staging, which may be used as an effective supplement to the selection of nasopharyngeal carcinoma as an effective supplement to the anatomical staging. The group of risk shifting subgroups further perfected the conduct of individualized therapy. Our findings need to be verified by independent samples in other centers, and the specific mechanisms that affect the potential of genetic variation in the pathway also require further functional verification.
【学位授予单位】：福建医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R739.63
[Abstract]:Background: with the progress of imaging diagnosis and radiotherapy technology, the local regional control rate of nasopharyngeal carcinoma has been greatly improved. Distant metastasis has become the main cause of treatment failure. How to identify patients with high metastasis risk before treatment is the key problem to improve the efficacy. Although clinical stages are guiding the treatment and prognosis judgment However, more and more studies have shown that individual genetic factors play an important role in this difference in prognosis. Transforming growth factor-beta, TGF- The abnormal signal transduction pathway is closely related to the occurrence and development of nasopharyngeal carcinoma. This study intends to explore the classical pathway of Smad dependence in 496 cases of Chinese Han nasopharyngeal carcinoma, that is, the association of the single nucleotide polymorphisms of the key genes (Single Nucleotide Polymorphism, SNP) to the distant metastasis risk of nasopharyngeal carcinoma in the TGF- beta 1/Smad pathway. Methods: a total of 496 patients with nasopharyngeal carcinoma without distant metastasis were enrolled in our hospital during the period of 2012.01-2013.05. All the patients were treated with intensity modulated radiation therapy and all blood samples were left before treatment. 12 label SNP (Tag SNP) of the key genes in the TGF- beta 1/Smad pathway were selected, and the base assisted laser desorption ionization time of flight mass spectrometry and Taq M were used. The an probe method was used for SNP typing. The correlation between SNP and distant metastasis risk of nasopharyngeal carcinoma was evaluated using the Kaplan-Meier and Cox proportional hazard model. In addition, the plasma TGF- beta 1 content was detected by ELISA method in 147 cases of corresponding patients, and the effect of TGF- beta 1 genotypes on the level of TGF- beta 1 was evaluated. The follow-up time of 40 months (range 4~51 months), 3 years of total survival and 3 years of non distant metastasis survival time were 91.8% and 85.1%.TGF- beta 1/Smad pathway included 12 Tag SNP types. We found that only TGF- beta 1:rs1800469 and TGF- beta 1:rs1800470 have independent predictive value for the distant metastasis risk of.TGF- beta 1:rs1800469 CC genotypes. Higher distant metastasis risk (HR0.560,95%CI 0.335-0.936, P=0.027) and mainly in advanced patients; TGF- beta 1:rs1800470TT genotype carriers also showed a higher risk of distant metastasis (HR 0.499,95%CI 0.301-0.827, P=0.007), which had predictive value in early and late patients. Further analysis found that there were two risk groups. The risk of distant metastasis was the highest, and the risk genotypes had the lowest risk of distant metastasis, which indicated that the two loci had the superposition effect. With the increase in the number of risk genes, the transfer risk increased gradually (P=0.012). The content of TGF- beta 1 in plasma was detected by ELISA, and two were found. There is no significant association between the polymorphism of the loci and the content of TGF- beta 1 in plasma (P0.05). Conclusion: we found that the TGF- beta 1:rs1800469 and TGF- beta 1:rs1800470 in the TGF- beta 1/Smad signaling pathway are associated with the risk of distant metastasis in patients with nasopharyngeal carcinoma. The two loci also have a superposition effect in assessing the risk of metastasis, with the number of carrying risk genes. The risk of transfer increases gradually. The two sites may affect the risk of metastasis not by regulating the levels of TGF- beta 1 in the plasma, and the specific mechanism remains to be further clarified. Our findings will help to screen the risk of high metastasis of nasopharyngeal carcinoma before treatment. Background: distant metastasis is the main reason for the failure of nasopharyngeal carcinoma treatment, and how to identify patients with high risk of metastasis before treatment is the key problem to improve the curative effect. Although clinical staging plays an important role in guiding the treatment and prognosis, it is the same clinical practice. After the same treatment, the therapeutic effects and prognosis may vary greatly. More and more studies have shown that individual genetic factors play an important role in this prognostic difference. The abnormalities of the transforming growth factor-beta (TGF- beta) signal transduction pathway and nasopharynx The first part of this study has identified the genetic variation of the 12 single nucleotide polymorphisms (Single Nucleotide Polymorphism, SNP) loci in the Smad dependent TGF- beta 1/Smad pathway, and found that the genetic variation of the pathway is associated with the risk of distant metastasis of nasopharyngeal carcinoma. The content of this part is intended to be targeted. The non Smad dependent pathway in this pathway, the label SNP (Tag SNP) site of the key gene in the PI3K/PTEN/AKT/m TOR signal transduction pathway, is typed to investigate whether the genetic variation of this pathway is associated with distant metastasis of nasopharyngeal carcinoma. Methods: a total of 496 cases of nasopharyngeal carcinoma without distant metastasis in our hospital during 2012.01-2013.05 period were included. All the patients were treated with intensity modulated radiation therapy and all blood samples were left before treatment. 16 label SNP (Tag SNP) of the key genes in the PI3K/PTEN/AKT/m TOR pathway were selected. The matrix assisted laser desorption ionization time of flight mass spectrometry and Taq Man probe were used for SNP typing. Kaplan-Meier and Cox proportional hazard model was used to evaluate the SNP and nasopharynx. In addition, we use the recursive partitioning analysis (RPA) analysis method to integrate the risk genotypes and anatomical factors to establish the RPA model, and use the Chi Chi information criterion (Akaike information criterion, AIC) and the Harar consensus index (Harrell 's concordance) index. Comparison of N staging, clinical staging and RPA model's predictive ability to transfer risk. Results: the median follow-up time was 40 months (4~51 months), 3 years of total survival and 3 years without distant metastasis were 91.8% and 85.1%. in 16 subtypes of Tag SNP only AKT1:rs3803300 and AKT1:rs2494738 against patients' distant metastasis wind. Risk has a significant predictive value,.AKT1:rs3803300 GG genotype and AKT1:rs2494738 GA/AA genotype have higher distant metastasis risk (AKT1:rs3803300 HR 0.536,95%CI 0.292-0.986, P=0.045; AKT1:rs2494738 HR 0.530,95%CI). The HR 0.443,95%CI 0.264-0.744 (P=0.002).RPA method was used to divide the patients into four different risk groups: RPA1 was a low risk group (N0-1 but without risk genotypes), RPA2 was a medium risk group (N0-1 and carrying risk genotypes), RPA3 was a high-risk group (N2-3 but without risk genotypes) and RPA4 was a high-risk group. It also has a significant prognostic value (HR1.846,95%CI 1.443-2.361, P0.001) for distant metastasis (P0.001). Compared with N staging and clinical staging, the RPA model has a lower AIC value and a higher C index, indicating the best fitting degree of the RPA model and the strongest ability to assess the risk of distant metastases. Conclusion: we found PI3K/PTEN/AKT/m TOR signaling. AKT1:rs3803300 and AKT1:rs2494738 in the road are associated with the risk of distant metastasis in nasopharyngeal carcinoma, and the risk genotypes composed of the two sites and the RPA model of N staging are superior to N staging and clinical staging, which may be used as an effective supplement to the selection of nasopharyngeal carcinoma as an effective supplement to the anatomical staging. The group of risk shifting subgroups further perfected the conduct of individualized therapy. Our findings need to be verified by independent samples in other centers, and the specific mechanisms that affect the potential of genetic variation in the pathway also require further functional verification.
【学位授予单位】：福建医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R739.63
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