【摘要】：背景:隨著影像診斷技術(shù)和放射治療技術(shù)的進(jìn)步,鼻咽癌的局部區(qū)域控制率得到很大提高,遠(yuǎn)處轉(zhuǎn)移成為治療失敗的主要原因。如何在治療前識(shí)別具有高轉(zhuǎn)移風(fēng)險(xiǎn)的患者成為提高療效的關(guān)鍵問(wèn)題。雖然臨床分期在指導(dǎo)治療及預(yù)后判斷上發(fā)揮了重要作用,然而相同臨床分期的患者在經(jīng)過(guò)同樣的治療手段后,其治療效果及病情轉(zhuǎn)歸可能存在很大的差異,越來(lái)越多的研究表明,個(gè)體遺傳因素在這種預(yù)后差異中扮演了重要的角色。轉(zhuǎn)化生長(zhǎng)因子β(transforming growth factor-beta,TGF-β)信號(hào)轉(zhuǎn)導(dǎo)通路的異常與鼻咽癌的發(fā)生發(fā)展密切相關(guān),本研究擬在496例中國(guó)漢族鼻咽癌患者中探討該通路Smad依賴的經(jīng)典途徑,即TGF-β1/Smad途徑中關(guān)鍵基因的單核苷酸多態(tài)性(Single Nucleotide Polymorphism,SNP)與鼻咽癌遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)的關(guān)聯(lián)。方法:研究共納入496例2012.01-2013.05期間于我院就診的初治無(wú)遠(yuǎn)處轉(zhuǎn)移的鼻咽癌患者,均接受調(diào)強(qiáng)放射治療且治療前均留有全血標(biāo)本。選取TGF-β1/Smad通路中關(guān)鍵基因的12個(gè)標(biāo)簽SNP(Tag SNP),采用基質(zhì)輔助激光解吸附電離飛行時(shí)間質(zhì)譜和Taq Man探針的方法行SNP分型。利用Kaplan-Meier及Cox比例風(fēng)險(xiǎn)模型評(píng)估各SNP與鼻咽癌遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)的關(guān)聯(lián)。此外,本研究還利用ELISA方法檢測(cè)了147例相對(duì)應(yīng)患者的血漿TGF-β1含量,評(píng)估TGF-β1不同基因型對(duì)血漿TGF-β1水平的影響。結(jié)果:全組患者中位隨訪時(shí)間40個(gè)月(范圍4~51個(gè)月),3年總生存及3年無(wú)遠(yuǎn)處轉(zhuǎn)移生存時(shí)間分別為91.8%和85.1%。TGF-β1/Smad通路中共有12個(gè)Tag SNP納入分型,我們發(fā)現(xiàn)僅TGF-β1:rs1800469和TGF-β1:rs1800470對(duì)遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)具有獨(dú)立預(yù)測(cè)價(jià)值。TGF-β1:rs1800469 CC基因型攜帶者具有更高的遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)(HR0.560,95%CI 0.335-0.936,P=0.027),且主要體現(xiàn)在晚期患者;TGF-β1:rs1800470TT基因型攜帶者也表現(xiàn)出更高的遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)(HR 0.499,95%CI 0.301-0.827,P=0.007),在早晚期患者中均具有預(yù)測(cè)價(jià)值。進(jìn)一步分析發(fā)現(xiàn)具有兩個(gè)風(fēng)險(xiǎn)基因型的患者遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)最高,具備一個(gè)風(fēng)險(xiǎn)基因型的次之,而不具備風(fēng)險(xiǎn)基因型的遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)最低,這說(shuō)明兩個(gè)位點(diǎn)具有疊加效應(yīng),隨著攜帶風(fēng)險(xiǎn)基因數(shù)量增加,轉(zhuǎn)移風(fēng)險(xiǎn)逐漸增加(P=0.012)。利用ELISA檢測(cè)血漿中TGF-β1的含量,發(fā)現(xiàn)兩個(gè)位點(diǎn)的基因多態(tài)性與血漿中TGF-β1的含量無(wú)明顯關(guān)聯(lián)(P0.05)。結(jié)論:我們發(fā)現(xiàn)TGF-β1/Smad信號(hào)通路中的TGF-β1:rs1800469和TGF-β1:rs1800470與鼻咽癌患者遠(yuǎn)處轉(zhuǎn)移的風(fēng)險(xiǎn)相關(guān)聯(lián),兩個(gè)位點(diǎn)在評(píng)估轉(zhuǎn)移風(fēng)險(xiǎn)上還具有疊加效應(yīng),隨著攜帶風(fēng)險(xiǎn)基因數(shù)量增加,轉(zhuǎn)移風(fēng)險(xiǎn)逐漸增加。這兩個(gè)位點(diǎn)對(duì)轉(zhuǎn)移風(fēng)險(xiǎn)的影響可能不是通過(guò)調(diào)控血漿中TGF-β1的含量發(fā)揮作用,具體機(jī)制有待于進(jìn)一步研究闡明。我們的發(fā)現(xiàn)若能在其它中心進(jìn)行獨(dú)立樣本的驗(yàn)證,將有助于在治療前篩選鼻咽癌高轉(zhuǎn)移風(fēng)險(xiǎn)的亞組人群,進(jìn)一步完善個(gè)體化治療的進(jìn)行。背景:遠(yuǎn)處轉(zhuǎn)移是目前鼻咽癌治療失敗的主要原因,如何在治療前識(shí)別具有高轉(zhuǎn)移風(fēng)險(xiǎn)的患者成為提高療效的關(guān)鍵問(wèn)題。雖然臨床分期在指導(dǎo)治療及預(yù)后判斷上發(fā)揮了重要作用,然而相同臨床分期的患者在經(jīng)過(guò)同樣的治療手段后,其治療效果及病情轉(zhuǎn)歸可能存在很大的差異,越來(lái)越多的研究表明,個(gè)體遺傳因素在這種預(yù)后差異中扮演了重要的角色。轉(zhuǎn)化生長(zhǎng)因子β(transforming growth factor-beta,TGF-β)信號(hào)轉(zhuǎn)導(dǎo)通路的異常與鼻咽癌的發(fā)生發(fā)展密切相關(guān)。本研究的第一部分已對(duì)Smad依賴經(jīng)典途徑,即TGF-β1/Smad途徑中的12個(gè)單核苷酸多態(tài)性(Single Nucleotide Polymorphism,SNP)位點(diǎn)進(jìn)行基因分型,發(fā)現(xiàn)該通路的遺傳變異與鼻咽癌的遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)相關(guān)聯(lián),本部分的內(nèi)容擬針對(duì)該通路中非Smad依賴的途徑,即PI3K/PTEN/AKT/m TOR信號(hào)傳導(dǎo)通路中關(guān)鍵基因的標(biāo)簽SNP(Tag SNP)位點(diǎn)進(jìn)行分型,探討該途徑遺傳變異是否與鼻咽癌遠(yuǎn)處轉(zhuǎn)移有關(guān)聯(lián)。方法:研究共納入496例2012.01-2013.05期間于我院就診的初治無(wú)遠(yuǎn)處轉(zhuǎn)移的鼻咽癌患者,均接受調(diào)強(qiáng)放射治療且治療前均留有全血標(biāo)本。選取PI3K/PTEN/AKT/m TOR通路中關(guān)鍵基因的16個(gè)標(biāo)簽SNP(Tag SNP),采用基質(zhì)輔助激光解吸附電離飛行時(shí)間質(zhì)譜和Taq Man探針的方法行SNP分型。利用Kaplan-Meier及Cox比例風(fēng)險(xiǎn)模型評(píng)估各SNP與鼻咽癌遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)的關(guān)聯(lián)。此外,我們利用遞歸分割(recursive partitioning analysis,RPA)的分析方法,整合風(fēng)險(xiǎn)基因型與解剖學(xué)因素建立RPA模型,并利用赤池信息量準(zhǔn)則(Akaike information criterion,AIC)和哈勒爾一致性指數(shù)(Harrell’s concordance index,C指數(shù))比較N分期、臨床分期和RPA模型對(duì)轉(zhuǎn)移風(fēng)險(xiǎn)的預(yù)測(cè)能力。結(jié)果:全組患者中位隨訪時(shí)間40個(gè)月(范圍4~51個(gè)月),3年總生存及3年無(wú)遠(yuǎn)處轉(zhuǎn)移生存時(shí)間分別為91.8%和85.1%。在16個(gè)納入分型的Tag SNP中僅AKT1:rs3803300和AKT1:rs2494738對(duì)患者的遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)具有顯著預(yù)測(cè)價(jià)值。AKT1:rs3803300 GG基因型與AKT1:rs2494738 GA/AA基因型具有更高的遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)(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)。聯(lián)合分析顯示攜帶風(fēng)險(xiǎn)基因者無(wú)遠(yuǎn)處轉(zhuǎn)移生存顯著低于不攜帶者(HR 0.443,95%CI 0.264-0.744,P=0.002)。RPA方法將患者分為四個(gè)不同風(fēng)險(xiǎn)組:RPA1為低危組(N0-1但無(wú)攜帶風(fēng)險(xiǎn)基因型),RPA2為中危組(N0-1且攜帶風(fēng)險(xiǎn)基因型),RPA3為高危組(N2-3但無(wú)攜帶風(fēng)險(xiǎn)基因型)和RPA4為極高危組(N2-3且攜帶風(fēng)險(xiǎn)基因型)。該RPA模型對(duì)遠(yuǎn)處轉(zhuǎn)移生存也具有顯著預(yù)后預(yù)測(cè)價(jià)值(HR1.846,95%CI 1.443-2.361,P0.001)。與N分期及臨床分期相比,RPA模型具有更低的AIC值以及更高的C指數(shù),說(shuō)明RPA模型擬合程度最好,評(píng)估遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)的能力最強(qiáng)。結(jié)論:我們發(fā)現(xiàn)PI3K/PTEN/AKT/m TOR信號(hào)通路中的AKT1:rs3803300和AKT1:rs2494738與鼻咽癌患者遠(yuǎn)處轉(zhuǎn)移的風(fēng)險(xiǎn)相關(guān)聯(lián),且這兩個(gè)位點(diǎn)組合的風(fēng)險(xiǎn)基因型與N分期組成的RPA模型對(duì)遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)的評(píng)估能力優(yōu)于N分期及臨床分期,可能可以作為解剖學(xué)分期的有效補(bǔ)充用于篩選鼻咽癌高轉(zhuǎn)移風(fēng)險(xiǎn)的亞組人群,進(jìn)一步完善個(gè)體化治療的進(jìn)行。我們的發(fā)現(xiàn)有待于在其他中心進(jìn)行獨(dú)立樣本的驗(yàn)證,且該通路遺傳變異影響轉(zhuǎn)移潛能的具體機(jī)制也需要后續(xù)進(jìn)一步的功能驗(yàn)證闡明。
[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.
【學(xué)位授予單位】：福建醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R739.63

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8 李菊蘭;蔡華成;梁傳余;韓偉;;生長(zhǎng)抑素Ⅱ型受體在鼻咽癌組織中的表達(dá)[A];中華醫(yī)學(xué)會(huì)第十次全國(guó)耳鼻咽喉-頭頸外科學(xué)術(shù)會(huì)議論文匯編（下）[C];2007年

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10 潘建基;;鼻咽癌臨床診治現(xiàn)狀和進(jìn)展[A];中國(guó)腫瘤內(nèi)科進(jìn)展 中國(guó)腫瘤醫(yī)師教育（2014）[C];2014年

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2 本報(bào)記者　 盧育輝;崇尚“紅�！本�,喜歡“咖啡”會(huì)友[N];廣東科技報(bào);2006年

3 本報(bào)記者　 羅艾樺;挑戰(zhàn)“廣東癌”[N];人民日?qǐng)?bào);2006年

4 仁華南;“回國(guó)發(fā)展是一項(xiàng)明智的選擇”[N];人民日?qǐng)?bào)海外版;2006年

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6 廣東省第二人民醫(yī)院 主任醫(yī)師 蔡長(zhǎng)青;病毒與某些癌癥[N];家庭醫(yī)生報(bào);2005年

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6 馬，

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