本文關(guān)鍵詞：紫杉醇相關(guān)外周神經(jīng)病變的單核苷酸多態(tài)性及黑色素瘤不同轉(zhuǎn)移灶免疫譜的差異研究　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 紫杉醇 外周感覺神經(jīng)病變 化療副反應(yīng) 中國漢族人群 黑素素瘤 免疫譜 C反應(yīng)蛋白 補體

【摘要】：[研究背景]化療介導(dǎo)的外周神經(jīng)病變是常見的劑量限制性藥物不良反應(yīng),影響患者生活質(zhì)量。紫杉醇為常用的化療藥物,尋找與其介導(dǎo)的外周感覺神經(jīng)病變(peripheral sensory neuropathy,PSN)相關(guān)的標記物具有重要意義。過去研究多集中在臨床病理因素上,結(jié)論不一。近年來,隨著藥物基因組學(xué)的發(fā)展,一些可能與2/3級紫杉醇介導(dǎo)PSN相關(guān)的單核苷酸基因多態(tài)性(single nucleotide polymorphism,SNP)位點在其他人種中得到證實。然而目前缺乏在中國漢族(Han Chinese in Beijing,CHB)人群中的相關(guān)研究數(shù)據(jù)。本研究旨在探討在CHB人群中,與2/3級紫杉醇介導(dǎo)PSN發(fā)生風(fēng)險相關(guān)的SNP位點。[研究方法]在2014年5月至2016年12月期間,入組北京協(xié)和醫(yī)院216名接受紫杉醇方案化療的中國漢族患者,提取外周血DNA。根據(jù)NCI-CTCAE標準,由受訓(xùn)的臨床醫(yī)生完成患者隨訪及PSN分級。查閱文獻,篩選所有全基因組關(guān)聯(lián)分析(genome wide association study,GWAS)研究或單基因研究報道的,在其他人種中,與2級及以上紫杉醇介導(dǎo)PSN可能相關(guān),且在NCBI-dbSNP數(shù)據(jù)庫的CHB人群中,最小等位基因頻率(Minor allele frequency,MAF)0.05的候選SNP位點。使用Sequenom MassARRARY iPLEX平臺測定患者DNA的候選SNP基因型。分析各SNP位點以及臨床病理因素與2/3級紫杉醇介導(dǎo)PSN發(fā)生的相關(guān)性。[研究結(jié)果]最終209名患者納入分析,在34個通過質(zhì)控的候選SNP位點中,僅 rs4141404:CA(LIMK2 與 2/3 級 PSN 顯著相關(guān)(OR 4.32,95%CI 2.37-7.89,校正 p0.0001),rs501461:TG(GLIS3)(OR 1.77,95%CI 1.07-2.92,p=0.027,校正p=0.75)的Bonferroni校正p值未達統(tǒng)計學(xué)意義。臨床病理單因素logistic回歸中,既往鉑類用藥史與發(fā)生2/3級PSN顯著相關(guān)(OR 1.99,95%CI 1.07-3.69,p=0.03)。在多因素logistic回歸中,rs4141404:CA(LIMK2)多態(tài)性以及既往鉑類用藥史與2/3級PSN發(fā)生風(fēng)險相關(guān)。[研究結(jié)論]本研究是首個在最大隊列的中國漢族人群中,獨立開展的紫杉醇介導(dǎo)PSN的藥物基因組學(xué)研究。Rs4141404:CA(LIMK2)多態(tài)性可能與發(fā)生紫杉醇介導(dǎo)的2/3級PSN相關(guān)。既往有鉑類用藥史這一臨床病理因素可能增加紫杉醇介導(dǎo)的2/3級PSN的發(fā)生風(fēng)險;這有助于指導(dǎo)紫杉醇化療方案的個體化選擇。[研究背景]黑色素瘤是最具有侵襲性的皮膚癌癥之一,隨著免疫治療的發(fā)展,晚期患者的總生存得到了大大提高,但針對治療反應(yīng)的臨床研究發(fā)現(xiàn),具有肝轉(zhuǎn)移的患者比具有肺轉(zhuǎn)移的患者治療反應(yīng)更差。長期以來,研究顯示免疫系統(tǒng)對腫瘤的生發(fā)和調(diào)節(jié)起重要作用。研究不同轉(zhuǎn)移病灶的免疫譜可以幫助人們更好的理解病灶之間的差異特點,為臨床治療策略提供一定的啟示。[研究方法]利用澳大利亞墨爾本Peter MacCallum癌癥中心募集的10名患者的尸檢癌癥轉(zhuǎn)移灶標本,對福爾馬林固定石蠟包埋的標本(FFPE)進行腫瘤灶的顯微解剖,使用nCounter Nanostring(?)技術(shù)進行免疫譜mRNA的測定,對所得數(shù)據(jù)進行肝臟轉(zhuǎn)移灶對比非肝臟轉(zhuǎn)移灶的差異表達分析,使用ClueGO進行差異表達基因構(gòu)成分析。使用逆轉(zhuǎn)錄實時定量PCR(qPCR)對差異表達明顯的CRP和C5基因進行測定,驗證Nanostring的結(jié)果。針對差異表達最顯著的基因,在手術(shù)活檢標本中進行免疫組化進一步驗證。對所有病灶進行CD3和PD-L1免疫組化染色,使用Vectra自動數(shù)字定量系統(tǒng)進行定量,比較組間差異。[研究結(jié)果]由于1個肝臟轉(zhuǎn)移灶的基因表達數(shù)據(jù)標準分數(shù)(z-score)＞3.0而被排除,分析共納入9個肝臟轉(zhuǎn)移灶、21個非肝轉(zhuǎn)移灶、5個正常組織。肝臟轉(zhuǎn)移灶和非肝轉(zhuǎn)移灶的免疫系統(tǒng)基因譜中,差異表達最大的基因是C反應(yīng)蛋白(CRP),顯著差異的基因主要涉及補體激活途徑。針對同一標本,qPCR對CRP和C5基因驗證的結(jié)果與Nanostring高度一致。進一步在3個手術(shù)肝轉(zhuǎn)移標本、7個非肝手術(shù)轉(zhuǎn)移標本進行CRP免疫組化檢查,其結(jié)果與Nanostring數(shù)據(jù)結(jié)果一致。此外,在肝臟和非肝臟轉(zhuǎn)移灶的腫瘤中心和浸潤邊緣,CD3和PD-L1表達水平均較低,組間無顯著差異。[研究結(jié)論]黑色素瘤患者肝轉(zhuǎn)移病灶和非肝轉(zhuǎn)移病灶中,CRP、補體等表達差異是構(gòu)成其免疫基因表達的主要差別,該研究結(jié)果可能為臨床免疫治療提供一定的靶向治療策略。
[Abstract]:[background] peripheral neuropathy chemotherapy mediated adverse reactions of drugs is a common dose limiting, affect life quality of patients. Paclitaxel chemotherapy drug used, find its mediated peripheral sensory neuropathy (peripheral sensory, neuropathy, PSN) has important significance related to mark the previous research. Focus on the clinical pathological factors, not a conclusion. In recent years, with the development of pharmacogenomics, some may be mediated by paclitaxel and 2/3 single nucleotide polymorphisms related to PSN (single nucleotide polymorphism, SNP) who is confirmed in other ethnic groups. However, the lack of China Han (Han Chinese in in Beijing CHB), relevant research data in the crowd. This study aims to investigate among CHB, 2/3 and paclitaxel mediated PSN risk related SNP locus. Research methods in May 2014 to 2016 12 During the month, the group of 216 Peking Union Medical College Hospital received paclitaxel chemotherapy China Han patients, extracted from peripheral blood of DNA. according to the NCI-CTCAE standard, by trained clinicians and patients completed follow-up PSN grading. The literature, all screening analysis of genome-wide association (genome wide association study, GWAS) or of single gene reported in. In other races, and 2 and above of paclitaxel mediated by PSN may be related, and in the NCBI-dbSNP database of the CHB population, the minimum allele frequency (Minor, allele frequency, MAF) SNP 0.05. The candidate candidate loci SNP genotype patients were determined using Sequenom DNA MassARRARY iPLEX platform. The SNP locus and clinical analysis pathological factors and 2/3 Kisugi Suke correlation between the results of the occurrence of PSN. Of 209 patients included in the final analysis], in 34 through the quality control of candidate SNP loci, only rs4141404: CA LIMK2 was significantly correlated with 2/3 level (PSN (OR 4.32,95%CI 2.37-7.89, P0.0001, rs501461:TG correction) (GLIS3) (OR 1.77,95%CI 1.07-2.92, p=0.027, adjusted p=0.75) Bonferroni correction p value did not reach statistical significance. The clinical pathology of single factor Logistic regression, 2/3 PSN level was significantly related to previous platinum drug history and occurrence (OR 1.99,95%CI 1.07-3.69, p=0.03). In logistic regression, rs4141404:CA (LIMK2) polymorphism and previous platinum drug history and 2/3 PSN risk related research conclusion. This study is the first in the largest cohort of China Han population, drug paclitaxel mediated genome independently by PSN research.Rs4141404:CA (LIMK2) polymorphism may be associated with the occurrence of paclitaxel mediated 2/3 PSN. With a history of platinum drug history the clinical pathological factors may increase the risk of developing paclitaxel mediated by 2/3 PSN; this will help Individual choice. Background melanoma in paclitaxel chemotherapy is one of the most aggressive skin cancer, along with the development of the immune therapy, the overall survival of patients with advanced has been greatly improved, but the clinical study of the treatment response, patients with liver metastasis than patients with pulmonary reaction metastasis is poor. For a long time, research shows that the immune system of the tumor development and plays an important role in the regulation. The difference between features can help people better understand the immune lesion of different metastatic lesions spectrum, autopsy of 10 patients of cancer metastasis specimens provide inspiration. Some research methods using Australia Melbourne Peter MacCallum raise the cancer center for clinical treatment strategies, on formalin fixed paraffin embedded specimens (FFPE) of microanatomy of tumors, the use of nCounter (Nanostring ?) determination of immune spectrum mRNA technology, the data were compared between non hepatic metastasis of liver metastasis using ClueGO expression analysis, analyses the differences between the composition of gene expression. Using quantitative reverse transcription PCR (qPCR) expression of CRP gene and C5 gene were determined for obvious differences, confirm the results of Nanostring. According to the differences of expression the most significant gene, immunohistochemistry was performed in surgical biopsy specimens verified. All lesions were stained for CD3 and PD-L1 immune group, the use of Vectra digital automatic quantitative system quantitatively, the difference between groups was compared. Results due to 1 of liver metastasis gene expression data standard score (Z-score) > 3 were excluded from the analysis included a total of 9 liver metastases, 21 non liver metastases and 5 normal tissues. Liver metastasis genes in tumor and non liver metastasis of the immune system, the biggest difference expression The gene is C reactive protein (CRP), significant differences of genes mainly involved in complement activation pathways. For the same specimen, qPCR of CRP and C5 gene results are highly consistent with Nanostring. The transfer samples were further in 3 liver surgery, 7 non metastatic liver surgery were tested by CRP immunohistochemical examination, the result with the data of Nanostring results. In addition, in the liver and non liver metastasis and infiltration of tumor center edge, the expression level of CD3 and PD-L1 were low, no significant difference between groups. Conclusion] patients with liver metastasis of melanoma lesions and non metastatic liver lesions, CRP, the difference is the main difference between the expression of complement structure the immune gene expression, the results of this study may provide a target to treatment strategies for clinical immunotherapy.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R739.5

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