本文選題：肝細(xì)胞癌(Hepatocellular + Carcinoma�。� 參考：《浙江大學(xué)》2016年博士論文

【摘要】：近年來,下一代測序技術(shù)(Next generation sequencing, NGS)迅猛發(fā)展,加速了腫瘤基因組學(xué)研究,幫助科學(xué)家找到了許多腫瘤特有的突變模式和驅(qū)動因子。生物信息技術(shù)對轉(zhuǎn)錄組測序、外顯子測序和全基因組測序得到海量數(shù)據(jù)的快速而精準(zhǔn)的分析促進(jìn)了NGS的發(fā)展。NGS應(yīng)用于腫瘤基因組學(xué)的研究揭示了許多不同類型癌癥的基因組和轉(zhuǎn)錄組的突變圖譜；幫助了科學(xué)家認(rèn)識到腫瘤的異質(zhì)性,還有腫瘤發(fā)生、發(fā)展以及對藥物抵抗的分子機(jī)制。此外,這些研究有助于癌癥的分子亞型的鑒定和劃分。本研究以肝細(xì)胞癌和前列腺癌為例,證明了下一代測序技術(shù)在癌癥分子機(jī)制研究和分子分型的個性化治療中的應(yīng)用的可行性。本文的第一部分第一章,我們對三例長期感染HBV肝癌患者的癌組織、癌旁組織和其正常血液樣本進(jìn)行全基因組測序。通過借助Complete Genomics全基因組測序平臺,我們鑒定了體細(xì)胞單核苷酸突變(Somatic single-Nucleotide Variation, SNV)包括單核苷酸多態(tài)性(Single Nucleotide Polymorphism, SNP)、小片段插入或缺失(Insertion or Deletion, Indel),染色體結(jié)構(gòu)變異(Structural Variation),還有基因拷貝數(shù)變化(Copy Number Variation,CNV)。我們分析比較了癌組織、癌旁組織和血液樣本的所有的突變類型并劃分了三個組別進(jìn)行具體分析：癌特有的突變、癌旁特有的突變以及癌和癌旁共有的突變(血液樣本沒有)。據(jù)我們所知,這是目前首次針對HBV感染肝癌患者的癌、癌旁和血液樣本同時進(jìn)行全基因組測序和比較分析。我們鑒定得到癌特有的突變、癌旁特有突變以及癌和癌旁共有(血液沒有)的突變位點(diǎn)以及重要生物學(xué)信號通路,對肝細(xì)胞癌發(fā)生和發(fā)展的分子機(jī)制的研究具有重要意義。在針對第一章的高通量測序的結(jié)果基礎(chǔ)上,本文的第一部分第二章在測序鑒定的突變結(jié)果中篩選了多個在以往文獻(xiàn)報道的腫瘤相關(guān)的單核苷酸多態(tài)性位點(diǎn)(SNP)和新發(fā)現(xiàn)的SNP以及結(jié)構(gòu)變異(SVs)在大量肝細(xì)胞病人的癌、癌旁和血液樣本中驗(yàn)證。在驗(yàn)證的結(jié)果中,我們發(fā)現(xiàn)抑癌基因—組蛋白H3K4三甲基化轉(zhuǎn)移酶KMT2C (Lysine-Specific Methyltransferase 2C),又稱MLL3 (mixed-lineage leukemia 3, MLL3) (C1114R)突變在肝細(xì)胞癌中非常普遍(癌、癌旁和血液的突變頻率分別是97.8%,96.2%和76.9%)。致癌基因VCX(L104P)是癌和癌旁共有,血液中沒有的突變頻率最高(癌和癌旁中突變頻率分別是14.6%和11.1%)的SNP位點(diǎn)。抑癌基因TP53 (R249S)位點(diǎn)在7.7%的癌組織中發(fā)生特異性突變,且該突變和不良預(yù)后顯著相關(guān)。我們還發(fā)現(xiàn)巨型蛋白AHNAK核蛋白2CAHNAK2)基因M1761I突變在100%的癌和癌旁中發(fā)生突變,在10%的HCC患者血液中發(fā)生突變。鋅指蛋白ZNF717的L689H突變在癌、癌旁和HCC患者血液里都發(fā)生突變(突變率分別是34%、23%和10%)多聚腺苷酸結(jié)合蛋白PABPC3 Y377H位點(diǎn)和人類白細(xì)胞Ⅱ型抗原HLA-DQB1的S233G位點(diǎn)在驗(yàn)證的HCC的在癌、癌旁和血液中100%檢測到。染色體結(jié)構(gòu)變異方面,我們發(fā)現(xiàn)17號染色體TK1胸苷激酶1 (Tyrosine Kinase 1)基因和8號染色體的非基因片段在癌和癌旁發(fā)生高頻融合(融合頻率分別是29%和16%)。整合分析癌和癌旁樣本外顯子和剪切位點(diǎn)的SNV對生物學(xué)信號通路的影響,我們發(fā)現(xiàn)以下2條信號通路在癌中發(fā)生特異性的顯著變化：胞外基質(zhì)受體互作(ECM-receptor interaction)和細(xì)胞粘附分子CAMs (Cell adhesion molecules)表明這些腫瘤微環(huán)境相關(guān)通路的改變可能是HCC發(fā)展的主要驅(qū)動力。然而,嗅覺誘導(dǎo)(Olfactory transduction)是在癌旁中發(fā)生特異變化的信號通路,預(yù)示著它可能與HBV介導(dǎo)的HCC的啟動相關(guān)。我們的研究表明,HBV介導(dǎo)的HCC的發(fā)生和發(fā)展過程共性和個性并存。我們找到的癌組織和癌旁組織發(fā)生的重要突變位點(diǎn)和生物學(xué)信號通路,可能是HCC發(fā)生和發(fā)展的關(guān)鍵驅(qū)動因子,對HCC的早期診斷和治療具有重要意義。本文的第二部分,我們對74例(50例FFPE樣本,24例新鮮組織樣本)接受前列腺根治術(shù)的低級別原位前列腺癌(Gleason=7)的樣本(44例未生化復(fù)發(fā)和30例生化復(fù)發(fā))進(jìn)行全外顯子組測序。針對外顯子測序找到的復(fù)發(fā)和未復(fù)發(fā)組的體細(xì)胞突變,我們用隨機(jī)森林機(jī)器學(xué)習(xí)算法鑒定能夠區(qū)分復(fù)發(fā)和未復(fù)發(fā)的標(biāo)志物。同時,鑒定了PCa復(fù)發(fā)相關(guān)的顯著突變位點(diǎn)、突變基因以及關(guān)鍵生物學(xué)過程。通過著重比較了復(fù)發(fā)組和未復(fù)發(fā)組的前列腺癌病人的外顯子組突變圖譜差異,我們找到了33個和復(fù)發(fā)特異相關(guān)的體細(xì)胞顯著突變基因,排前6位的是STK31、ALMS1、PCSK5、 AHRR和NCOR2。33個顯著突變基因絕大部分都是首次被報道。在復(fù)發(fā)前列腺癌樣本顯著突變的基因中,ALMS1 (p.E15delinsEE)和NCOR2 (p.Q78delinsQQ)各自存在高頻的非移碼插入(分別為46%和43%)。MAP3K9的第一個外顯子的113位發(fā)生CCT堿基非移碼缺失(p.38_39del),缺失頻率為37%; KDM6B基因的第9個外顯子的796位發(fā)生ACC缺失(p.252_253del),缺失頻率為17%。此外,20%的復(fù)發(fā)樣本中IDI2基因的第5個外顯子402位發(fā)生終止獲得突變(p.Y134X)。這些突變都很大程度上可能對蛋白質(zhì)的表達(dá)產(chǎn)生影響,可能參與重要的腫瘤發(fā)展、轉(zhuǎn)移相關(guān)的生物學(xué)通路。使用隨機(jī)森林機(jī)器學(xué)習(xí)算法,鑒定到22個突變集,用于高效區(qū)分發(fā)展緩慢和發(fā)展快速的前列腺癌樣本,是復(fù)發(fā)預(yù)測的潛在標(biāo)志物。METS影響巨噬細(xì)胞分化(METS affect on Macrophage Differentiation)是復(fù)發(fā)組特有的顯著變化信號通路。在復(fù)發(fā)的PCa中,該通路的關(guān)鍵基因：NCOR2、HDAC2和METS發(fā)生顯著突變,可能進(jìn)一步抑制TAMs的增殖,促進(jìn)其分化為M2型,從而促進(jìn)腫瘤細(xì)胞的侵襲和周圍炎癥反應(yīng)。第二部分研究揭示了PCa復(fù)發(fā)組和未復(fù)發(fā)組的基因突變圖譜,鑒定到復(fù)發(fā)相關(guān)的重要突變、基因和生物學(xué)通路。此外,研究還找到了能夠區(qū)分發(fā)展緩慢和發(fā)展快速的突變集,作為復(fù)發(fā)預(yù)測的候選標(biāo)志物。該研究對前列腺癌的分子分型和個性化治療具有重要意義。
[Abstract]:In recent years, the rapid development of Next generation sequencing (NGS) has accelerated the study of tumor genomics, helping scientists find a number of tumor specific mutation patterns and driving factors. Bioinformation technology has been sequenced, exon sequencing and whole genome sequencing to get a rapid and accurate score of massive data. The development of NGS's development.NGS applied to tumor genomics has revealed the mutation map of many genomes and transcripts of different types of cancer; it has helped scientists to recognize the heterogeneity of tumors, and the molecular mechanisms of tumorigenesis, development and drug resistance. In addition, these studies contribute to the molecular subtypes of cancer. Identification and division. In this study, the feasibility of the application of next generation sequencing in molecular mechanism research and individualized treatment of molecular typing was demonstrated in the case of hepatocellular carcinoma and prostate cancer. Chapter 1, Chapter 1 of this article, three cases of cancer tissue, para cancer tissue and normal blood samples of three patients with long-term infection of HBV liver cancer. Complete genome sequencing. By using Complete Genomics whole genome sequencing platform, we identified somatic single nucleotide mutation (Somatic single-Nucleotide Variation, SNV) including single nucleotide polymorphisms (Single Nucleotide Polymorphism, SNP), small fragment insertion or deletion (Insertion or), chromosome structure Variation (Structural Variation) and gene copy number change (Copy Number Variation, CNV). We analyzed and compared all types of mutations in cancer tissue, para cancer tissue and blood samples and divided three groups into specific analyses: cancer specific mutations, paracancerous mutations, and cancer and common mutations near Cancer (blood samples) As far as we know, it is the first time that this is the first time to sequence and compare the whole genome of the cancer of the HBV infected patients with liver cancer, the para cancer and the blood samples. We have identified the cancer specific mutations, the paracancerous endemic mutations, the mutation sites of the cancer and the side of the cancer and the important biological signal pathways, and the liver cells. The study of the molecular mechanisms of carcinogenesis and development is of great significance. On the basis of high throughput sequencing in the first chapter, the first part of this article, in the second chapter, screened a number of tumor related single nucleotide polymorphisms (SNP) and newly discovered SNP and structural changes in the previously reported mutation results. SVs is verified in a large number of patients with hepatocellular carcinoma, para cancer and blood samples. In the results, we found that the tumor suppressor gene, the histone H3K4 tri methylation transferase KMT2C (Lysine-Specific Methyltransferase 2C), also known as MLL3 (mixed-lineage leukemia 3, MLL3) (C1114R) mutation is very common in hepatocellular carcinoma (cancer, adjacent to cancer) The frequency of mutation of the blood is 97.8%, 96.2% and 76.9% respectively. The oncogene VCX (L104P) is the common mutation of cancer and cancer, and the highest mutation frequency in the blood (cancer and the mutation frequency in the side of cancer is 14.6% and 11.1% respectively). The tumor suppressor gene TP53 (R249S) site has a specific mutation in 7.7% of the cancer tissue, and the mutation and poor prognosis Significant correlation. We also found mutations in the giant protein AHNAK nucleoprotein 2CAHNAK2 gene M1761I mutation in 100% of cancer and cancer, mutation in the blood of 10% HCC patients. The L689H mutation of the zinc finger protein ZNF717 in the cancer, the side of the cancer and the blood of the HCC patients (the mutation rate is 34%, 23% and 10%) polyadenylate binding eggs The S233G loci of the white PABPC3 Y377H site and human leucocyte type II antigen HLA-DQB1 were detected in the HCC of cancer, adjacent to the cancer and 100% in the blood. The chromosome structural variation, we found that the 17 chromosome TK1 thymidine kinase 1 (Tyrosine Kinase 1) gene and the non gene fragment of chromosome 8 have high frequency fusion between cancer and cancer. The combined analysis of the effects of SNV on the biological signal pathways of the exons and shear sites of the paracancerous and paracancerous samples, we found that the following 2 signalling pathways changed significantly in cancer: extracellular matrix receptor interaction (ECM-receptor interaction) and cell adhesion molecule CAMs (Cell adhesion molecules). The changes in the microenvironment related pathways of these tumors may be the main driving force for the development of HCC. However, the olfactory induction (Olfactory transduction) is a specific signaling pathway in the paracancerous, suggesting that it may be associated with the initiation of HBV mediated HCC initiation. Our study shows that the occurrence and development of HBV mediated HCC is common in common. The important mutation sites and biological signaling pathways that occur in the cancer and paracancerous tissues we find may be the key driving factors for the occurrence and development of HCC, and are important for the early diagnosis and treatment of HCC. In the second part of this article, we accepted the prostate in 74 cases (50 FFPE samples, 24 fresh tissue samples). A total exon group was sequenced in a sample of low grade orthotopic prostate cancer (Gleason=7) (44 cases of non biochemical recurrence and 30 cases of biochemical recurrence). The recurrent and non recurrent somatic mutations found in the recrudescent and non recurrent group were identified. We used random forest machine learning algorithms to identify the markers that could distinguish between recurrent and non recurrence. PCa recurrence related significant mutation sites, mutation genes, and key biological processes were determined. By comparing the mutations in the exons of the prostate cancer patients in the recurrent and non recurrent groups, we found 33 significant mutations in the somatic cells associated with the recurrence specificity, and the top 6 were STK31, ALMS1, PCSK5, AHRR and NC. Most of the OR2.33 significant mutations were reported for the first time. In the genes with significant mutations in the recurrent prostate cancer samples, ALMS1 (p.E15delinsEE) and NCOR2 (p.Q78delinsQQ) respectively have high frequency non graft insertion (46% and 43%).MAP3K9 of the 113 exons of the first exon, CCT base non shift code deletion (p.38_39del). The loss of frequency was 37%; 796 of the ninth exons of the KDM6B gene had ACC deletion (p.252_253del), the frequency of the deletion was 17%., and the fifth exons of the IDI2 gene in 20% of the recurrent samples were terminated by the mutation (p.Y134X). These mutations, to a large extent, may affect the expression of protein and may be involved in important tumors. Development, transfer related biological pathways. Using a random forest machine learning algorithm, 22 mutation sets have been identified to efficiently distinguish between slow development and rapid development of prostate cancer samples. The potential marker of recurrence prediction.METS affects macrophage differentiation (METS affect on Macrophage Differentiation), which is unique to the recurrent group. In the recurrent PCa, significant mutations in the key genes of the pathway, NCOR2, HDAC2 and METS, may further inhibit the proliferation of TAMs and promote its differentiation into M2 type, thus promoting the invasion of the tumor cells and the surrounding inflammatory response. The second part of the study revealed the genetic mutation map of the PCa and the non recurrent groups, and identified the identification of the gene mutations in the recurrent and non recurrent PCa groups. The major mutations, genetic and biological pathways related to recurrence. In addition, the study has also found a mutation set that distinguishes slow development and rapid development as a candidate marker for recurrence prediction. This study is of great significance for molecular typing and individualized treatment of prostate cancer.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R735.7;R737.25

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