結(jié)直腸癌（CRC）是最常見的胃腸道惡性腫瘤之一。在發(fā)達(dá)國家和發(fā)展中國家,結(jié)直腸癌均是男性和女性由于癌癥致死的第二大最常見原因。在所有結(jié)直腸癌的報告病例中,Ⅲ期患者所占比例為三分之一。通常Ⅲ期患者的預(yù)后較差,30-50%病人在5年內(nèi)會出現(xiàn)腫瘤復(fù)發(fā)和轉(zhuǎn)移。本研究工作的重點是使用二代測序技術(shù)和生物信息學(xué)工具來分析一名長期存活的Ⅲ期結(jié)直腸癌患者的突變情況,并將所得到的基因組信息與The Cancer Genome Atlas（TCGA）數(shù)據(jù)庫進(jìn)行比較。本論文中,我們研究了一位40歲中國漢族女性患者的病例的基因組變異情況。該患者有結(jié)直腸癌相關(guān)的癥狀,包括腹部不適、里急后重和嚴(yán)重背痛,并于2008年10月被安徽醫(yī)科大學(xué)第一附屬醫(yī)院接診入院。其腫瘤大小為3cm×3cm,并已侵襲了漿膜層,腫瘤覆蓋腸管的3/4�；颊呓�(jīng)檢查后被診斷為Ⅲ期結(jié)直腸癌。該患者經(jīng)過根治性手術(shù)和中藥奧沙利鉑和槐耳顆粒的輔助治療后,預(yù)后良好,生存期超過8年。我們通過全基因組測序,分析了生殖系突變和體細(xì)胞突變,并獲得了基因組改變的全部數(shù)據(jù)。我們在該患者中鑒定出194個生殖系突變。經(jīng)過公共數(shù)據(jù)庫過濾后,其中有20個生殖系突變基因與Can... 

【文章來源】：中國科學(xué)技術(shù)大學(xué)安徽省 211工程院校 985工程院校

【文章頁數(shù)】：113 頁

【學(xué)位級別】：博士

【文章目錄】：
DEDICATION
ACKNOWLEDGEMENTS
ABSTRACT
摘要
LIST OF ABBREVIATIONS
CHAPTER 1 Introduction
    1.1 Risk factors of colorectal cancer
        Non-modifiable factors
            Age
            History of adenomatous polyps
            Family history of colorectal cancer
            Inherited genetic risk
        Modifiable factors
            Environmental risk factors
            Nutritional practices
            Physical activity and obesity
            Cigarette smoking
            Heavy alcohol consumption
    1.2 Colorectal cancer diagnosis and staging
    1.3 Tumor staging
    1.4 Colorectal cancer symptoms
    1.5 Management of colorectal cancer
        Surgery
        Chemotherapy for resectable metastatic colorectal cancer
        Chemotherapy for Unresectable Metastatic Colorectal cancer
        Combination chemotherapy with Traditional Chinese Medicine
    1.6 Next-Generation Sequencing Technology
        Second-generation sequencing platforms
    1.7 NGS applications in cancer research
        Whole Genome Sequencing
        Targeted DNA Sequencing
        Exome sequencing
        RNA Sequencing
    1.8 Dissertation outline
CHAPTER 2 Materials and Methods
    2.1 Study samples
    2.2 DNA extraction and library preparation
    2.3 Whole genome sequencing
    2.4 Bioinformatics analysis
        2.4.1 Mapping
        2.4.2 Marking of reads duplicates
        2.4.3 Local realignment and base quality score recalibration
        2.4.4 Germline variants detection
        2.4.5 Somatic variants detection
            2.4.5.1 Lancet
            2.4.5.2 Mutect
            2.4.5.3 SomaticIndelDetector
        2.4.6 Annotations
            2.4.6.1 ANNOVAR
            2.4.6.2 VEP
            2.4.6.3 The 1000 Genomes Project
            2.4.6.4 The Exome Aggregation Consortium
        2.4.7 Copy number alternation and structural variation analysis
        2.4.8 Evaluation of somatic mutational signature
    2.5 Mutation significance analysis
    2.6 Gene Ontology Enrichment analysis
    2.7 TCGA analysis
CHAPTER 3
    3.1 Tumor purity and coverage statistics
    3.2 Germline mutations
    3.3 Somatic mutations
    3.4 Mutational signatures in the patient
    3.5 Structural variation and copy number alternation analysis
    3.6 Gene Ontology enrichment
    3.7 TCGA results
    3.8 Discussion
CHAPTER 4
    4.1 Conclusions
    4.2 Future perspectives
References
Publications



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