第一部分 中国青老年人散发性结直肠癌突变基因差异分析: 目的：针对前期得到的青老年人CRC全外显子测序结果，对比两组在体细胞突变数目和拷贝数变异（CNV）方面的差异，结合基因富集分析和肿瘤驱动基因筛选，探究青年人CRC发生的潜在分子机制。方法：根据10对青年人和老年人散发性CRC标本的全外显子测序数据，统计非同义突变数目和CNV，进行非参数秩和检验。利用R语言对两组差异突变基因进行富集分析，并将青老年人CRC差异突变基因与CGC数据库作对比，以筛选可能的肿瘤驱动基因。结果：青年人CRC的基因突变数目显著少于老年人组（P = 0.038）。青年人CRC的拷贝数缺失变异显著少于老年人CRC（P = 0.001），而拷贝数扩增变异虽然也少于老年人CRC，但差异尚不显著（P = 0.195）。富集结果显示，相比于老年人，青年人CRC高频突变的基因主要富集在8条生物学过程，即Wnt信号通路、O-聚糖处理、胆固醇外流等，而老年人组基因则富集在不同的5条生物学过程。此外，CGC数据库中青年组高频突变或相对高突变的基因包括BRAF，CTNNB1，EPHA3，FAT4，MSH2，MUC4，RANBP2，SPEN等。结论：青年组CRC的体细胞突变数目和CNV少于老年组，且青年人CRC独特的癌变通路可能与某些生物学过程和突变基因有关。第二部分 联合多种数据库及R语言分析NR1H4在结直肠癌中的表达及意义: 目的：联合多种癌症相关数据库和R语言，分析NR1H4在CRC中的表达情况、可能涉及的致癌机制及其对患者预后的影响。方法：利用GEO数据库筛选结直肠腺癌差异表达基因后，利用DAVID工具进行富集分析，并用STRING数据库构建蛋白-蛋白相互作用（PPI）网络。此外，用Oncomine数据库验证NR1H4在CRC等多种肿瘤中的差异表达情况，并通过TCGA及GEPIA分析NR1H4对CRC患者生存预后的影响。结果：NR1H4在包括CRC在内的多种类型肿瘤中表达量明显下降。结肠腺癌差异表达基因的富集分析显示，NR1H4富集在3条生物学过程和1条KEGG通路中，分别是炎症反应、胆汁酸和胆盐转运、凋亡过程负调控和胆汁分泌通路。PPI分析显示，包括NR1H4在内的多个基因可能是结直肠肿瘤的调控枢纽基因。预后分析显示，NR1H4低表达的结肠癌患者总生存期（OS）和无病生存期（DFS）均低于NR1H4高表达患者，但差异尚不具有显著性。结论：NR1H4在CRC中显著低表达，且该基因可能通过多种机制影响CRC的发生、发展和预后。 第三部分 亚太地区结直肠癌筛查评分的改良及与粪便潜血免疫化学检测结合的验证: 目的：亚太地区结直肠癌筛查（APCS）评分是筛查进展期期结直肠新生物（ACN）高危人群的有效方法，但仍需进一步修改，并与粪便潜血免疫化学检测（FIT）相结合。本研究旨在改良验证APCS评分，并评价改良后评分与FIT的结合在ACN风险分层中的应用。方法：这项前瞻性和多中心研究分别招募了955名（前期完成）和1201名中国无症状体检人群，形成建模队列和验证队列。参与者接受了风险因素问卷、结肠镜检查和FIT。采用多元logistic回归分析，用C统计量、敏感度和阴性预测值（NPVs）比较筛选效率。结果：改良APCS模型纳入了年龄、体重指数（BMI）、家族史、糖尿病、吸烟和饮酒作为危险因素，将受试者分为低风险（AR）和高风险（HR）。在验证队列中，HR层组患ACN的风险增加了3.4倍（95% CI 1.8-6.4）。改良APCS评分的C统计量为0.69 ± 0.04，而原始模型为0.67 ± 0.04。改良APCS评分联合FIT筛查ACN高危人群的敏感度为76.7%，而单独应用FIT或改良APCS评分的敏感度分别为36.7%和70.0%。改良评分联合FIT预测ACN的NPV为98.0%，而单独FIT或APCS评分的NPVs分别为97.0%和97.9%。结论：改良APCS评分模型及其与FIT的联合可以有效地从中国无症状体检人群中筛查出CRC高危人群。

Part 1. Genetic comparison of Chinese young-onset and late-onset sporadic colorectal cancer: Objective: To compare genetic differences between colorectal cancer (CRC) in Chinese young-onset and late-onset populations based on whole-exome sequencing (WES) data obtained before. And to explore the potential mechanisms of young-onset CRC by gene enrichment analysis and tumor driver genes screening. Methods: Based on WES data from 10 pairs of young-onset and late-onset sporadic CRC samples, the numbers of non-synonymous somatic mutations and copy number variations (CNVs) were analyzed, and the nonparametric rank sum test was carried out. Differential mutation genes of the two groups were used for enrichment analysis by R and were compared with CGC database to screen tentative tumor driver genes. Results: The number of somatic mutations in young-onset CRC was significantly lower than that in late-onset people (P = 0.038). For CNV, the number of deletion mutations in young-onset CRC was lower than that in late-onset CRC (P = 0.001), and amplification mutations in young-onset CRC tended to be less yet with no significance (P = 0.195). Enrichment analysis showed that compared to late-onset group, mutation genes with higher frequencies in young-onset CRC were mainly enriched in eight biological processes, namely Wnt signaling pathway, O-glycan processing, cholesterol efflux and so on. Diver genes for young-onset CRC included BRAF, CTNNB1, EPHA3, FAT4, MSH2, MUC4, RANBP2, and SPEN. Conclusion: The number of somatic mutations and CNVs of young-onset CRC are generally lower than those in late-onset group, and the unique carcinogenesis pathway of young-onset CRC may be related to some specific biological processes and mutated genes. Part 2. Expression and significance of NR1H4 in colorectal cancer analyzed by the combination of multiple databases and R: Objective: To analyze the expression level of NR1H4 in CRC, and to explore its tentative carcinogenesis pathways and the effect on the prognosis of CRC patients. Methods: After screening differentially expressed genes in colorectal adenocarcinoma by GEO database, the protein-protein interaction (PPI) network was constructed with STRING database. Besides, Oncomine database was used to verify the differential expression of NR1H4 in CRC and other tumor types, and TCGA and GEPIA were used to analyze the effect of NR1H4 on survival and prognosis of CRC patients. Results: The expression of NR1H4 in various types of tumors including CRC decreased significantly. The enrichment analysis of differentially expressed genes in colorectal adenocarcinoma showed that NR1H4 was enriched in three biological processes and one KEGG pathway, namely inflammatory response, bile acid and bile salt transport, negative regulation of apoptosis process and bile secretion pathway. PPI analysis showed that several genes including NR1H4 might be hub genes of CRC carcinogenesis. The prognosis analysis showed that the overall survival and disease-free survival of colon cancer patients with low NR1H4 expression seemed to be shorter than those with high expression, but the difference was not significant.Conclusion: NR1H4 is significantly under-expressed in CRC, and it may affect the development of CRC through various mechanisms. Part 3. Improvement of Asia-Pacific Colorectal Screening score and evaluation of its use combined with fecal immunochemical test: Objective: The Asia-Pacific Colorectal Screening (APCS) score is used for screening high-risk groups of advanced colorectal neoplasia (ACN) patients. This paper aimed to improve the APCS score and evaluate its use with the fecal immunochemical test (FIT) in stratifying the risk of ACN.Methods: This prospective and multicenter study enrolled 955 (completed before) and 1201 Chinese asymptomatic participants to form the derivation and validation set, respectively. Participants received the risk factor questionnaire, colonoscopy and FIT. Multiple logistic regression was applied, and C-statistic, sensitivity and negative predictive values (NPVs) were used to compare the screening efficiency.Results: A modified model was developed incorporating age, body mass index (BMI), family history, diabetes, smoking and drinking as risk factors, stratifying subjects into average risk (AR) or high risk (HR). In the validation set, the HR tier group had a 3.4-fold (95% CI 1.8-6.4) increased risk for ACN. The C-statistic for the modified score was 0.69 ± 0.04, and for the original score 0.67 ± 0.04. The sensitivity of the modified APCS score combined with FIT for screening ACN high-risk cohorts was 76.7% compared with 36.7% of FIT alone and 70.0% of the modified APCS score alone. The NPVs of the modified score combined with FIT for ACN were 98.0% compared with 97.0% of FIT alone and 97.9% of the modified APCS score alone.Conclusion: The modified score and its use with the FIT are efficient in selecting the HR group from a Chinese asymptomatic population.