去泛素化酶基因拷贝数变异与大肠癌发病及预后的关系

The Ubiquitin-proteasome system (UPS) play importmant roles in the development of colorectal cancer due to its subtly regulation of the WNT, PI3K-Akt, P53 and TGF-β signal transduction pathways. The UPS is a reversible action by the regulation of de-ubiquitinases (DUBs). The DUBs could also regulate the stability of key oncogene and tumor suppressor genes. Scientists have recently focus on the DUBs. Copy number variants (CNV) could change the gene dosage, affect the gene activity and gene expresion and increase the risk of colorectal cancer. Yet no in vivo and in vitro study and epidemiologic study aimed to explore the relationships between the copy number variants of DUBs and colorectal cancer, and their interactions with environmental factors on the colorectal cancer. Therefore, we carry out a case-control study to explore the associations between copy number variants of DUBs and colorectal cancer risk, and their interactions with environmental factors on colorectal cancer risk, hoping to explore the biomarker panels for the early prevention of colorectal cancer. We then conducted a cohort study to explore the associations between copy number variants of DUBs and the prognosis of colorectal cancer, and their interactions with environmental factors on the prognosis of colorectal cancer, hoping to explore the biomarker panels for the individualized treatment of colorectal cancer.

泛素-蛋白酶体途径能精细调节与大肠癌密切相关的WNT、PI3K-Akt、P53及TGF-β信号转导通路而在大肠癌的发生发展中发挥重要作用。它是一个被严格调控的可逆过程，受细胞内特异的去泛素化酶的负调控。去泛素化酶也能调控重要的癌基因和抑癌基因稳定性。因此，去泛素化酶逐渐成为肿瘤学领域的研究热点。基因拷贝数变异可以改变基因剂量、影响基因的活性和表达、增加大肠癌的发病风险。但是迄今为止尚没有去泛素化酶基因拷贝数变异与大肠癌关系的体内外研究及人群流行病学研究，更没有其与环境因素的交互作用和大肠癌关系的人群流行病学研究。本研究拟采用病例对照研究探索去泛素化酶基因拷贝数变异及其和环境因素的交互作用与大肠癌发病的关系，为大肠癌的早期预防提供生物标志物；采用队列研究探索去泛素化酶基因拷贝数变异及其和环境因素的交互作用与大肠癌预后的关系，为大肠癌的个体化治疗提供理论依据。

研究目标：探索去泛素化酶基因拷贝数变异及其和环境因素的交互作用与大肠癌发病的关系。探索去泛素化酶基因拷贝数变异及其和环境因素的交互作用与大肠癌预后的关系。.研究方法：采用1:1病例对照研究，在黑龙江省肿瘤医院及医大二院医院征得医生患者同意后收集散发大肠癌病例及对照共468对。调查大肠癌有关因素，并采集血样。用ABI Taqman® Copy Number Assays 试剂盒定量检测外周血中去泛素化酶基因拷贝数变异情况。采用队列研究对310例病例进行随访，收集预后相关信息并分析基因拷贝数变异与大肠癌预后的关系。.结果：CYLD及USP9X基因的拷贝数变异和大肠癌发病的风险相关。CYLD拷贝数缺失增加大肠癌发病风险（P﹤0.05 OR=4.18 95%CI：2.03-8.62）。USP9X拷贝数扩增增加大肠癌发病风险（P﹤0.05 OR=1.71 95%CI：1.25-2.34）。CYLD基因拷贝数变异与鱼类食物的摄入存在交互作用（P=0.048）。另外存在一些有统计学意义的联合作用.未发现其他基因拷贝数变异与大肠癌发病风险之间的关系。.预后研究表明大肠癌的病理分型、术前 CA19-9 和 CEA 水平、Duck’s 分期和是否转移都与大肠癌的预后生存有关,研究并未发现CYLD、USP9X拷贝数变异与大肠癌预后之间的关系。.结论：CYLD与USP9X基因拷贝数变异可能与大肠癌发生相关。