拷贝数变异与胰腺癌遗传易感性的关联研究

In recent years, pancreatic cancer incidence and mortality rates are rising in our country. Pancreatic cancer is conceal, progress fast, poor prognosis.Screening reliable biomarkers, early prevention and early diagnosis of pancreatic cancer is the key to improve the prognosis. Copy number variation of the genome wide distribution, direct/indirect effect on purpose gene or the coding of RNA expression, further influence disease phenotype, may become a new warning labels on pancreatic cancer. In the study, 1000 patients with pancreatic cancer and we based on 2000 cases of normal controls SNP high-throughput microarray data, preliminary screening out and pancreatic cancer susceptibility of related 57 copy number variation. This project is in a separate large population (1000 cases of pancreatic cancer and 2000 cases of normal controls) case-control study to test the above copy number variation and Chinese people relationship in pancreatic cancer susceptibility, and using technology to capture the conformation chromatin platform system to elucidate the biological mechanisms, for the crowd of pancreatic cancer early warning and early prevention to provide the theory basis and the new clues.

近年来，我国胰腺癌的发病率和死亡率均呈上升趋势。胰腺癌发病隐匿、进展快、预后差，筛选可靠的生物学标记，进行早期预防和早期诊断是改善胰腺癌预后的关键。拷贝数变异在基因组中分布广泛，可直接/间接影响目的基因或非编码RNA的表达、进而影响疾病表型，有可能成为胰腺癌发病新的预警标志。前期研究中，我们依据1000例胰腺癌和2000例正常对照的高通量SNP芯片数据，初步筛查出与胰腺癌易感性相关的57个拷贝数变异。本项目拟在另一独立的大样本量（1000例胰腺癌和2000例正常对照）病例-对照研究中验证上述拷贝数变异与中国人群胰腺癌易感性的关联关系，并运用染色质构象捕获等技术平台系统阐明其生物学机制，为胰腺癌的人群预警及早期预防提供理论依据和新的线索。

UGT2B17是机体重要的第二相代谢酶，参与多种内源性和外源性物质的代谢过程，UGT2B17基因的多态可影响其代谢酶活性进而与疾病的易感性相关。我们通过研究包括有病理证实的中国胰腺癌患者406例和1579例中国正常对照。利用特异引物PCR的方法检测不同人群UGT2B17 基因的CNV多态性，UGT2B17基因的del/del、del/ins和ins/ins基因型在胰腺癌患者中的分布频率分别为：72.9%、24.0%和3.1%，在正常对照人群中的分布频率分别为：66.6%、30.7%和2.7%。病例组和对照组的基因型分布均符合Hardy-Weinberg平衡。多变量logistic回归分析结果显示，与UGT2B17 del/del基因型携带者相比，携带del/ins基因型罹患胰腺癌的风险显著降低，其OR值为0.77（95% CI = 0.60–0.99; P=0.04），而携带ins/ins基因型不增加胰腺癌的发病风险（OR = 0.98, 95% CI = 0.51–1.89; P=0.96）；性别分层结果显示，在女性中呈现出类似的关联效果。总之，本研究确证了亚洲人群UGT2B17基因的缺失较白色人种更为常见，UGT2B17基因分布以纯合性缺失型为主，证明了不同人种间遗传背景的差异。首次证实UGT2B17基因的缺失多态与汉族人胰腺癌的发病风险相关，在女性中尤为显著。