Molecular characterization of precursor lesions of bile duct cancer

胆管癌(胆管癌)是一种治疗选择有限的令人沮丧的疾病，大多在晚期发现。最近的研究表明，肿瘤的进展遵循腺瘤-癌的顺序，并且存在胆管癌的非侵袭性前体病变。然而，非侵袭性前驱病变的分子致癌机制和预后价值仍很不清楚。本研究的总体目标是系统地研究从非侵袭性病变到浸润性癌进展过程中的分子变化，并验证胆道癌发生中存在不同途径的假说。具体目的是(1)收集和表征大量的胆管癌(胆管癌)及其前驱病变的样本收集，(Ii)从系统的角度研究胆管癌变过程中常见致癌途径和候选基因的分子变化，重点是(11)从非侵袭性病变(BLIN、IPNB和ITPN)向侵袭性胆管细胞癌(CCC)进展过程中常见致癌途径和候选基因的分子变化特征，以及(11)从非侵袭性病变(BLIN、IPNB和ITPN)到侵袭性胆管细胞癌(CCC)进展过程中未知候选基因的识别，(LLI)以表征肿瘤进展过程中后续蛋白表达的变化，以及(IV)比较AIMS II-III与胰腺癌发生的结果，重点是PanIN和胃IPMN。最终，对胆道癌前驱病变的详细描述将为胆道癌的发病机制提供新的见解，并可能有助于改善胆管癌患者的诊断、治疗和危险分层。

Bile duct cancer (cholangiocarcinoma) is a dismal disease with limited treatment options that is mostly detected at late stages. Recent studies show that tumor progression follows an adenoma-carcinoma sequence and non-invasive precursor lesions of bile duct cancer exist. However, the molecular carcinogenesis and the prognostic value of non-invasive precursor lesions remain largely unclear.The overall goal of this research project is to investigate the molecular changes that follow the progression from non-invasive lesions to invasive carcinoma in a systematic approach and to test the hypothesis that distinct pathways in the carcinogenesis of biliary cancer exist.The specific aims are (I) to assemble and characterize a large sample collection of bile duct cancer (cholangiocarcinoma) and its precursor lesions, (II) to characterize the multistep carcinogenesis of cholangiocarcinoma in a systematic approach with focus on (lI.l) the characterization of molecular changes of common oncogenic pathways and candidate genes during progression from non-invasive lesions (BilIN, IPNB and ITPN) to invasive cholangiocarcinoma (CCC) and (lI.ll) the identification of unknown candidate genes that follow the progression from non-invasive lesions (BilIN, IPNB and ITPN) to invasive cholangiocarcinoma (CCC), (llI) to characterize the subsequent changes in protein expression during the tumor progression and (IV) to compare the results of aims II-III to pancreatic carcinogenesis with special emphasis on PanIN and gastric IPMN. Eventually, a detailed characterization of precursor lesions of bile duct cancer will provide new insights in the pathogenesis of bile duct cancer and may help to improve diagnosis, treatment and risk stratification of patients with cholangiocarcinoma.