Molecular characterization of precursor lesions of bile duct cancer

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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.