Identification of genomic and transcriptomic alterations in intraductal papillary and tubulopapillary neoplasms of the bile duct

• Applicant: Professorin Dr. Stephanie Rössler
• Subject Area: Pathology ; Gastroenterology
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497786653

Cholangiocarcinoma (CCA) is a biliary tract cancer with dismal prognosis due to late diagnosis precluding curative surgical resection and the lack of effective systemic therapeutic options. Recently, we published an integrative analysis on distinct CCA precursor lesions, i.e. intraductal papillary (IPNB) and tubulopapillary (ITPN) neoplasms of the bile duct (Goeppert et al. Gut, 2021; IF: 23.059). Using panel sequencing, we demonstrated that IPNB/ITPN and the corresponding invasive CCA share common mutations. In addition, genome-wide DNA methylation profiling revealed that IPNB/ITPN may arise from different cells-of-origin. Currently, we aim at identifying early genetic alterations which may be found in certain subtypes of IPNB/ITPN and at revealing early transcriptomic alterations involved in CCA development. Previous panel sequencing data of our comprehensive and well-characterized cohort showed that a subgroup of IPNB/ITPN does not exhibit any hot spot mutations. Therefore, deeper analysis of these cases by whole exome sequencing, gene expression profiling and identification of gene fusions by RNA sequencing may reveal novel oncogenic mechanisms. For this project, whole exome sequencing and RNA sequencing of non-neoplastic bile duct, the corresponding precursor lesions (30 IPNB and 20 ITPN) and the invasive CCA samples of 50 patients (total N=150) will be performed in order to reveal molecular alterations in early cholangiocarcinogenesis which may be of great importance for future screening programs in high-risk patients (e.g. Primary Sclerosing Cholangitis) and putative treatment options.

• DFG Programme: Research Grants