Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis
Open Access
- 31 January 2022
- Vol. 71 (2), 391-401
- https://doi.org/10.1136/gutjnl-2020-322983
Abstract
Objective A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options. Design We analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling. Results Patients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but ROBO2 mutations occurred exclusively in invasive CCA and CTNNB1 mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin. Conclusion Integrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.Funding Information
- Deutsche Krebshilfe (70113922)
- Deutsche Forschungsgemeinschaft (Project-ID 314905040)
- Horizon 2020 Framework Programme (No 667273)
- Helmholtz Association (N/A)
This publication has 48 references indexed in Scilit:
- Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathwaysLaboratory Investigation, 2014
- Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathwayHepatology, 2013
- Intraductal papillary neoplasm of the bile ductWorld Journal of Gastroenterology, 2013
- Intraductal papillary neoplasm of the bile duct: A biliary equivalent to intraductal papillary mucinous neoplasm of the pancreas?Hepatology, 2012
- Exome sequencing of liver fluke–associated cholangiocarcinomaNature Genetics, 2012
- SLIT2 Attenuation during Lung Cancer Progression Deregulates β-Catenin and E-Cadherin and Associates with Poor PrognosisCancer Research, 2010
- Regulation of Commissural Axon Pathfinding by Slit and its Robo ReceptorsAnnual Review of Cell and Developmental Biology, 2006
- Biliary papillary tumors share pathological features with intraductal papillary mucinous neoplasm of the pancreasHepatology, 2006
- Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesionsHepatology, 2005
- Altered Expression of β-Catenin without Genetic Mutation in Intrahepatic CholangiocarcinomaLaboratory Investigation, 2001