Z Gastroenterol 2021; 59(01): e39-e40
DOI: 10.1055/s-0040-1722052
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Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal cholangiocarcinogenesis

B Goeppert
1   University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
,
D Stichel
2   German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neuropathology, Heidelberg, Germany
,
R Toth
3   German Cancer Research Center (DKFZ), Cancer Epigenomics, Heidelberg, Germany
,
S Fritzsche
1   University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
,
M Loeffler
1   University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
,
AM Schlitter
4   Technical University of Munich, Institute of Pathology, Munich, Germany
,
O Neumann
1   University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
,
Y Assenov
3   German Cancer Research Center (DKFZ), Cancer Epigenomics, Heidelberg, Germany
,
MN Vogel
5   University Hospital Heidelberg, Diagnostic and Interventional Radiology, Heidelberg, Germany
,
A Mehrabi
6   Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
,
K Hoffmann
6   Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
,
B Köhler
6   Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
,
C Springfeld
6   Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
,
D Weichenhan
3   German Cancer Research Center (DKFZ), Cancer Epigenomics, Heidelberg, Germany
,
C Plass
3   German Cancer Research Center (DKFZ), Cancer Epigenomics, Heidelberg, Germany
,
I Esposito
7   University Hospital Düsseldorf, Institute of Pathology, Düsseldorf, Germany
,
P Schirmacher
1   University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
,
A von Deimling
2   German Cancer Research Center (DKFZ), Clinical Cooperation Unit Neuropathology, Heidelberg, Germany
,
S Rössler
1   University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
› Institutsangaben
 

Question 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.

Methods We analyzed a clinicopathologically well-characterized patient cohort (N=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) 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 analyzed 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 CCA patients without IPNB/ITPN. ITPN localized mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small and large duct type intrahepatic CCA. IPNB exhibited mutational profiles of perihilar and distal 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.

Conclusions Integrative analysis revealed that IPNB and ITPN harbor distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles, and IPNB/ITPN may represent a distinctive, intermediate form of intra- and extrahepatic cholangiocarcinogenesis.



Publikationsverlauf

Artikel online veröffentlicht:
04. Januar 2021

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