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Charting co-mutation patterns associated with actionable drivers in intrahepatic cholangiocarcinoma
Gajanan Kendre1, Karthikeyan Murugesan2, Tilman Brummer3
1Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
Journal of Hepatology
|December 17, 2022
Summary
This study reveals key genomic patterns in intrahepatic cholangiocarcinoma (iCCA), identifying co-mutations that can guide targeted therapy development for this rare cancer.
Area of Science:
- Genomics and Precision Oncology
- Gastrointestinal Cancer Research
Background:
- Intrahepatic cholangiocarcinoma (iCCA) is a rare gastrointestinal cancer with significant genomic heterogeneity.
- This heterogeneity poses challenges for developing effective targeted therapies.
- Analyzing large datasets is crucial for understanding molecular subgroups and identifying genomic patterns in rare cancers.
Purpose of the Study:
- To provide a comprehensive genomic landscape of iCCA.
- To identify co-mutational spectra of therapeutically relevant oncogenic driver genes.
- To establish a knowledge base for developing targeted therapies and predicting drug resistance.
Main Methods:
- Retrospective analysis of 6,130 iCCA patients from the FoundationCORE database.
- Comprehensive panel sequencing (FoundationOne platform) evaluating short variants, fusion-rearrangements, and copy number alterations in over 300 genes.
- Assessment of tumor mutational burden (TMB) and microsatellite instability (MSI) status.
Main Results:
- Detailed cartography of the iCCA genomic landscape.
- Identified co-mutational spectra for key driver genes (IDH1/2, FGFR2, ERBB2, BRAF, MDM2, BRCA1/2, MET, KRASG12C).
- Observed negative selection of RTK/RAS/ERK pathway co-alterations and enrichment of epigenetic modifiers (ARID1A, BAP1) with IDH1/2 and FGFR2 alterations. RNF43 and KMT2D were frequent in MSIhigh and TMBhigh tumors.
Conclusions:
- Understanding prevalent genomic constellations is critical for iCCA treatment strategy development.
- The study serves as a resource for clinical trial feasibility, preclinical model development, and resistance prediction.
- Molecular diagnostics are recommended for iCCA patients due to the frequency of targetable alterations.
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