Highlights
- •Branch evolution is the predominant pattern in ICC, collectively shaped by parallel evolution and chromosome instability.
- •ICC may metastasize through polyclonal seeding.
- •Competition between subclonal populations can be used to develop new treatment strategies, like adaptive therapy.
- •Targeted therapy against truncal alterations is a promising treatment strategy.
Background & Aims
Intrahepatic cholangiocarcinoma (ICC) is the second-most lethal primary liver cancer.
Little is known about intratumoral heterogeneity (ITH) and its impact on ICC progression.
We aimed to investigate the ITH of ICC in the hope of helping to develop new therapeutic
strategies.
Methods
We obtained 69 spatially distinct regions from six operable ICCs. Patient-derived
primary cancer cells (PDPCs) were established for each region, followed by whole-exome
sequencing (WES) and multi-level validation.
Results
We observed widespread ITH for both somatic mutations and clonal architecture, shaped
by multiple mechanisms, like clonal “illusion”, parallel evolution and chromosome
instability. A median of 60.3% of mutations were heterogeneous, among which 85% of
the driver mutations were located on the branches of tumor phylogenetic trees. Many
truncal and clonal driver mutations occurred in tumor suppressor genes, such as TP53, SMARCB1 and PBRM1 that are involved in DNA repair and chromatin-remodeling. Genome doubling occurred
in most cases (5/6) after the accumulation of truncal mutations and was shared by
all intratumoral sub-regions. In all cases, ongoing chromosomal instability is evident
throughout the evolutionary trajectory of ICC. The recurrence of ICC1239 provided
evidence to support the polyclonal metastatic seeding in ICC. The change of mutation
landscape and internal diversity among subclones during metastasis, such as the loss
of chemoresistance mediator, can be used for new treatment strategies. Targeted therapy
against truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, was developed in 5/6 patients.
Conclusions
Integrated investigations of spatial ITH and clonal evolution may provide an important
molecular foundation for enhanced understanding of tumorigenesis and progression in
ICC.
Lay summary
We applied multiregional whole-exome sequencing to investigate the evolution of intrahepatic
cholangiocarcinoma (ICC). The results revealed that many factors, such as parallel
evolution and chromosome instability, may participate and promote the branch diversity
of ICC. Interestingly, in one patient with primary and recurrent metastatic tumors,
we found evidence of polyclonal metastatic seeding, indicating that symbiotic communities
of multiple clones existed and were maintained during metastasis. More realistically,
some truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be promising treatment targets in patients with ICC.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: March 15, 2018
Accepted:
February 12,
2018
Received in revised form:
February 5,
2018
Received:
December 9,
2017
Identification
Copyright
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
