Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma

Dong, L.-Q. et al. (2018) Spatial and temporal clonal evolution of intrahepatic cholangiocarcinoma. Journal of Hepatology, 69(1), pp. 89-98. (doi: 10.1016/j.jhep.2018.02.029) (PMID:29551704)

Abstract

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 aim to investigate its ITH in hope of helping develop new therapeutic strategies. Methods: We obtained 69 spatially distinct regions from 6 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% mutations were heterogeneous mutations, among which 85% of the driver mutations 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 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 subregions. 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, may be used for new treatment strategy. Targeted therapy against truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be 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 trajectory of ICC. The results revealed that many fuels, 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 some clues 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, can be promising treatment targets for ICC patients.

• Item Type: Articles
• Keywords: Branch evolution, clonal evolution, intrahepatic cholangiocarcinoma, intratumor heterogeneity, patient-derived primary cancer cells, whole exome sequencing.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Yuan, Dr Ke
• Authors: Dong, L.-Q., Shi, Y., Ma, L.-J., Yang, L.-X., Wang, X.-Y., Zhang, S., Wang, Z.-C., Duan, M., Zhang, Z., Liu, L.-Z., Zheng, B.-H., Ding, Z.-B., Ke, A.-W., Gao, D.-M., Yuan, K., Zhou, J., Fan, J., Xi, R., and Gao, Q.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Science and Engineering > School of Computing Science
• Journal Name: Journal of Hepatology
• Publisher: Elsevier
• ISSN: 0168-8278
• ISSN (Online): 1600-0641
• Published Online: 16 March 2018
• Copyright Holders: Copyright © 2018 European Association for the Study of the Liver
• First Published: First published in Journal of Hepatology 69(1):89-98
• Publisher Policy: Reproduced in accordance with the publisher copyright policy