Trunk and Branch Drivers Distinguish Early vs Late Mutations in Hepatocellular Carcinoma Interview with:
Sara Torrecilla Recio

PhD Student
Mount Sinai Liver Cancer Program – Division of Liver Diseases Icahn School of Medicine at Mount Sinai
New York, NY What is the background for this study?

Response: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which represents the second-leading cause of cancer related death worldwide. The landscape of molecular alterations in HCC has been thoroughly explored using next-generation sequencing technologies in single biopsies of tumors. However, in the recent years it has been demonstrated that not all the regions of a tumor harbor the same molecular alterations. This intra-tumor heterogeneity may lead to a misinterpretation of the molecular landscape of the malignancy since not all the molecular alterations would be captured by single-biopsies. What are the main findings?

Response: Our study aimed to simplify this problem by focusing in characterizing those alterations that arise early in  Hepatocellular carcinoma evolution and thus, are shared among all the malignant cells of a single nodule. Since these alterations are the first hits in tumor transformation they are termed as “trunk” alterations. In contrast, those alterations that arise later in few tumor cell subclones generating the observed heterogeneity as a result of treatment pressure or hypoxia are named as “branch”.

Through the study of mutations and copy-number alterations in pre-malignant lesions and early tumors, we showed that mutations in TERT, TP53 and CTNNB1 genes are frequent early events in hepatocellular carcinoma development. Analysis of these genes in 2 independent set of samples showed that these mutations are shared between different regions of the same tumor and between primary and metastatic lesions in a high percentage of cases (85-90%). According to these results, TERT, TP53 and CTNNB1 mutations are trunk alterations in HCC since they are early events and ubiquitously. What should readers take away from your report?

Response: Although the extensive molecular heterogeneity in hepatocellular carcinoma, our study demonstrates that TERT, TP53 and CTNNB1 mutations are trunk alterations that are ubiquitously distributed at the intra- and inter-tumoral level in a high percentage of patients. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in hepatocellular carcinoma. What recommendations do you have for future research as a result of this study?

Response: Although the molecular characterization of tumors provides us with a picture of all alterations accumulated in the nodule over time, distinguishing trunk from branch alterations can lead to a more successful implementation of personalized medicine. Early trunk alterations would represent ideal therapeutic targets since they are distributed in all malignant cells of a tumor. In contrast, because they appear later in tumor evolution, branch alterations should be taken into account for their potential role in resistance to treatments. Is there anything else you would like to add?

Response: This work is supported by grants from the Recanati / Miller Transplantation Institute, the U.S. Department of Defense (CA150272P3), European Commission Framework Program 7 (HEPTROMIC, proposal number 259744) and Horizon 2020 Program (HEPCAR, proposal number 667273-2), the Asociación Española Contra el Cáncer (AECC), Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2013-41027 and SAF 2016-76390) and Grup de Recerca Consolidat –- Recerca Translacional en Oncologia Hepàtica. AGAUR (Generalitat de Catalunya), SGR 1162. Thank you for your contribution to the community.


AACR 2017 Abstract

#3944 Characterization of molecular heterogeneity in hepatocellular carcinoma: Trunk and branch drivers. Sara Torrecilla, Daniela Sia, Andrew N. Harrington, Zhongyang Zhang, Genis Camprecios, Agrin Moeini, Toffanin Sara, Isabel Fiel, Ke Hao, Monica Higuera, Laia Cabellos, Helena Cornella, Milind Mahajan, Yujin Hoshida, Augusto Villanueva, Sander Florman, Myron Schwartz, Josep Llovet. Icahn School of Medicine at Mount Sinai, New York, NY

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Last Updated on April 18, 2017 by Marie Benz MD FAAD