期刊
JOURNAL OF HEPATOLOGY
卷 67, 期 6, 页码 1222-1231出版社
ELSEVIER
DOI: 10.1016/j.jhep.2017.08.013
关键词
Liver cancer; Gatekeeper; Driver; Tumor evolution; Clonality
资金
- Spanish Ministry of Economy and Competitiveness [BES-2014-068300, EEBB-I-16-11251]
- Juan de la Cierva Fellowship
- U.S. Department of Defense [CA150272P3]
- Tisch Cancer Institute
- American Association for the Study of Liver Diseases Foundation (AASLDF) Alan Hofmann Clinical and Translational Award
- European Commission Framework Program 7 (HEPTROMIC) [259744]
- Horizon Program (HEPCAR) [667273-2]
- Recanati/Miller Transplantation Institute
- Asociacion Espanola Contra el Cancer (AECC)
- Samuel Waxman Cancer Research Foundation
- Spanish National Health Institute [SAF2013-41027, SAF 2016-76390]
- Grup de Recerca Consolidat -- Recerca Translacional en Oncologia Hepatica
- AGAUR (Generalitat de Catalunya) [SGR 1162]
Background & Aims: According to the clonal model of tumor evolution, trunk alterations arise at early stages and are ubiquitous. Through the characterization of early stages of hepatocarcinogenesis, we aimed to identify trunk alterations in hepatocellular carcinoma (HCC) and study their intra- and inter-tumor distribution in advanced lesions. Methods: A total of 151 samples representing the multistep process of hepatocarcinogenesis were analyzed by targeted-sequencing and a single nucleotide polymorphism array. Genes altered in early lesions (31 dysplastic nodules [DNs] and 38 small HCCs [sHCC]) were defined as trunk. Their distribution was explored in: a) different regions of large tumors (43 regions, 21 tumors), and b) different nodules of the same patient (39 tumors, 17 patients). Multinodular lesions were classified as intrahepatic metastases (IMs) or synchronous tumors based on chromosomal aberrations. Results: TERT promoter mutations (10.5%) and broad copy-number aberrations in chromosomes 1 and 8 (3-7%) were identified as trunk gatekeepers in DNs and were maintained in sHCCs. Trunk drivers identified in sHCCs included TP53 (23%) and CTNNB1 (11%) mutations, and focal amplifications or deletions in known drivers (6%). Overall, TERT, TP53 and CTNNB1 mutations were the most frequent trunk events and at least one was present in 51% of sHCCs. Around 90% of mutations in these genes were ubiquitous among different regions of large tumors. In multinodular HCCs, 35% of patients harbored IMs; 85% of mutations in TERT, TP53 and/or CTNNB1 were retained in primary and metastatic tumors. Conclusions: Trunk events in early stages ( TERT, TP53, CTNNB1 mutations) were ubiquitous across different regions of the same tumor and between primary and metastatic nodules in > 85% of cases. This concept supports the knowledge that single biopsies would suffice to capture trunk mutations in HCC. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据