Abstract
Abstract Cancer metastasis is still the major cause of death, and poorly understood mechanistically. Therefore, increasing number of studies begins to study the genetic profiles of metastatic samples. However, studies from different tumor types show contradicting conclusions on evolution pattern. In this study, we focus on metastasis in hepatocellular carcinoma (HCC). We analyzed 92 primary and their matched 177 metastatic samples from a cohort of 64 HCC patients encompassing 10 distinct metastatic sites. To study the heterogeneity, we generated multi-regional exome and RNA sequencing for both primary and metastatic tumors. The inferred phylogenies showed both monoclonal (48 %) and polyclonal (52%) metastasis. The polyclonal metastasis is further divided into two subgroups: single branch-multiple waves and multiple-branch metastasis, while the majority of polyclonal evolution is derived from single branch-multiple waves metastasis (12 out of 13). In addition, we observed similar frequency of early, intermediate and late dissemination for tumor metastasis. Therefore, both the clonal and temporal heterogeneity lead to the genetic diversity in metastasis of HCC, which results in the inconsistency in driver (potentially targetable) mutations between primary and metastatic tumor samples for over 60% of patients in our cohort. To identify the potential driver genes for metastasis, we included another two cohorts including no-relapse/metastasis (n=32) and intrahepatic relapse (n=42) as a control. However, similar to published datasets, only TP53 showed a significant increase of frequency in metastatic cohort compared with other cohorts. To conclude, to our knowledge, we provided by far the largest metastatic HCC cohort of multi-regional sequencing and revealed the complex evolutionary history of HCC metastasis regarding to the clonal and temporal composition. We speculate that huge heterogeneity in HCC, especially in metastatic tumors, may be the main reason for frequent failure in targeted therapy in HCC. Citation Format: Yun-Fan Sun, Pin Wu, Ze-Jian Wang, Min-Fang Song, Kai-Qian Zhou, Li-Ye Zhang, David P. Peng, Jia Fan. Multiregional sequencing reveals the heterogeneity and underlying complex evolutionary history in liver cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3628.
Published Version
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