Comprehensive Genomic Insights Into Dynamic Mechanism Underlying The Development Of Non-Malignant Human Liver Disease Into Hepatocellular Carcinoma

Aim: Hepatocellular carcinoma (HCC) is a dynamically developing disease. However, the molecular and evolutionary mechanism underlying the development of human non-malignant liver disease into HCC remains largely unknown. Methods: We performed whole-genome sequencing studies on 3 different types of samples (e.g. liver cirrhosis (LC), dysplastic liver nodules (DN), and hepatocellular carcinoma (HCC)) which were collected simultaneously from each of 8 liver cancer patients. Bioinformatics analysis was performed on somatic mutations, mutational signatures, copy number alterations, structure variants, telomere length, and phylogenetic trees. Results: Surprisingly, few passenger mutations were shared across LC, DN and HCC samples within each patient. Compared with the non-malignant LC and DN samples, HCC was characterized by significantly greater number of somatic mutations (particularly oncogenic mutations), copy number alterations, genomic rearrangements, as well as shorter telomeres. HCC exhibited much similar mutational signatures as dysplastic nodules but different from background cirrhotic liver. Several mutational signatures (e.g. COSMIC signatures 16, 22, 24) were substantially more active in tumor and DN samples than LC, while some mutational signatures (e.g. signatures 5, 8) were universal and equally active in both non-malignant hepatocytes and HCC. Most somatic copy number alterations (SCNAs) were only observed in HCC and no overlap across different samples was found. In contrast to universal subclonal SCNAs, minimal subclonal diversification of mutations was identified in HCC, implying the majority of mutations are acquired at the earliest stages. Conclusions: HCC can be characterized by punctuated evolution of mutations in short bursts followed by subclonal diversification driven by SCNAs. Despite little overlap of mutations, the mutational context indicates a common mutagenesis mechanism underlying HCC and DN, which is different from LC. Citation Format: Xiangyu Zhang, Ran Cao, Kaiqian Zhou, Xinyu Wang, Cheng Zhou, Feiyu Chen, Hua Bao, Xue Wu, Yang W. Shao, Jia Fan, Jian Zhou, Zheng Wang. Comprehensive genomic insights into dynamic mechanism underlying the development of non-malignant human liver disease into hepatocellular carcinoma [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 LB-309.