Abstract 1255: Identification of mutational landscape predicting efficacy of immune checkpoint blockades and recurrent mutations related to high tumor mutational burden in hepatocellular carcinoma by next generation sequencing
Authors: Li Li , Wen Zhaohong , Overman Michael J. , Rao Xiaosong , Yi Yuting , Guan Yanfang , Liang Jun 
Published: August 2019

Abstract
Introduction: HCC is an aggressive and genetic heterogeneous disease. Several disrupted signaling pathways have been identified, though actionable targets are limited. The majority of systemic chemotherapy and targeted therapy (tyrosine kinase inhibitors (TKIs) or monoclonal antibodies) have demonstrated minimal to no clinical activity. Immunotherapy has emerged as a potentially transformative strategy with attractive and long-lasting responses in HCC. However, the clinical efficacy of immune check point blockades (ICB) is limited to a select subset of patients and is hampered by drug resistance.
Methods: In this study, we focused on tumor cell intrinsic factors and conducted a hybridization-capture methodology and targeted 1 Mb of genomic coding sequence ( Gene Plus1021 Panel). Analysis of 81 HCC tumors and matching plasma normal samples was performed to characterize the landscape of somatic mutations especially those related to the sensitivity, resistance and hyper progression of ICB therapy in HCC. For genes identified in our study significantly correlated with tumor mutational burden (TMB), We further did the verification in The Cancer Genome Atlas (TCGA)-LIHC. 363 HCC tumor samples were included in the cohort and the data was downloaded from cBioPortal website (http://www.cbioportal.org/).
Results: We analyzed 81 HCC tumor samples accepted in Peking University International Hospital from January 2015 to Jun 2018 who did not receive ICB therapy at the time of taking specimen. The top quartile (7 muts/Mb) of TMB distribution was used as the cutoff value to define high tumor mutational burden (TMB-H). There were 26 cases (32.10%) with high TMB. Among all the 81 samples analyzed we detected no mismatch repair deficiency (dMMR), but identified five gene mutations having a significant correlation with high TMB including TP53, CTNNB1, ARID1A, MLL and NCOR1, p=0.0439, 0.0196, 0.0023, 0.0247 and 0.0076, retrospectively. We further did the verification in The Cancer Genome Atlas (TCGA)-LIHC. Gene mutations of TP53, CTNNB1, and MLL were proved to be highly associated with TMB-H status, p=0.0009, 0.0016 and 0.0013, retrospectively. Moreover, gene mutations of ARID1A, TP53 and MLL were proved to implicate poor overall survival. We detected 2 mutations (2.47%) in POLE, 2 mutations (2.47%) in PTEN, 1 mutation (1.23%) in DNMT3A, and 1 sample (1.23%) with high microsatellite instability (MSI-H). TMB value for the only one sample in MSI-H status was 9 muts/Mb (TMB-H). Instead of dMMR, one TP53 mutation and one ARID1A mutation were detected in this sample.
Conclusions: TMB-high and crucial driver gene mutations associated with high mutation load should be evaluated as potential predictive biomarkers in datasets of HCC patients treated with ICB therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Li Li, Zhaohong Wen, Michael J. Overman, Xiaosong Rao, Yuting Yi, Yanfang Guan, Jun Liang. Identification of mutational landscape predicting efficacy of immune checkpoint blockades and recurrent mutations related to high tumor mutational burden in hepatocellular carcinoma by next generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1255.