Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced hepatocellular carcinoma.

Abstract

e15606 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies with a particularly high prevalence in China. The genomic profiling in HCC had been widely explored with tissue biopsy, however, given the intrinsic risks of invasive approach, blood-based circulating tumor DNA (ctDNA) has been proposed as a promising alternative. In this study, we aim to investigate whether the ctDNA may serve as a reliable tool to provide a more accurate molecular snapshot of HCC in Chinese patients. Methods: Plasma samples from 385 Chinese patients with advanced HCC were assayed for somatic genomic alternations by hybrid capture-based next-generation sequencing (NGS) with 150 genes and a mean sequencing depth of more than 3000×. The results were compared with our internal tissue genomic database of Chinese HCC patients (N = 873) tested by NGS and TCGA database (N = 373) tested by whole exome sequencing. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: Among 385 patients with ctDNA testing, somatic genomic alternations were detected in 97% of the patients (median = 5 alterations/patient). The most prevalent SNV mutations from ctDNA sequencing were TP53 (45.7%), TERT (19.5%), CTNNB1 (12.5%), and LRP1B (8.3%) compared to our tissue database (TP53 (61.2%), CTNNB1 (15.6%), TERT (13.3%), and LRP1B (11.0%)). While in TCGA database, the most common SNV mutations were found in TP53 (30.1%), CTNNB1 (26.0%), LRP1B (8.8%), ARID1A (8.6%), and SPTA1 (7.5%). Moreover, the level of MSAF was associated with detectable variant types, evidenced by a significant higher MSAF level observed when amplifications (P < 0.0001) or fusions (P = 0.008) were detected in the samples. Conclusions: Molecular analysis of patients with advanced HCC through ctDNA can serve as a reliable alternative to tissue biopsy. Chinese HCC patients may have different mutational landscapes to Western population. The utility of ctDNA analysis can provide therapeutically exploitable genomic profiles to identify potentially actionable gene alterations for targeted therapies.