In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2056-2056
Abstract:
Liver cancer is a leading cause of death worldwide where somatic mutation plays a key role in tumorigenesis. As such, many recent researches have been conducted using DNA sequencing methods to study somatic mutations in liver cancer, such as whole-exome sequencing (WES), panel sequencing, and whole-genome sequencing (WGS). However, our understanding of genomic landscape of liver tumorigenesis has been limited by a low number of quality samples from diverse clinical contexts. Here, we explore comprehensive genomic landscape of liver cancer throughout its tumorigenesis using large-scale whole-genome sequencing of hepatocellular carcinoma (HCC) in various cancer stages and liver conditions. Total 500 patients of HCCs were enrolled in this study and whole-genome sequenced. 462 samples that passed quality control were included for final analysis. Most of the samples (427; 92%) were obtained from surgical resection and the rest (35; 8%) from liver transplantation. We used a standard WGS analysis pipeline from read mapping to variant calling of single-base substitution (SBS), indel, structural variation (SV), and copy number variation (CNV). Downstream data analyses were performed using in-house scripts with a particular focus on mutational signatures. To study how genome changes as HCC progresses, we classified samples into three groups by T stage: T1, T2, and T3/4. The number of samples for each group was 205 (44%), 222 (48%), and 35 (8%), respectively. There was no significant difference in the number of SBSs and indels, but the number of SVs was significantly higher in T3/4 (the mean of T1/2 vs. T3/4 = 51 vs. 93; p=0.001). Major mutational signatures were SBS5, 40 (both clock-like), 12 (unknown), and 22 (aristolochic acid) for SBSs and ID1, 2, 5 (all clock-like), and 3 (tobacco smoking) for indels. The proportion of ID2, characterized by 1bp deletion at homopolymer site, was increased in the samples of higher T stage (the mean proportion of T1/2 vs. T3/4=11% vs. 16%; p=0.01). The higher-stage samples also harbored more frequent whole-genome duplication (WGD) and loss of heterozygosity (LOH) (the frequency of WGD in T1/2 vs. T3/4=42% vs. 68%, p & lt;0.001; the mean LOH fraction of T1/2 vs. T3/4=0.12 vs. 0.19, p & lt;0.001). There was a significant enrichment of driver mutations of multiple genes (e.g., TP53, MTCP1, CCND3, etc.) in T3/4 group. Interestingly, in surgically resected T1 samples, ID2 proportion was the only significant contributor to early recurrence over tumor size, N stage, mean ploidy, and LOH fraction (n=199, p=0.05; Cox regression). Overall, we found that HCCs at different T stages exhibit some common and yet apparently distinguishing genomic features. We believe that the comprehensive genomic profile of HCC across cancer stages will provide deep insights into the genomic evolution of HCC and one day lend itself to clinicogenomic bases for better HCC management in the future. Citation Format: Seongyeol Park, Suk Kyun Hong, Joonoh Lim, YoungRok Choi, Boram Yi, Jaemo Koo, June-Young Koh, Ryul Kim, Nam-Joon Yi, Jeong Seok Lee, Kyung-Suk Suh, Kwang-Woong Lee, Young Seok Ju. Large-scale whole genome sequencing of hepatocellular carcinoma reveals stepwise cancer evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2056.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-2056
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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