# Landscape of Somatic and Age‐Related Pathogenic Structural Variations in Hepatocellular Carcinoma Revealed by Long‐Read Sequencing

## TL;DR

This study uses long-read sequencing to reveal age-related and HBV-related structural variations in liver cancer genomes, highlighting key genomic changes linked to younger patients.

## Contribution

The study identifies DPRX as a novel HBV integration hotspot and reveals age-related differences in HBV-related HCC genomic alterations.

## Key findings

- Somatic structural variations are more prevalent in HBV-related hepatocellular carcinoma.
- Younger patients (≤ 35 years old) show higher deletion frequencies and HBV integration burdens.
- Chromosome 1 and the DPRX locus are key hotspots for HBV integration in younger patients.

## Abstract

Hepatocellular carcinoma (HCC) was characterized by a highly complex genome, with structural variations (SVs) playing a significant role in its development. In this study, we employed Oxford Nanopore Technology long‐read sequencing in paired tumor and adjacent normal liver tissues from 74 Chinese HCC patients to thoroughly characterize the landscape of somatic SVs. Our analysis revealed that somatic SVs were more prevalent in hepatitis B virus (HBV)‐related HCC, with chromosome 1 emerging as a major hotspot, and several members of the chromosome 1 open reading frame (C1orf) family genes expression level exhibited significant age‐related difference. Notably, HBV‐related HCC cases exhibited a higher frequency of deletions, particularly among younger ones (≤ 35 years old). In addition, we observed an increased burden of HBV integration events in younger ones. Remarkably, the divergent‐paired related homeobox (DPRX) loci was identified as a novel gene for HBV integration in younger patients. Together, these findings delineated the somatic SV landscape in HCC and underscored age‐associated HBV‐related genomic alterations as key pathological features of hepatocarcinogenesis.

This study leveraged long‐read sequencing (LRS) to provide a comprehensive analysis of structural variations (SVs) in the human hepatocellular carcinoma (HCC) genome. Somatic SVs were found to be more prevalent in HBV‐related HCC, with chromosome 1 emerging as the primary hotspot for these alterations. Notably, HBV‐related HCC exhibited a significantly higher frequency of deletions, particularly among younger patients (≤ 35 years old). TERT and DPRX loci were identified as recurrent hotspots for HBV integration. In addition, younger individuals showed a greater burden of HBV integration.