The Hidden Scars of Hepatitis B

How Viral DNA Shatters Our Genomes and Drives Liver Cancer

An Ancient Foe's Modern Threat

Hepatitis B virus (HBV) is a stealthy adversary. Despite the availability of a vaccine, chronic HBV infection affects over 290 million people worldwide and causes nearly 1 million annual deaths from liver cancer and cirrhosis 6 . What makes HBV particularly sinister is its ability to vandalize our genetic blueprint even decades before cancer appears.

Key Facts

  • 290 million chronic HBV infections worldwide
  • 1 million annual deaths from HBV-related complications
  • Viral integration occurs within days of infection
Recent Breakthrough

Bionano Genomics' whole-genome imaging reveals how HBV shatters chromosomes and hijacks cellular machinery—transforming infected liver cells into time bombs.

Decoding the Invasion: HBV's Genomic Vandalism

1. The Virus That Writes Itself Into Your DNA

HBV belongs to a rare family of DNA viruses that reverse-transcribe their genome. When HBV infects liver cells, its double-stranded linear DNA (dslDNA) form bypasses the usual viral replication pathway. Instead, it hijacks the cell's DNA repair machinery to integrate into human chromosomes—a process occurring within days of initial infection 6 .

Viral Enhancers

Hyperactivate cancer genes beyond normal levels

Fusion Proteins

Like HBx-FN1 that disrupt cell functions

Chromosomal Breakpoints

Triggering massive rearrangements

2. Two Paths to Cancer

Groundbreaking studies of 177 HCC patients reveal two distinct carcinogenic mechanisms 1 4 :

HBV inserts its powerful enhancer near genes like TERT (telomerase) or CCNE1 (cell cycle control). This turns these genes "always on," accelerating cell division. In one case, an HBV enhancer increased TERT expression 200-fold—far exceeding levels seen with other mutations 3 .

HBV integrates near centromeres (chromosome anchors), unleashing structural havoc:
  • Deletion of chromosome 17p (harboring TP53, the "guardian of the genome")
  • Amplification of MYC (a master oncogene) on chromosome 8q
  • Chromothripsis: shattering of entire chromosome arms followed by chaotic reassembly
Top Genes Targeted by HBV Integration
Gene Function Tumor Frequency Non-Tumor Frequency
TERT Telomerase subunit 48/177 (27%) 10/170 (6%)
FN1 Extracellular matrix 14/170 (8%) 56/170 (33%)
KMT2B Epigenetic regulator 3/177 (2%) 4/170 (2%)
CCNE1 Cell cycle control 4/177 (2%) <1%
CCND1 Cell cycle control 16/426* (3.8%) 1/426 (0.02%)
*Data aggregated from 1 2 3 . CCND1 integration was identified in recent re-analysis.

The Breakthrough Experiment: Mapping Genomic Landmines

Study Design: The French Cohort Investigation

Researchers analyzed 177 HCC tumors and 170 matched non-tumor tissues from predominantly European/African patients using a multi-pronged approach 1 4 :

Step-by-Step Methodology
  1. Viral Capture Sequencing
    Custom biotinylated probes targeted HBV genotypes A-H and human hotspots. Captured fragments sequenced via Illumina MiSeq.
  2. Long-Read Validation
    PacBio SMRT sequencing reconstructed complex rearrangements in 3 tumors.
  3. Bionano Whole-Genome Imaging
    Ultra-high molecular weight DNA labeled at specific motifs and linearly imaged via nanochannel arrays.

Key Findings

Clonal Selection

Tumors showed 31% clonal integrations vs. 1% in non-tumor tissue, indicating cancer-driven selection 1 .

Structural Carnage

Bionano revealed HBV-induced chromothripsis at chromosome 17p (TP53) and 8q (MYC).

New Hotspots

Re-analysis uncovered recurrent integrations in CCND1/FGF19 locus (11q13.3): 3.8% of tumors 2 .

Mitochondrial Impact

8% of samples showed integration in mitochondrial genes (e.g., ND4) 2 .

Structural Variants Linked to HBV Integration Sites
Variant Type Chromosome Driver Gene Affected Frequency in HBV+ HCC
Deletion 17p TP53 (tumor suppressor) 41% of cases with centromeric HBV
Focal Gain 5p TERT 10%
Amplification 8q MYC 15%
Translocation 11q13.3 CCND1/FGF19 3.8%
Data from 1 2 4

The Scientist's Toolkit: Deciphering Genomic Scars

Bionano Saphyr

Optical genome mapping detected megabase-scale deletions/amplifications from HBV integration.

Viral Capture Probes

(SeqCap EZ) HBV/human junction enrichment identified 6,610 breakpoints in non-tumor tissue.

GRIDSS VIRUSBreakend

Virus integration caller found 23% more integrations than prior methods 2 .

T2T-CHM13 Genome

Complete human reference resolved integrations in centromeres/repeats.

Single-Molecule Real-Time

(PacBio) Long-read sequencing reconstructed complex HBV-human fusion sequences.

Clinical Impact: From Scars to Solutions

HBV integration leaves lasting fingerprints that predict cancer aggression:

Clinical Insights
  • Youthful Victims: Patients under 40 with high integration burden develop larger tumors and have 5-year survival <20% 1 3 .
  • The Antiviral Advantage: Non-tumor liver with replicating HBV had 82% more integrations, underscoring the urgency of early therapy 1 6 .
  • New Targets: 11q13.3-integrated tumors may respond to FGFR4 inhibitors (e.g., pemigatinib) targeting FGF19 overexpression 2 .

HBV integrations create oncogenic 'field effects'—transforming entire liver regions into a mutation timebomb.

Dr. Jessica Zucman-Rossi 5
Clinical Implications
  • Early detection of integration signatures
  • Personalized treatment approaches
  • Monitoring of high-risk patients

Conclusion: Mapping the Path Forward

The era of optical genome mapping has exposed HBV as a master manipulator of our chromosomes. Its ability to shatter, rearrange, and amplify genomic regions reveals why HBV-related cancers often resist conventional therapies. Yet these very scars point to solutions:

Prevention

Vaccination and early antivirals to limit integrations

Detection

Liquid biopsies detecting integration signatures in blood

Treatment

Precision therapies targeting CCND1, FGF19, or TERT in integrated tumors

As Bionano and long-read sequencing illuminate the "dark matter" of our genome, we gain power to defuse HBV's timebombs—one shattered chromosome at a time.

References