HBV DNA Integration into Telomerase or MLL4 Genes and TERT Promoter Point Mutation as Three Independent Signatures in...

Area of Science:

• Hepatology
• Genetics
• Oncology

Background:

• Hepatocellular carcinoma (HCC) classification requires genetic insights, particularly for Hepatitis B virus-related HCC (HBV-HCC).
• HBV-HCC presents unique genetic features, including HBV DNA integrations and somatic mutations, necessitating a refined classification system.

Purpose of the Study:

• To develop a novel genetic classification for HBV-HCC by integrating HBV DNA integrations and common somatic mutations.
• To utilize a capture-sequencing platform for precise genetic profiling of HBV-HCC samples.

Main Methods:

• Analyzed 153 HBV-HCC samples using capture sequencing to identify HBV integrations and three key somatic mutations.
• Classified HBV-HCC into four distinct groups based on the presence of HBV-TERT integration, HBV-MLL4 integration, or TERT promoter point mutation.

Main Results:

• Four HBV-HCC groups were defined: G1 (HBV-TERT integration, 25.5%), G2 (HBV-MLL4 integration, 10.5%), G3 (TERT promoter mutation, 30.1%), and G4 (no mutations, 34.0%).
• Group G3 showed higher male-to-female ratio, cirrhosis rates, and poorer post-resection outcomes, while G4 exhibited the best prognosis.
• Transcriptomic analysis revealed distinct groupings, with G2 showing an active immune profile potentially responsive to immune checkpoint inhibitors. HBV DNA analysis offered insights into carcinogenesis.

Conclusions:

• A simple, robust genetic classification for HBV-HCC was successfully developed and validated.
• This classification system enhances the understanding of HBV-HCC and promotes harmonization in clinical studies.