Integrated genomic analyses identify oncogenic pathway interplay in hepatocarcinogenesis defining specific molecular...

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) is a complex cancer with diverse genomic alterations.
• Understanding HCC molecular heterogeneity is crucial for targeted therapies and improved patient outcomes.

Purpose of the Study:

• To establish a robust molecular classification of HCC by integrating multi-omic data.
• To identify distinct HCC subtypes and their associated driver mutations for clinical relevance.

Main Methods:

• Integrative analysis of genomic, transcriptomic, epigenomic, and proteomic data from 529 HCC samples.
• Validation of identified molecular subtypes in an independent cohort of 807 HCC cases.
• Utilized transcriptomic scores to assess pathway activities related to key mutations.

Main Results:

• Identified nine robust molecular subtypes of HCC, including common (CTNNB1/APC, TP53, AXIN1/IRF2) and rare (TP53+CTNNB1, BAP1, CCNA2/E1, HNF1A) subtypes.
• Discovered two immune-related subtypes (U^Hot, U^Interm) with undetermined drivers.
• Demonstrated that AXIN1, TP53 mutations, and BAP1 loss impact key cellular pathways (β-catenin, p53).
• The rare TP53+CTNNB1^ex3 subtype is highly aggressive, with TP53 mutation preceding CTNNB1 alteration.

Conclusions:

• A refined molecular classification of HCC into nine subtypes provides a framework for understanding disease biology.
• This classification enables a more precise approach to HCC treatment and precision medicine.
• Further research into immune-related subtypes may reveal novel therapeutic targets.