Ancestry-Linked Genomic Signatures in HCC and cHCC–CCA - ESMO Open, Feb. 2026

This landmark genomic analysis presents one of the largest real-world datasets of hepatocellular carcinoma (HCC) and combined hepatocellular–cholangiocarcinoma (cHCC–CCA), encompassing 2,372 HCC and 150 mixed histology cases profiled using clinical-grade next-generation sequencing (FoundationOne platform).

What was done

Comprehensive genomic profiling assessed >290 cancer-related genes, tumour mutational burden (TMB), and microsatellite status across five genetic ancestries and both sexes.

Key findings

Sex-based differences:

Women had lower rates of TERT, MYC, and CTNNB1 alterations, but higher BAP1 mutations.

Ancestry-linked variation:

East Asian patients showed higher frequencies of TP53, MUTYH, and TET2 alterations, along with more TMB-high tumours—suggesting biologically distinct molecular subgroups.

cHCC–CCA is molecularly distinct:

Compared with classic HCC, mixed tumours had significantly higher rates of IDH1, IDH2, and FGFR2 alterations, many of which are therapeutically actionable.

Actionable alterations:

Potentially targetable genomic events were identified in:

19.5% of HCC

34.7% of cHCC–CCA

Diagnostic refinement:

In 37 cases, genomic findings prompted re-evaluation and revision of the original histological diagnosis—highlighting the diagnostic power of NGS.

Clinical implications

This study reinforces that integrated molecular diagnostics should become standard of care in cHCC–CCA and considered in advanced HCC, not only to identify therapeutic targets but also to refine diagnosis.

Precision oncology in liver cancer is no longer theoretical—it is becoming clinically relevant.