Abstract
Backgrounds/Aims
Combined hepatocellular-cholangiocarcinoma (cHC-CC), which generally has a poor prognosis, comprises of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and diverse components with intermediate features between HCC and CC. Histological subtypes with stem cell features (the SC subtype) have different clinicopathological significance in cHC-CC. The mutational status may reflect the clinicopathological subgroup of cHC-CC together with the histological subtype.
Methods
We examined the mutational statuses of KRAS, IDH1 or 2 (IDH1/2), ARID1A, the TERT promoter, and p53 and their relationships with clinicopathological features in 53 patients with cHC-CC. Background liver diseases were hepatitis B (n=9), hepatitis C (22), alcohol (5), nonalcoholic fatty liver disease (NAFLD) (8), and unknown (9).
Results
Mutations in KRAS, IDH1/2, ARID1A, the TERT promoter and p53 were detected in 4 (7.5%), 6 (11.8%) 7 (13.2%), 16 (31.3%), and 24 patients (45.3%), respectively. KRAS mutations correlated with higher histological diversity scores and a higher M-factor (p<0.05). ARID1A mutations correlated with alcohol, smaller tumor sizes, lower grade of co-existent HCC, and AFP-positivity and were associated with cholangiolocellular carcinoma subtype-predominant (p<0.05). TERT promoter mutations correlated with hepatitis B, an intermediate subtype-predominant histology, higher clinical stage, and higher N-factor (p<0.05) and were associated with gender (female-predominant) and previous therapy. p53 mutations correlated with AFP-positivity (p<0.05).
Conclusion
The results of the mutational analysis revealed that cHC-CC has diverse types of mutations and also that mutations in the TERT promoter and ARID1A may reflect etiological impact, different histological subtypes, histogenesis and tumor aggressiveness. These results suggest the potential efficacy of molecular-based subclassification of cHC-CC.
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