TP53/KRAS Co-Mutations Create Divergent Prognosis Signatures in Intrahepatic Cholangiocarcinoma

Background: Due to high invasiveness and heterogeneity, the morbidity and mortality of intrahepatic cholangiocarcinoma (ICC) remain unsatisfied. Recently, the exploration of genomic variants has decoded the underlying mechanisms of initiation and progression for multiple tumors, while has not been fully investigated in ICC.Methods: We comprehensively analyzed 899 clinical and somatic mutation data of ICC patients from three large-scale cohorts. Based on the mutation landscape, we identified the common high-frequency mutation genes (FMGs). Subsequently, the clinical features, prognosis, tumor mutation burden (TMB), and pharmacological landscape from patients with different mutation carriers were further analyzed.Results: We found TP53 and KRAS were the common FMGs in the three cohorts. Kaplan-Meier survival curves and univariate and multivariate analysis displayed that TP53 and KRAS mutations were associated with poor prognosis. Considering the co-mutation phenomenon of TP53 and KRAS, we stratified patients into Double-WT, Single-Hit, and Double-Hit phenotypes by mutation status. Patients with the three phenotypes showed significant differences in the mutation landscape. Additionally, compared with Double-WT and Single-Hit phenotypes, patients with Double-Hit presented a dismal prognosis and significantly high TMB. Through chemotherapy sensitivity analysis, we identified a total of 30 sensitive drugs for ICC patients, of which 22 were drugs sensitive to Double-WT, 7 were drugs sensitive to Double-Hit, and only one was a drug sensitive to Single-Hit.Conclusion: Our study defined a novel mutation classification based on the common FMGs, which may contribute to the individualized treatment and management of ICC patients.

Automated summary

This study comprehensively analyzed the clinical and somatic mutation data of ICC patients from large-scale cohorts, and identified TP53 and KRAS as the common high-frequency mutation genes associated with poor prognosis. The study also classified patients into different mutation phenotypes and found that Double-Hit patients had a dismal prognosis and high TMB. Through chemotherapy sensitivity analysis, the study identified several drugs sensitive to ICC patients.