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

Frontiers in Genetics

卷:13

Zhaohui Hua¹  Zhenyu Peng¹  Gaopo Cai¹  Chunguang Guo¹  Yaming Guo¹  Zhen Li¹  Xinwei Han²  Zaoqu Liu²  Hui Liu³  Yunfang Chen⁴  Yin Yu⁵ 

[1] Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;

[2] Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China;

[3] Department of Nursing, Zhumadian Central Hospital Affiliated to Huanghuai University, Zhumadian, China;

[4] Department of Oncology, Zhumadian Central Hospital Affiliated to Huanghuai University, Zhumadian, China;

[5] Department of Pathophysiology, School of Basic Medical Sciences, The Academy of Medical Science, Zhengzhou University, Zhengzhou, China;

关键词: intrahepatic cholangiocarcinoma;    mutation;    TP53;    KRAS;    prognosis;    TMB;   

DOI  :  10.3389/fgene.2022.844800

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown