DataSheet1_TP53 /KRAS Co-Mutations Create Divergent Prognosis Signatures in Intrahepatic Cholangiocarcinoma.docx

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.

研究背景：肝内胆管癌（intrahepatic cholangiocarcinoma, ICC）具有高侵袭性与异质性，其发病率与死亡率仍未得到有效控制，临床结局不佳。近年来，基因组变异研究已阐明多种肿瘤发生发展的潜在分子机制，但相关研究在肝内胆管癌领域尚未得到充分探索。

研究方法：本研究综合分析了来自3个大规模队列的899例肝内胆管癌患者的临床数据与体细胞突变数据。基于突变图谱，我们鉴定出高频突变基因（frequently mutated genes, FMGs）。随后，我们进一步分析了携带不同突变类型患者的临床特征、预后情况、肿瘤突变负荷（tumor mutation burden, TMB）以及药理学特征。

研究结果：我们发现TP53与KRAS是3个队列中共同的高频突变基因。Kaplan-Meier生存曲线以及单因素与多因素分析显示，TP53与KRAS突变与不良预后显著相关。考虑到TP53与KRAS的共突变现象，我们根据突变状态将患者分为“双野生型（Double-WT）”、“单突变型（Single-Hit）”与“双突变型（Double-Hit）”三种表型。三种表型患者的突变图谱存在显著差异。此外，与“双野生型”和“单突变型”患者相比，“双突变型”患者预后极差且肿瘤突变负荷显著升高。通过化疗敏感性分析，我们共鉴定出30种对肝内胆管癌患者敏感的药物，其中22种对“双野生型”患者敏感，7种对“双突变型”患者敏感，仅1种对“单突变型”患者敏感。

研究结论：本研究基于共同高频突变基因定义了一种全新的突变分类体系，该体系或可为肝内胆管癌患者的个体化治疗与临床管理提供重要参考依据。