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

Abstract

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.

Molecular Profile of Intrahepatic Cholangiocarcinoma

“…After study selection, 77 studies [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ,…”

“…The most prevalent mutations were in TP53 (42.7%), ARID1A (21.7%), KRAS (15.7%), IDH1 (8.7%), CDKN2A (7.8%), BAP1 (6.7%), suppressor of others against decapentaplegic ( SMAD4 ) (6.5%), and PIK3CA (6.0%). Guo et al [ 19 ] investigated 899 patients with ICC and found that TP53 (18–40%) and KRAS (10–18%) were high-frequency mutation genes. Other mutations were found in ARID1A , SMAD4 , spectrin repeat-containing nuclear envelope protein 1 ( SYNE1 ), mucin 16 ( MUC16 ), BAP1 , LDL receptor-related protein 1B ( LRP1B ), fibrous sheath-interacting protein 2 ( FSIP2 ), ephrin type-A receptor 2 ( EPHA2 ), IDH1 , IDH2 , polybromo 1 ( PBRM1 ), v-raf murine sarcoma viral oncogene homolog B1 ( BRAF ), ATM , FGFR2 , C16orf3 , human leukocyte antigen A ( HLA-A ), HLA-C , titin gene ( TTN ), family with sequence similarity 230 member A ( FAM230A ), AHNAK2 , and CTD-3193O13.9.…”

“… * According to Guo et al and Weinberg et al [ 16 , 19 ]. TP53 : tumor protein p53 ; IDH1 : isocitrate dehydrogenase 1 ; IDH2 : isocitrate dehydrogenase 2 ; KRAS : Kirsten rat sarcoma virus ; ARID1A : AT-rich interactive domain-containing protein 1A ; BAP1 : BRCA1-associated protein-1 ; BRAF : V-raf murine sarcoma viral oncogene homolog B ; FGFR2 : fibroblast growth factor receptor 2 ; Her2 : human epidermal growth factor receptor 2 .…”

Cholangiocarcinoma: Molecular Abnormalities and Cells of Origin

“…The relevant cooperation of TP53 and KRAS in promoting the development and the malignancy of iCCA is directly supported by a recent study reporting a molecular and clinicopathologic analysis on 3 large cohorts of iCCA patients extensively characterized at molecular and clinical levels: TP53 and KRAS mutations were associated with a poor prognosis and this phenomenon was particularly evident for double mutant ( TP53/KRAS ) patients. 70…”

“…The relevant cooperation of TP53 and KRAS in promoting the development and the malignancy of iCCA is directly supported by a recent study reporting a molecular and clinicopathologic analysis on 3 large cohorts of iCCA patients extensively characterized at molecular and clinical levels: TP53 and KRAS mutations were associated with a poor prognosis and this phenomenon was particularly evident for double mutant (TP53/ KRAS) patients. 70 Guest et al 71 reported the development of an iCCA model based on chronic liver inflammation and transfection with mutant TP53 leads to the development of iCCA generated from cholangiocytes: in these tumors, the induction of NOTCH3 is required for oncogenic transformation of cholangiocytes. Interestingly, NOTCH3 was found to be the NOTCH family receptor mostly overexpressed in human iCCAs.…”