A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including <i>TP53:IDH1, IDH1:KRAS, TP53:BAP1</i>, and <i>IDH1:FGFR2</i> Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease.
<i>KRAS/NRAS</i> mutations are common in ICC tumours and 6-32% of patients also have isocitrate dehydrogenase 1 and 2 (<i>IDH1</i> and <i>IDH2</i>) gene mutations associated with metabolic changes.
The present results demonstrated a higher participation of Ki-ras gene mutations in EHC than found in previous studies, and provided a confirmation and extension of the results earlier reported by Tada et al. and Tsuda et al. for IHC.
Overexpression of MDM2 protein in intrahepatic cholangiocarcinoma: relationship with p53 overexpression, Ki-67 labeling, and clinicopathological features.
Here we report the development of a genetically engineered mouse model of IHCC that incorporates two of the most common mutations in human IHCC, activating mutations of Kras (Kras(G12D)) and deletion of p53.
The most frequent genetic aberrations (GAs) observed were tumor protein 53 (TP53; 27%), cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B; 27%), KRAS (22%), AT-rich interactive domain-containing protein 1A (ARID1A; 18%), and isocitrate dehydrogenase 1 (IDH1; 16%) in IHCCA; KRAS (42%), TP53 (40%), CDKN2A/B (17%), and SMAD4 (21%) in EHCCA; and TP53 (59%), CDKN2A/B (19%), ARID1A (13%), and ERBB2 (16%) in GBCA.
We analyzed the loss of heterozygosity (LOH) and microsatellite instability (MSI) of hMSH2, hMLH1, and p53 genes in 55 patients with intrahepatic cholangiocarcinoma by using polymerase chain reaction based microsatellite markers D2S119, D3S1611, and TP53, respectively and determined the association between microsatellite alterations and patient survival.
IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation.
KRAS is mutated in 23 of 98 (23%) bile duct-type intrahepatic cholangiocarcinomas and in only 1 of 76 (1%) cholangiolar-type intrahepatic cholangiocarcinomas.
The most common alterations were TP53, KRAS, and CDKN2A in gallbladder carcinoma; TP53, KRAS, PIK3CA, and BRAF in intrahepatic cholangiocarcinoma; and TP53 and SMAD4 in extrahepatic cholangiocarcinoma.
In this study, we analyze a large set of intrahepatic cholangiocarcinoma tumors (n = 54) for mutations in these genes and compare the clinical outcomes of wild type versus KRAS and BRAF mutant cases.
Patients with ERBB2-mutated ICCs tended to have a worse prognosis than those with wild-type or PIK3CA-mutated ICCs but a better prognosis than those with KRAS-mutated ICCs.
IDH1/2 (p=0.0005) and BAP1 (p=0.0097) mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC.
These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA.
These data suggest that each of the examined genes is involved in the development of ICC and that the p53 and K-ras mutation may play a role in the tumor growth pattern.
We find that TP53-defective ICC patients are more likely to be HBsAg-seropositive, whereas mutations in the oncogene KRAS are nearly exclusively found in HBsAg-seronegative ICC patients.
Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma.
In addition, point mutations of ras and p53 were examined genetically in selected ICC cases by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequence analysis.