A series of nine CC, 15 HCC-CC and three separated HCC and CC lesions ('collision tumors') were screened for loss of heterozygosity (LOH) using 400 microsatellite markers and for p53 and beta-catenin mutations.
Accumulation of multiple genetic alterations are involved in the tumorigenesis of CC, of which genetic alterations of APC and DCC occur at a relatively early stage, and of OGG1 and p53 occur at a relatively late stage during development of CC.
Here we characterize Notch in human-resected CC, a toxin-driven model in rats, and a transgenic mouse model in which p53 deletion is targeted to biliary epithelia and CC induced using the hepatocarcinogen thioacetamide.
We investigated the occurrence of K-ras codon 12 and 13 mutations, p53 protein accumulation, and Ki-67 expression in tumor tissue from PSC patients (n=33) who had developed cholangiocarcinoma, using bile duct specimens exised at liver transplantation of PSC patients without cholangiocarcinoma (n=15) as controls
Significantly more cholangiocarcinomas from the West Virginia group were p53-immunohistochemical-positive than from the non-West Virginia group (67% vs. 20%; p < 0.05). p53 mutations did not differ in the 2 groups in respect to site or specific type.
An example is the identification of arginine missense mutations of isocitrate dehydrogenases-1 and -2 (IDH1/2) in glioma, acute myeloid leukemia (AML), chondrosarcomas, and cholangiocarcinoma.
Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC.
The presence of TP53 mutations or upregulation of MDM2 gene expression in 9 of the 13 cholangiocarcinomas strongly supports that the impairment of the p53 pathway is an important and specific step in cholangiocarcinoma pathogenesis.
Mutations of the p53 gene were found in two cases, at codon 244 (GGC to TGC) in the cholangiocellular carcinoma component of case 1 (mixed type, showing an intimate intermingling of both elements) and at codon 234 (TAC to AAC) in both components of case 5 (combined type, consisting of contiguous but independent masses of both elements).
For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA.
Finally, in somatic mutation analysis, tumor-normal paired 14 tissue and 6 bile samples were analyzed, genomic alterations of EGFR, FGFR1, ABL1, PIK3CA, and CDKN2A gene were seen in the diffusely infiltrating type CC, and TP53, KRAS, APC, GNA11, ERBB4, ATM, SMAD4, BRAF, and IDH1 were altered in the mass-forming type CC group.
Only a few studies have evaluated the clinicopathological significance of the p53 protein expression and s-p53-Abs level in patients with cholangiocarcinoma.
Besides, the expression of CXCL7 was significantly associated with the Ki67 expression, but not associated with CA199, AFP, or P53 expression in cholangiocarcinoma.
Hepatocellular carcinoma and choangiocarcinoma display heterogeneity at both morphologic and molecular levels Cholangiocellular carcinoma is most commonly associated with IDH 1/2 mutations.
Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma.
These data indicate that p53 is important for the activation of autophagy in nutrient-deprived cholangiocarcinoma cells, and thus contributes to cell survival and chemoresistance.