Kras and Tp53 Mutations Cause Cholangiocyte- and Hepatocyte-Derived Cholangiocarcinoma

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver cancer epidemiologically linked with liver injury, which has poorly understood incipient stages and lacks early diagnostics and effective therapies. While iCCA is conventionally thought to arise from the biliary tract, studies have suggested that both hepatocytes and biliary cells (cholangiocytes) may give rise to iCCA. Consistent with the plasticity of these cell lineages, primary liver carcinomas exhibit a phenotypic range from hepatocellular carcinoma (HCC) to iCCA, with intermediates along this spectrum. Here, we generated mouse models to examine the consequence of targeting mutant and, common alterations in human iCCA, to different adult liver cell types. Selective induction of these mutations in the SOX9 population, predominantly consisting of mature cholangiocytes, resulted in iCCA emerging from premalignant biliary intraepithelial neoplasia (BilIN). In contrast, adult hepatocytes were relatively refractory to these mutations and formed rare HCC. In this context, injury accelerated hepatocyte-derived tumorigenesis and promoted a phenotypic switch to iCCA. BilIN precursor lesions were absent in the hepatocyte-derived iCCA models, pointing toward distinct and direct emergence of a malignant cholangiocytic phenotype from injured, oncogenically primed hepatocytes. loss enhanced the reprogramming of hepatocytes to cholangiocytes, which may represent a mechanism facilitating formation of hepatocyte-derived iCCA. Overall, our work shows iCCA driven by and may originate from both mature cholangiocytes and hepatocytes, and factors such as chronic liver injury and underlying genetic mutations determine the path of progression and resulting cancer phenotype. The histopathogenesis of biliary tract cancer, driven by and mutations, can be differentially impacted by the cell of origin within the mature liver as well by major epidemiologic risk factors. .

Comprehensive genomic profile of cholangiocarcinomas in China

“…The most common mutations in iCCA were found to be IDH1/2, BAP1, KRAS, TP53, SMAD4 and ARID1A, whereas common mutations in exCCA were identified in KRAS, TP53, SMAD4, SKT11, ERBB2, PTEN, ATM and NF1 (10,44). TP53 may play a key role in enabling hepatocyte-derived iCCA (30,18), and KRAS mutations in the absence of TP53 mutations can drive exCCA (41,45). The present study demonstrated that the most frequent alterations of TP53, KRAS, SMAD4, CDKN2A, TERT and ARID1A were found in both iCCA and exCCA.…”

“…Changes in the p53 gene have been reported in >50% of patients with cancer, including those with CCA (30,31). Studies have reported TP53 as a potential diagnostic biomarker in esophageal cancer and head and neck cancer (32,33).…”

“…KRAS, the main subtype of the RAS gene family, has been reported to promote a variety of lethal human tumors, such as lung, colon and pancreatic cancer (36,37). Several studies have reported KRAS as a tumor biomarker (37)(38)(39) and that the co-mutation of TP53 and KRAS in many tumors (30,40). Consistent with previous studies (41)(42)(43), the most frequent mutations of KRAS occurred at the 12 and 13th amino acid sites in Chinese patients with CCA, and co-mutations of TP53 and KRAS were also detected with a high frequency, suggesting that KRAS mutations are conserved in most tumors.…”

Network Pharmacology Based Research into the Effect and Mechanism of Yinchenhao Decoction Against Cholangiocarcinoma

“…Regarding MAPK1, it can be activated by osteopontin, a phosphorylated glycoprotein involved in various human cancers, and implicated in activating the MEK/MAPK pathway, therefore promote the growth and metastasis of intrahepatic cholangiocarcinoma [30] . TP53 loss may drive the reprogramming of hepatocytes to biliary cells, which may be related to the formation of intrahepatic cholangiocarcinoma [31] . VEGFA plays an important part in tumor angiogenesis.…”

Exome sequencing of 22 genes using tissue from patients with biliary tract cancer

“…Despite that the NGS panel was originally tailored for analyzing patients with CRC, several of the detected mutations have suggested clinicopathological features and involvement in the tumorigenesis of BTC. Mutations in ARID1A has been associated with poor prognosis and TP53 and KRAS, conventionally classified as a tumor suppressor and oncogene, respectively, may play an intriguing role in the plasticity of hepatocytes and cholangiocytes during the early tumorigenesis . However, the phenotypic consequences of mutational aberrations are for most of the genes still vastly under‐reported, and future work may elucidate the specific role in tumorigenesis.…”