Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas

Abstract

Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas, and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine (5hmC) and higher 5-methylcytosine (5mC) levels, as well as increased dimethylation of histone H3K79. Mutations in IDH1 or IDH2 were associated with longer overall survival (p = 0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (p = 0.021). IDH1 and IDH2 mutations are 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. We identified 2,309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.

Mutational landscape of intrahepatic cholangiocarcinoma

“…Such clustering enables early detection of IDH1 mutation in circulating tumour DNA as a way to screen for potential ICC tumours. In contrast to many previous studies 23,24,41 , mutations in IDH2 were not found in our cohort of ICC patients. Mutations in IDH1 and IDH2 have been found to cause a gain-of-function in the production of 2-hydroxyglutarate and to alter histone and DNA methylation 60 .…”

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

“…IDH1 and 2 mutations, recently shown to be among the most frequent mutations in intrahepatic cholangiocarcinomas, 48,50 were absent in intraductal tubulopapillary neoplasms. Likewise, loss of SMAD4 was restricted to a single example.…”

High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers

“…On the other hand, single CDKN2A, IDH2, MET, and RET somatic mutations were observed only in the invasive counterpart of matched samples. IDH2 mutations have never been described in gastric cancers and are rare in the gastrointestinal tract, with the exception of intrahepatic cholangiocarcinomas [25]. The diagnostic impact of CDKN2A, MET, and RET in discriminating among preinvasive and early invasive lesions should be tested in a larger prospective series of HG-IEN, whereas the germline variants in ATM, KDR, KIT, PIK3CA, and TP53 that are shared by both HG-IEN and EGC lesions should be evaluated for their potential to identify predisposition to gastric cancer.…”