Identification Of IDH Mutation In Cholangiocarcinoma And Study On The Mechanism Of Mutation Inhibition Of ALKBH

Mutations in the genes encoding isocitrate dehydrogenase, IDH1and IDH2, have been reported in low grade gliomas, acute myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1and IDH2mutations in34of326(10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1or IDH2had lower5-hydroxymethylcytosine and higher5-methylcytosine levels, as well as increased dimethylation of histone H3lysine79. Mutations in IDH1or IDH2were associated with longer overall survival, and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection. IDH1and IDH2mutations may also cause a stress that leads to p53activation. We identified2309genes that were significantly hypermethylated in19cholangiocarcinomas with mutations in IDH1or 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 IDH1or IDH2in different types of tumors.It is reported that IDH1and IDH2mutations result in a gain of function to produce D-2-hydroxyglutarate (D-2-HG), an antagonist of α-ketoglutarate (α-KG) and putative oncometabolite, and hypermethylation in genomic DNA and Histone is caused by competitive inhibition of α-KG ependent dioxygenase Tet DNA hydroxylase and Jmjc-domain-containing histone demethylase, respectively. We found that2-HG could inhibit ALKBH family a-KG-dependent dioxygenases, which play important roles in DNA alkylating damage repair. The inhibition of alkylating repair system resulted in activated DNA damage pathways in glioma samples. U87MG cells expressing mutant IDH1are sensitized to multiple classical DNA alkylating agents. Our results suggest that impairment of DNA repair may contribute to tumorigenesis by IDH mutations.