Mutant IDH1 Confers an in Vivo Growth in a Melanoma Cell Line with BRAF Mutation

Abstract

Melanoma is the most deadly tumor of the skin, and systemic therapies for the advanced stage are still limited. Recent genetic analyses have revealed the molecular diversity of melanoma and potential therapeutic targets. By screening a cohort of 142 primary nonepithelial tumors, we discovered that about 10% of melanoma cases (4/39) harbored an IDH1 or IDH2 mutation. These mutations were found to coexist with BRAF or KIT mutation, and all IDH1 mutations were detected in metastatic lesions. BRAF-mutated melanoma cells, additionally expressing the cancer-related IDH1 mutant, acquired increased colony-forming and in vivo growth activities and showed enhanced activation of the MAPK and STAT3 pathways. Genome-wide gene expression profiling demonstrated that mutant IDH1 affected the expression of a set of genes. Especially, it caused the induction of growth-related transcriptional regulators (Jun, N-myc, Atf3) and the reduction of Rassf1 and two dehydrogenase genes (Dhrs1 and Adh5), which may be involved in the carcinogenesis of IDH1-mutated tumors. Our analyses demonstrate that IDH1 mutation works with other oncogenic mutations and could contribute to the metastasis in melanoma. Melanoma is the most malignant tumor of the skin, and the median survival rate of patients with metastatic tumors is less than 1 year.1 Although the incidence of melanoma has been increasing around the world, systemic therapies for the advanced stage are still limited. 2Recent studies have provided a clearer picture of the molecular events leading to melanoma development and progression.3,4 Since the identification of prevalent activating mutations of BRAF kinase, 5 further molecular studies have clarified the role of this pathway and others in melanomagenesis. 6 Recent genetic investigations have also demonstrated specific genotype-phenotype correlations that would be potentially informative in the context of the molecular subclassification of melanoma and therapeutic target molecules.7 For example, the c-kit gene mutations have been frequently reported in acral lentiginous/mucosal melanomas and are associated with better responsiveness to the inhibitor, imatinib. -10Recently, unbiased whole-exon resequencing analysis of glioblastoma multiforme has revealed recurrent mutation of the two IDH (isocitrate dehydrogenase) isoforms, IDH1 and IDH2.11 Subsequent analysis showed that these mutations are frequent in glioma and associated with better prognosis 12,13 ; furthermore, they have also been detected in a subset (about 8% to 16%) of acute myeloid leukemia (AML).14 -17 These enzymes convert isocitrate to ␣-ketoglutarate (␣-KG) with concurrent reduction of NADPH, but IDH1 is localized in the cytosol 18 whereas IDH2 is localized in mitochondria. 19 Mutations of the two genes affect the residues responsible for hydrophilic interactions with the substrate, and have been shown to impair the enzymatic activity, and therefore they are considered to be loss-of-function alleles.12 However, because the mutations are clustered in specific residues and only...

The CpG Island Methylator Phenotype: What's in a Name?

“…86, 87), and melanoma (10%; ref. 88), whereas in other solid tumors IDH1 mutations are infrequent (<5%) or absent (89,90). Interestingly, the IDH1/2 mutations in melanoma are also accompanied by a loss of 5hmC in melanoma progression (67).…”

Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML

“…Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 were originally identified in glioma, 1,2 acute myeloid leukemia (AML), myeloproliferative neoplasm, and myelodysplastic (MDS) syndrome patients [3][4][5] but are increasingly found in a diverse set of other tumor entities such as chondrosarcoma, 6 lymphoma, 7 melanoma, 8 and thyroid cancer. 9 In cytogenetically normal AML, mutated IDH1 is found in 10.9% of patients, 10 whereas mutated IDH2 is found in 12.1%.…”

Isocitrate Dehydrogenase 1 (IDH1) Mutation in Breast Adenocarcinoma Is Associated With Elevated Levels of Serum and Urine 2-Hydroxyglutarate

“…In addition to gliomas, IDH mutations have been discovered in various other solid tumors, including cholangiocarcinoma [1], chondrosarcoma [22,23], prostatic adenocarcinoma [24], and melanoma [25], among others [26][27][28][29], with codon R132 of IDH1 the most commonly mutated site.To date, IDH mutations have not been reported in breast carcinomas. With this report, we describe the case of a patient with metastatic hormone receptor-positive adenocarcinoma of the breast, whose tumor exhibited an IDH1 p.R132L mutation, and whose serum and urine displayed marked elevations of the oncometabolite 2-HG.…”