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

Shibata, Tatsuhiro; Kokubu, Akiko; Miyamoto, Masashi; Sasajima, Yuko; Yamazaki, Naoya

doi:10.1016/j.ajpath.2010.12.011

Cited by 117 publications

(88 citation statements)

References 43 publications

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“…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).…”

Section: Idh Mutations In Other Cancer Typesmentioning

confidence: 99%

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

et al. 2013

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Although the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term "CIMP" has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast, endometrial, gastric, glioblastoma (gliomas), hepatocellular, lung, ovarian, pancreatic, renal cell, and prostate cancers, as well as for leukemia, melanoma, duodenal adenocarninomas, adrenocortical carcinomas, and neuroblastomas. CIMP has been reported to be useful for predicting prognosis and response to treatment in a variety of tumor types, but it remains unclear whether or not CIMP is a universal phenomenon across human neoplasia or if there should be cancer-specific definitions of the phenotype. Recently, it was shown that somatic isocitrate dehydrogenase-1 (IDH1) mutations, frequently observed in gliomas, establish CIMP in primary human astrocytes by remodeling the methylome. Interestingly, somatic IDH1 and IDH2 mutations, and loss-of-function mutations in ten-eleven translocation (TET) methylcytosine dioxygenase-2 (TET2) associated with a hypermethylation phenotype, are also found in multiple enchondromas of patients with Ollier disease and Mafucci syndrome, and leukemia, respectively. These data provide the first clues for the elucidation of a molecular basis for CIMP. Although CIMP appears as a phenomenon that occurs in various cancer types, the definition is poorly defined and differs for each tumor. The current perspective discusses the use of the term CIMP in cancer, its significance in clinical practice, and future directions that may aid in identifying the true cause and definition of CIMP in different forms of human neoplasia. Cancer Res; 73(19); 5858-68. Ó2013 AACR.

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Section: Idh Mutations In Other Cancer Typesmentioning

confidence: 99%

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

et al. 2013

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“…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%.…”

Section: Introductionmentioning

confidence: 99%

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

Chaturvedi¹,

Cruz²,

Jyotsana³

et al. 2013

Blood

188

150

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Key Points• IDH1 promotes leukemogenesis in vivo in cooperation with HoxA9.• Pharmacologic inhibition of mutant IDH1 efficiently inhibits AML cells of IDH1-mutated patients but not of normal CD34 1 bone marrow cells.Mutations in the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are frequently found in glioma, acute myeloid leukemia (AML), melanoma, thyroid cancer, and chondrosarcoma patients. Mutant IDH produces 2-hydroxyglutarate (2HG), which induces histone-and DNA-hypermethylation through inhibition of epigenetic regulators. We investigated the role of mutant IDH1 using the mouse transplantation assay. Mutant IDH1 alone did not transform hematopoietic cells during 5 months of observation. However, mutant IDH1 greatly accelerated onset of myeloproliferative disease-like myeloid leukemia in mice in cooperation with HoxA9 with a mean latency of 83 days compared with cells expressing HoxA9 and wild-type IDH1 or a control vector (167 and 210 days, respectively, P 5 .001). Mutant IDH1 accelerated cell-cycle transition through repression of cyclindependent kinase inhibitors Cdkn2a and Cdkn2b, and activated mitogen-activated protein kinase signaling. By computational screening, we identified an inhibitor of mutant IDH1, which inhibited mutant IDH1 cells and lowered 2HG levels in vitro, and efficiently blocked colony formation of AML cells from IDH1-mutated patients but not of normal CD341 bone marrow cells. These data demonstrate that mutant IDH1 has oncogenic activity in vivo and suggest that it is a promising therapeutic target in human AML cells. (Blood.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR1) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR1 breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme. The Oncologist 2014; 19:602-607 Implications for Practice: Isocitrate dehydrogenase (IDH) mutations have been identified in various hematologic and solid-tumor malignancies. To date, there are no published reports of these mutations in breast cancer. With this article, we describe a case of hormone receptor-positive adenocarcinoma of the breast with an IDH1 (p.R132L) mutation. The impacted patient had markedly elevated levels of serum and urine 2-hydroxyglutarate, an oncometabolite that accumulates as a result of the neomorphic activity of the altered IDH enzyme. IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma, and these findings may carry future therapeutic implications, given the emergence of targeted therapies against the altered IDH protein.

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

Cited by 117 publications

References 43 publications

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

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

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

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

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