IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. Mutations at Arg132 of IDH1 are typically heterozygous mutations and considered gain of function mutations that lead to increased levels of 2-hydroxyglutarate which are believed to alter epigenetic regulation (ie, DNA methylation) in AML. Mutations of IDH1 appear to be mutually exclusive of mutations in TET2, another gene involved in regulation of DNA methylation, and also exclusive of mutations in IDH2. Mutations of IDH1 have been shown to lead to increased DNA methylation in AML. Recurrent missense mutation of Arg 132 in IDH1 has been reported in approximately 5-15% of cases of acute myeloid leukemia and is often associated with a normal karyotype, wild type CEBPA, wild type FLT3 and the presence of NPM1 mutations. In addition, this mutation has been reported in approximately 10-20% of cases with leukemic transformation of myeloproliferative neoplasms and has been reported in less than 5% of chronic phase primary myelofibrosis, less than 5% of myelodysplastic syndrome and rare cases of polycythemia vera, essential thrombocytosis and chronic myelomonocytic leukemia. The prognostic impact of IDH1 mutations in AML appears uncertain, however, in the settings of primary myelofibrosis and polycythemia vera, the presence of IDH1 mutation is independently associated with inferior survival. Mutant IDH1 represents a therapeutic target in some clinical settings.

IDH1 or IDH2 mutations are found in >70% of lower grade diffusely infiltrative gliomas and in >90% of secondary glioblastoma. IDH mutational status has been reported to be a favorable prognostic indicator relative to wild-type gliomas of similar histology, regardless of grade. Therapeutic strategies exploiting mutated IDH protein, including through direct inhibition and vaccine-based approaches, are currently the subject of preclinical research and clinical trials.

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies. A case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma has been reported (5). IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma, suggesting 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.

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and billary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. Reports have shown that melanoma cases can harbor IDH1 mutations. An IDH1 R132C mutation was found in a melanoma metastasis to the lung. IDH1 mutations were found to coexist with BRAF or KIT mutations, and all were detected in metastatic lesions. Coexistence of IDH1 R132C mutation with KRAS has also been reported in a single case of lung adenocarcinoma (Sequist et al., Ann Oncol., 22:2616-2624, 2011). The clinical significance of this mutation with regards to response to anti-IDH1 therapy in lung cancer is unknown.

Reports have shown that melanoma cases can harbor IDH1 mutations. An IDH1 R132C mutation was found in a melanoma metastasis to the lung. IDH1 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 have been shown to have increased colony-forming and in vivo growth activities.

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies. Mutations in IDH1 and IDH2 have been reported in intrahepatic cholangiocarcinomas. IDH1 mutation has been associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. IDH1 mutation has been described to be a feature of intrahepatic cholangiocarcinomas.

IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and biliary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. IDH1 mutation has been reported in up to 2% of colorectal adenocarcinomas. The clinical significance of this mutation with regards to response to anti-IDH1 therapy in colorectal cancer is unknown. Results should be interpreted in conjunction with other laboratory and clinical findings.

IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and biliary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. IDH1 mutations have been reported in 1-2% of lung adenocarcinomas. The clinical significance of this mutation with regards to response to anti-IDH1 therapy in lung cancer is unknown. Results should be interpreted in conjunction with other laboratory and clinical findings.

This gene is a known cancer gene.

This gene is a known cancer gene.

This is a cancer genes

IDH1 is an enzyme localized to the cytoplasm and peroxisomes and involved in citrate metabolism. IDH-mutant tumors have aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in several malignancies including AML, central nervous system and biliary tract. Strikingly, IDH1 mutations were rarely detected in the other solid tumor types. While IDH1 mutations have been reported in 1-2% of lung adenocarcinomas, the clinical significance of this mutation with regards to response to anti-IDH1 therapy in lung cancer is unknown. This specific IDH1 p.PR119Q has been identified in numerous reports, but it has not been biochemically characterized and its effect on protein function is unknown. Results should be interpreted in conjunction with other laboratory and clinical findings.

IDH1 or IDH2 mutations are found in >70% of lower grade diffusely infiltrative gliomas and in >90% of secondary glioblastoma. IDH mutational status has been reported to be a favorable prognostic indicator relative to wild-type gliomas of similar histology, regardless of grade. Therapeutic strategies exploiting mutated IDH protein, including through direct inhibition and vaccine-based approaches, are currently the subject of preclinical research and clinical trials.

Mutations of NPM1 have been reported in approximately 25-35% of cases of acute myeloid leukemia (AML). The mutations of NPM1 are frameshift mutations in the C-terminus of the protein that alter the C-terminal amino acid sequence and are associated with aberrant cytoplasmic localization of the protein. NPM1 mutations in AML are typically associated with a normal karyotype and may co-exist with FLT3 mutations. The presence of NPM1 mutations has been associated with improved complete remission rates, but not necessarily overall survival, in multivariate analysis including assessment of the variety of more recently discovered mutations that may be present in AML. In addition, cytogenetically normal AML with mutated NPM1, without FLT3 ITD or mutated DNMT3A, has been considered to be a favorable genetic risk group according to some studies, although other studies suggest that coexistant mutations in IDH1 or IDH2 may be required for the favorable risk effect of NPM1.

BCOR is a ubiquitously expressed nuclear protein that is a transcriptional corepressor important in several cellular processes. Somatic, nonsense and frameshift mutations throughout BCOR have been reported in approximately 7% of chronic myelomonocytic leukemia, 4% of patients with myelodysplastic syndrome(MDS), 4% of primary acute myeloid leukemia and appear to be associated with RUNX1 and DNMT3A mutations . Also, BCOR mutations may be enriched among cases of AML lacking NPM1, CEBPA, FLT3-ITD, IDH1 and MLL-PTD alterations. BCOR mutations tend to be subclonal in MDS, clonal in primary AML and are believed to have significance as loss of function mutations in a tumor suppressor gene that affect the functional allele in male and female patients. The presence of BCOR mutation in patients with MDS and AML has been associated with poorer overall survival according to some studies.

BCOR is a ubiquitously expressed nuclear protein that is a transcriptional corepressor important in several cellular processes. Somatic, nonsense and frameshift mutations throughout BCOR have been reported in approximately 7% of chronic myelomonocytic leukemia, 4% of patients with myelodysplastic syndrome(MDS), 4% of primary acute myeloid leukemia and appear to be associated with RUNX1 and DNMT3A mutations . Also, BCOR mutations may be enriched among cases of AML lacking NPM1, CEBPA, FLT3-ITD, IDH1 and MLL-PTD alterations. BCOR mutations tend to be subclonal in MDS, clonal in primary AML and are believed to have significance as loss of function mutations in a tumor suppressor gene that affect the functional allele in male and female patients. The presence of BCOR mutation in patients with MDS and AML has been associated with poorer overall survival according to some studies.

DNMT3A is a DNA methyltransferase. Recurrent, somatic, heterozygous mutations in DNMT3A have been reported in approximately 18-25% of cases of acute myeloid leukemia (up to 34% of normal karyotype AML), 12-18% of cases of myelodysplastic syndrome, up to 15% of myeloproliferative neoplasms, less than 5% of cases of chronic myelomonocytic leukemia and 15% of cases of adult, eary T cell precursor acute lymphoblastic leukemia. DNMT3A is also one of the most frequently mutated genes in CHIP and CCUS. Mutations in DNMT3A may occur together with mutations in other genes including JAK2, FLT3, IDH1/IDH2, ASXL1, TET2 and NPM1. DNMT3A mutations have been associated with reduced enzymatic activity or altered histone binding, as well as reduced DNA methylation in various genomic regions and altered gene expression in some models. Codon R882 is a hotspot for mutations in DNMT3A. DNMT3A mutations may be associated with adverse prognosis in specific subtypes of AML according to some, but not all studies; the prognostic significance of DNMT3A in AML may depend on patient age, type of DNMT3A mutation (R882 or non-R882 mutation) and the co-existence (or absence) of specific mutations in other genes. DNMT3A mutations may also be associated with adverse prognosis in MDS according to some studies.

JAK2 is a non-receptor tyrosine kinase that mediates signaling via the JAK-STAT pathway. The somatic, activating mutation V617F in the pseudokinase domain of JAK2 has been reported in over 90% of patients with polycythemia vera, 40-70% of essential thrombocythemia, 40-60% of primary myelofibrosis and 50% of MDS/MPN with Ring Sideroblasts and Thrombocytosis. JAK2 mutations have also been reported in CHIP. The small percentage of cases of polycythemia vera that do not carry the JAK2 V617F mutation have somatic, activating mutations in JAK2 exon 12 which typically affect the region encompassing codons 536-547 and are in-frame deletions/insertions, duplications of 8-12 amino acids or missense mutations. Mutations in JAK2 are typically mutually exclusive with mutations in the thrombopoietin receptor (MPL) and calreticulin (CALR), but JAK2 mutations may co-exist with mutations in other genes (ie, IDH1, SF3B1, TET2, ASXL1, etc). Ruxolitinib is a JAK2 inhibitor that has been approved for use in patients with intermediate- and high-risk primary myelofibrosis and is under study in other JAK2+ MPNs. Other JAK2 inhibitors (eg, Pacritinib) are also in various stages of study.

IDH2 is a mitochondrial enzyme involved in citrate metabolism. Mutations at Arg140 and Arg172 of IDH2 are typically heterozygous mutations and considered gain of function mutations that lead to increased levels of 2-hydroxyglutarate which is believed to alter epigenetic regulation (ie, DNA methylation) in AML. Mutations of IDH2 appear to be mutually exclusive of mutations in TET2, another gene involved in regulation of DNA methylation, and also exclusive of mutations in IDH1. Mutations of IDH2 have been shown to lead to increased DNA methylation in AML. IDH2 mutations have been reported in 10-20% of AML and are often associated with a normal karyotype. IDH2 mutations have been reported in less than 5% of cases of MDS and less than 10% of myeloproliferative neoplasms. The prognostic impact of IDH2 mutations in AML appears uncertain due to conflicting reports. In the setting of essential thrombocytosis, primary myelofibrosis and MDS, the presence of IDH2 mutations is associated with reduced survival. Therapeutic targeting with an FDA approved mutant IDH2 inhibitor (enasidenib (AG-221)) has been reported for patients with relapsed or refractory IDH2-mutated AML.

Ten-Eleven Translocation-2 (TET2) encodes a dioxygenase that converts 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promotes DNA demethylation. TET2 is a tumor suppressor gene and loss-of-function via mutations, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutations is a common event in myeloid and lymphoid malignancies. TET2 is also present in about 10% of otherwise healthy elderly individuals with clonal hematopoiesis of indeterminate potential (CHIP) and in some patients with unexplained cytopenia but who do not satisfy diagnostic criteria for MDS, so-called clonal cytopenia with undetermined significance (CCUS). Mutations in TET2 occur in 50-60% of chronic myelomonocytic leukemias. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. TET2 mutations are also found in 20-40% of systemic mastocytosis, 36% of blastic plasamcytoid dendritic cell neoplasm, 12-32% of acute myeloid leukemia, 10-20% of primary myelofibrosis, 10-33% of myelodysplastic syndromes, 10% of myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), 22% of polycythemia vera, and 16% of essential thrombocythemia. TET2 mutations are absent in juvenile myelomonocytic leukemia and show a low prevalence (less than 5%) in pediatric AML. Among lymphoid neoplasms, TET2 mutations are reported in approximately 30% of angioimmunoblastic lymphomas and less than 15 % of other mature T cell lymphomas and mature B cell lymphomas. In general, the mutations in TET2 are typically loss of function variants (frameshift, missense, nonsense mutations) that may be monoallelic or biallelic and occur throughout the gene. TET2 mutations tend to be mutually exclusive of mutations in IDH1/IDH2. TET2 mutations are associated with unfavorable outcomes and shorter survival after hematopoietic stem cell transplantation in patients with myelodysplastic syndrome (PMID: 25092778). In acute myeloid leukemia with wild-type FLT3-ITD and normal karyotype or intermediate-risk cytogenetic abnormalities, TET2 mutations are associated with an unfavorable prognosis.

SRSF2 is a member of the serine/arginine-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. It interacts with other spliceosomal components bound to both the 5- and 3-splice sites during spliceosome assembly. SRSF2 mutations typically occur as missense mutations at Pro95. SRSF2 mutations have been reported in approximately 40% of cases of chronic myelomonocytic leukemia, but they may not have prognostic significance in that entity. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. In addition, SRSF2 mutations have been reported in approximately 15-20% of cases of myelodysplastic syndrome. SRSF2 mutations have also been described in 5-20% of patients with acute myeloid leukemia and appear to be enriched among AML patients with reduced blast counts. SRSF2 has been found to be mutated in approximately 10% of cases of primary myelofibrosis where mutations may occur together with mutations in JAK2, MPL, TET2, CBL, ASXL1, EZH2, IDH1/2. SRSF2 mutations are also present in 8% of blastic plasmacytoid dendritic cell neoplasm and 3% of polythemia vera. SRSF2 mutations tend to be (although are not entirely) exclusive of mutations in other splicing factor components. SRSF2 mutations are associated with a poor prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes), primary myelofibrosis, polycythemia vera, and KIT D816V-mutated advanced systemic mastocytosis. SRSF2 mutations are also reported to be highly specific for secondary acute myeloid leukemia, and may also be helpful in identifying a subset of elderly patients with de novo acute myeloid leukemia and therapy-related AML with worse clinical outcomes.