Although CEBPA mutations have been described in AML, the significance of this mutation in this tumor is unclear.

Mutations of the transcription factor CEBPA (CCAAT/enhancer binding protein alpha) have been reported in approximately 15% of patients with acute myeloid leukemia (AML) with a normal karyotype. CEBPA plays a role in the differentiation of granulocytes. Two types of mutations have been reported: N-terminal changes which result in a truncated dominant negative isoform lacking one of the N terminal domain transactivation domains and C-terminal mutations which are in-frame insertions or deletions affecting the leucine zipper and preventing dimerization and DNA binding. Patients may carry both N- and C-terminal mutations affecting different alleles. Isolated, biallelic ("double") mutations (not single mutation) of CEBPA appear to be associated with a favorable-risk group of normal karyotype AML. CEBPA mutations have also been reported in association with hereditary myeloid disorders; 5-10% of CEBPA double mutant AML cases may harbor germline mutations. Recommend correlation with clinical findings including family history and genetic counseling, if there is clinical suspicion of an inherited disorder.

Although CEBPA mutations have been described in AML, the significance of this mutation in this tumor is unclear.

This gene is a known cancer gene.

This gene is a known cancer gene.

GATA2 is a member of the GATA transcription factors which play a role in hematopoiesis. GATA2 mutations in the zinc finger domains have been described in accelerated phase and blasts phase chronic myelogenous leukemia as well as 5-10% of acute myeloid leukemia and familial syndromes with a predisposition to acute myeloid leukemia and myelodysplastic syndromes. Co-existing mutations in ASXL1 have been reported in a subset of patients with mutations in GATA2 and are believed to represent an important step in myeloid transformation, particularly to chronic myelomonocytic leukemia in young female patients. Other reports suggest that in cases of AML, GATA2 mutations have a higher prevalence among cases with biallelic CEBPA mutations and were not observed in cases with monoallelic CEBPA mutations. In general, the GATA2 pathogenic mutations are loss-of-function mutations (nonsense, frameshift, splice site mutations or missense mutations(codons 349-398)) and are believed to result in impairment of granulocyte differentiation. In MDS, GATA2 mutations may be associated with a poor prognosis. If clinical findings and family history are concerning for an inherited disorder, then genetic counseling may be helpful, if clinically indicated.

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.

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.

WT1 encodes for a transcription factor containing an N-terminal transactivation domain and a C-terminal zinc-finger domain necessary for the development of the urogenital system. The precise roles of WT1 in normal and malignant hematopoiesis remain uncertain. New emerging supports a novel role of WT1 in the regulation of epigenetic programs through its interaction with TET proteins in the 5=hydroxymethylation of cytosines. WT1 mutations are found in 6% of acute myeloid leukemia overall, and about 8-13% in cytogenetically normal AML. Higher frequencies are present in biallelic CEBPA mutated acute myeloid leukemia (14%), followed by t(15;17)/PML-RARA (11.0%), and FLT3-ITD (8.5%,). WT1 mutations are associated with younger age in AML. WT1 mutations are typically putative loss of function mutations and most frequently occur in exon 7 or exon 9. About 75% of these mutations are frameshift, and the remaining are missense, nonsense, splice site or inframe indel mutations. In some cases two or more mutations in WT1 may occur. In addition, WT1 mutations may coexist with mutations in NPM1, FLT3, among others. WT1 is overexpressed in the majority of AML, giving rise to the concept that it may act as both a tumor suppressor and oncogene, depending on the context. Several studies showed that WT1 mutations are associated with a worse prognosis in cytogenetically normal acute myeloid leukemia, although one study including patients from three German-Austrian AML study protocols demonstrated no association with overall survival or relapse-free survival. Given its over-expression in AML, clinical trials employing peptide vaccination strategy against WT1 has been ongoing in AML patients.

RUNX1(AML1, CBFA2) encodes the alpha subunit of core binding factor and is a transcription factor important in normal hematopoietic development. RUNX1 mutations have been reported in approximately 10% of myelodysplastic cases, 5-15% of acute myeloid leukemia, 8-37% of chronic myelomonocytic leukemia, 10% of T cell acute lymphoblastic leukemia, 3% of systemic mastocytosis, 2% of essential thrombocythemia and 2% of polycythemia vera. The mutations include frameshift, missense, nonsense, and splice site mutations. Typically, the Runt domain and the region just downstream of the Runt domain are affected and the mutations tend to be monoallelic. AML with RUNX1 mutation which does not fulfill the diagnostic criteria for other specific AML subtypes in the categories of AML with recurrent genetic abnormalities, therapy-related myeloid neoplasms, or AML with myelodysplasia-related changes is now classified the provisional entity of AML with mutated RUNX1. RUNX1 mutations may be associated with Trisomy 8 or MLL-PTD in AML according to some studies. They tend not to occur in AML cases with favorable cytogenetic findings and appear to be exclusive of NPM1 or CEBPA mutations in AML. Myeloid neoplasms, predominantly MDS/AML, developing in patients, usually at a young age, with a familial platelet disorder and germline monoallelic RUNX1 mutations are categorized as myeloid neoplasms with germline RUNX1 mutation. Of note, RUNX1 may also be involved in large intragenic deletions and translocations (e.g., t(8;21)(RUNX1-ETO), t(3;21)(RUNX1-EVI1), t(12;21)(TEL-RUNX1) which are not detected by this assay. Mutated RUNX1 is a poor-risk prognostic marker in AML unless it co-occurs with favorable-risk AML subtypes (NCCN Guidelines for AML). RUNX1 nonsense or frameshift mutations are associated with an unfavorable prognosis in myelodysplastic syndrome, independent of IPSS, IPSS-R, age, and other gene mutations (NCCN Guidelines for Myelodysplastic Syndromes). RUNX1 mutations are independently associated with unfavorable outcomes and shorter survival after hematopoietic stem cell transplantation in patients with myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia. RUNX1 mutations are also associated with an unfavorable prognosis chronic myelomonocytic leukemia and systemic mastocytosis.