ETV6 is a transcriptional repressor and is frequently involved in translocations with a variety of different partner genes in a range of hematologic malignancies. Mutations of ETV6 have been described in <5% of myelodysplastic syndromes and appear to be more frequent (ie, 10-24% of cases) in early T cell precursor type (immature) acute lymphoblastic leukemias. In addition, ETV6 mutations have been reported in association with hereditary myeloid disorders. These mutations occur throughout the gene and typically correspond to loss of function mutations (nonsense and frameshift mutations). ETV6 mutations may occasionally occur in a homozygous/hemizygous manner and tend to occur with mutations in NOTCH1 in lymphoblastic leukemia. In MDS, ETV6 mutations have been independently associated with an adverse prognosis. If clinical findings and family history are concerning for the presence of an inherited disorder, then genetic counseling may be helpful, if clinically indicated.

This gene is a known cancer gene.

This gene is a known cancer gene.

ETV6 is a transcriptional repressor and is frequently involved in translocations with a variety of different partner genes in a range of hematologic malignancies. Mutations of ETV6 have been described in <5% of myelodysplastic syndromes and appear to be more frequent (ie, 10-24% of cases) in early T cell precursor type (immature) acute lymphoblastic leukemias. In addition, ETV6 mutations have been reported in association with hereditary myeloid disorders. These mutations occur throughout the gene and typically correspond to loss of function mutations (nonsense and frameshift mutations). ETV6 mutations may occasionally occur in a homozygous/hemizygous manner and tend to occur with mutations in NOTCH1 in lymphoblastic leukemia. In MDS, ETV6 mutations have been independently associated with an adverse prognosis. If clinical findings and family history are concerning for the presence of an inherited disorder, then genetic counseling may be helpful, if clinically indicated.

WHSC1 (also known as NSD2 or MMSET) is a H3K36 methyltransferase that converts unmodified H3K36 to the monomethylated and dimethylated forms. NSD2 was recently found to show clonal and subclonal p.E1099K or p.D1125N activating alterations in 15% of t(12;21) ETV6-RUNX1–containing and 15% of TCF3-PBX1 contaning pediatric B-ALLs. The p.E1099K mutation appears to be less prevalent in other types of B-ALL(less than 5%) and both mutations appear to be absent in T-ALL, pediatric AML and adult ALL. In experimental models, increased H3K36 dimethylation and decreased unmodified H3K36 was associated with the NSD2 p.E1099K variant or the t(4;14) translocation( which leads to overexpression of NSD2). Overexpression of NSD2 in t(4;14)-positive multiple myeloma (MM) is also associated with globally increased levels of H3K36 dimethylation and decreased K27 trimethylation. NSD2 is considered to be a potential therapeutic target for a subset of cases of pediatric B-ALL.