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|Ref Type||Journal Article|
|Authors||Topka S, Vijai J, Walsh MF, Jacobs L, Maria A, Villano D, Gaddam P, Wu G, McGee RB, Quinn E, Inaba H, Hartford C, Pui CH, Pappo A, Edmonson M, Zhang MY, Stepensky P, Steinherz P, Schrader K, Lincoln A, Bussel J, Lipkin SM, Goldgur Y, Harit M, Stadler ZK, Mullighan C, Weintraub M, Shimamura A, Zhang J, Downing JR, Nichols KE, Offit K|
|Title||Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia.|
|Abstract Text||Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|ETV6||N385fs||frameshift||loss of function - predicted||ETV6 N385fs results in a change in the amino acid sequence of the Etv6 protein beginning at aa 385 of 452, likely resulting in premature truncation of the functional protein (UniProt.org). N385fs results in decreased transcriptional regulation of known target genes and impaired protein localization to the nucleus (PMID: 26102509), and therefore, is predicted to lead to a loss of Etv6 protein function.|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ETV6 inact mut||acute lymphoblastic leukemia||not applicable||N/A||Clinical Study||Risk Factor||In multiple clinical studies, ETV6 inactivating germline mutations were shown to be a risk factor for the development of acute lymphocytic leukemia (PMID: 26522332, PMID: 26102509, PMID: 25807284).||25807284 26102509 26522332|