title: Functional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent.
abstract: BACKGROUND
  Hematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management.
  
  
  METHODS
  Herein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time.
  
  
  CONCLUSIONS
  This case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.
authors.affiliation: Division of Hematology and Oncology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Leonard
authors.affiliation: Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Philipp W
authors.initials: PW
authors.lastname: Raess
authors.affiliation: Department of Pathology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dunlap
authors.affiliation: Center for Hematologic Malignancies, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Hayes-Lattin
authors.affiliation: Department of Cell, Developmental, and Cancer Biology, Portland, OR, USA.|Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: Center for Hematologic Malignancies, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. traere@ohsu.edu.|Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA. traere@ohsu.edu.
authors.forename: Elie
authors.identifier: http://orcid.org/0000-0001-8844-2345
authors.initials: E
authors.lastname: Traer
mesh_terms: D000208:Acute Disease; D020558:GTP Phosphohydrolases / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007951:Leukemia, Myeloid / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008479:Mediastinal Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009364:Neoplasm Recurrence, Local; D009373:Neoplasms, Germ Cell and Embryonal / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011728:Pyridones / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000627:therapeutic use*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D016159:Tumor Suppressor Protein p53; C560077:trametinib; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: Acute myeloid leukemia; Germ cell neoplasm; High-throughput nucleotide sequencing; NRAS; Trametinib