title: Detection of an activated JAK3 variant and a Xq26.3 microdeletion causing loss of PHF6 and miR-424 expression in myelodysplastic syndromes by combined targeted next generation sequencing and SNP array analysis.
abstract: Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis and progression to acute leukemia. In patients ineligible for hematopoietic stem cell transplantation, azacitidine is the only treatment shown to prolong survival. However, with the availability of a growing compendium of cancer biomarkers and related drugs, analysis of relevant genetic alterations for individual MDS patients might become part of routine evaluation. Therefore and in order to cover the entire bone marrow microenvironment involved in the pathogenesis of MDS, SNP array analysis and targeted next generation sequencing (tNGS) for the mostly therapy relevant 46 onco- and tumor-suppressor genes were performed on bone marrow biopsies from 29 MDS patients. In addition to the detection of mutations known to be associated with MDS in NRAS, KRAS, MPL, NPM1, IDH1, PTPN11, APC and MET, single nucleotide variants so far unrelated to MDS in STK11 (n=1), KDR (n=3), ATM (n=1) and JAK3 (n=2) were identified. Moreover, a recurrent microdeletion was detected in Xq26.3 (n=2), causing loss of PHF6 expression, a potential tumor suppressor gene, and the miR-424, which is involved in the development of acute myeloid leukemia. Finally, combined genetic aberrations affecting the VEGF/VEGFR pathway were found in the majority of cases demonstrating the diversity of mutations affecting different nodes of a particular signaling network as an intrinsic feature in MDS patients. We conclude that combined SNP array analyses and tNGS can identify established and novel therapy relevant genomic aberrations in MDS patients and track them in a clinical setting for individual therapy selection.
authors.affiliation: Institute of Pathology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Kunze
authors.affiliation: Institute of Pathology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gamerdinger
authors.affiliation: Institute of Pathology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Leßig-Owlanj
authors.affiliation: Institute of Pathology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Sorokina
authors.affiliation: Institute of Pathology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Brobeil
authors.affiliation: Institute of Pathology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Mehmet Kemal
authors.initials: MK
authors.lastname: Tur
authors.affiliation: Department of Internal Medicine V, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Blau
authors.affiliation: Department of Internal Medicine V, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Burchardt
authors.affiliation: Ambulance for Hematology, Gießen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Käbisch
authors.affiliation: Ambulance for Hematology, Gießen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schliesser
authors.affiliation: Clinic for Internal Medicine, Hospital Frankfurt/Oder, Frankfurt/Oder, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehl
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Internal Medicine V, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Rummel
authors.affiliation: Department of Internal Medicine V, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.affiliation: Institute of Medical Microbiology and Virology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hain
authors.affiliation: Institute of Medical Microbiology and Virology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Trinad
authors.initials: T
authors.lastname: Chakraborty
authors.affiliation: Institute of Pathology, University Hospital Gießen and Marburg, Gießen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bräuninger
authors.affiliation: Institute of Pathology, University Hospital Gießen and Marburg, Gießen, Germany. Electronic address: stefan.gattenloehner@patho.med.uni-giessen.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
mesh_terms: D001853:Bone Marrow / Q000201:enzymology / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D053616:Janus Kinase 3 / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D005819:Genetic Markers; C554214:MIRN424 microrna, human; D035683:MicroRNAs; C000716967:NPM1 protein, human; C502542:PHF6 protein, human; D012097:Repressor Proteins; D000090243:Nucleophosmin; C507933:JAK3 protein, human; D053616:Janus Kinase 3
keywords: MDS; SNP array; Targeted next generation sequencing