title: Mutations in idiopathic cytopenia of undetermined significance assist diagnostics and correlate to dysplastic changes.
abstract: Cytopenia is common in the elderly population and etiology may be difficult to assess. Here, we investigated the occurrence of mutations in patients with idiopathic cytopenia of undetermined significance and the usefulness in improving diagnostics. We included 60 patients with persistent cytopenia > 6 months without definite diagnosis of hematological neoplasm after routine assessment. Bone marrow material underwent a blinded morphology review and DNA was sequenced with a targeted 20 gene panel representing the most commonly mutated genes in myelodysplastic syndrome. Thirty seven (62%) patients carried at least one mutation at inclusion, and of these 95% carried a mutation in TET2, ASXL1, SRSF2, or DNMT3A. The most commonly mutated gene was TET2 observed in 43% of all patients. During one to eight years follow-up seven patients progressed to a myeloid neoplasm and six of these had a detectable mutation at study entry. Median time to progression was 53 months (range 10-78), and at time of progression each patient had at least two mutations detected. Mutations in TP53 and NRAS were not present in patients at inclusion, but identified as secondary hits triggering progression. The morphology review was concordant in 68% of all cases, and 93% of the cases reclassified into the group "highly suspicious for MDS" had a mutation. All patients who had a concordant review "highly suspicious for MDS" had at least two mutations detected. Overall, we show that morphology examination is challenging in this heterogeneous group and targeted sequencing helps identify patients at risk of progression. Am. J. Hematol. 91:1234-1238, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jakob Werner
authors.initials: JW
authors.lastname: Hansen
authors.affiliation: Department of Clinical Genetics Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Maj Karoline
authors.initials: MK
authors.lastname: Westman
authors.affiliation: Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Lene Dissing
authors.initials: LD
authors.lastname: Sjö
authors.affiliation: Department of Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Leonie
authors.initials: L
authors.lastname: Saft
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Lasse Sommer
authors.initials: LS
authors.lastname: Kristensen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Andreas Due
authors.initials: AD
authors.lastname: Ørskov
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Treppendahl
authors.affiliation: Department of Clinical Genetics Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Mette Klarskov
authors.initials: MK
authors.lastname: Andersen
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Grønbaek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001856:Bone Marrow Examination; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics*; D010198:Pancytopenia / Q000209:etiology / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A