title: Targeted Next-Generation Sequencing in Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia Aids Diagnosis in Challenging Cases and Identifies Frequent Spliceosome Mutations in Transformed Acute Myeloid Leukemia.
abstract: OBJECTIVE
  Optimal integration of next-generation sequencing (NGS) into clinical practice in hematologic malignancies remains unclear. We evaluate the utility of NGS in myeloid malignancies.
  
  
  METHODS
  A 42-gene panel was used to sequence 109 cases of myelodysplastic syndrome (MDS, n = 38), chronic myelomonocytic leukemia (CMML, n = 14), myeloproliferative neoplasm (MPN, n = 24), and MDS and/or MPN transformed to acute myeloid leukemia (AML, n = 33).
  
  
  RESULTS
  At least one pathogenic mutation was identified in 74% of cases of MDS, 100% of CMMLs, and 96% of MPNs. In contrast, only 47% of cases of MDS (18/38) and 7% (1/14) of CMMLs exhibited abnormal cytogenetics. In diagnostically difficult cases of MDS or CMML with normal cytogenetics, NGS identified a pathogenic mutation and was critical in establishing the correct diagnosis. Spliceosomal genes and epigenetic modifiers were frequently mutated. Spliceosome mutations were also frequently detected in AML arising from MDS, CMML, or MPN (39%) compared with the reported rate in de novo AML (7%-14%).
  
  
  CONCLUSIONS
  In difficult cases of MDS or MPN, NGS facilitates diagnosis by detection of gene mutations to confirm clonality, and AMLs evolving from MDS or MPN carry frequent mutations in spliceosomal genes.
authors.affiliation: From the Department of Pathology.
authors.forename: Erica
authors.initials: E
authors.lastname: Reinig
authors.affiliation: Knight Cancer Institute.
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.affiliation: Knight Cancer Institute, Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland.
authors.forename: Elie
authors.initials: E
authors.lastname: Traer
authors.affiliation: From the Department of Pathology, Knight Cancer Institute.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Arora
authors.affiliation: From the Department of Pathology, Knight Cancer Institute.
authors.forename: Shari
authors.initials: S
authors.lastname: Brown
authors.affiliation: Knight Cancer Institute.
authors.forename: Rogan
authors.initials: R
authors.lastname: Rattray
authors.affiliation: From the Department of Pathology, Knight Cancer Institute.
authors.forename: Rita
authors.initials: R
authors.lastname: Braziel
authors.affiliation: From the Department of Pathology, Knight Cancer Institute.
authors.forename: Guang
authors.initials: G
authors.lastname: Fan
authors.affiliation: From the Department of Pathology, Knight Cancer Institute.
authors.forename: Richard
authors.initials: R
authors.lastname: Press
authors.affiliation: From the Department of Pathology, Knight Cancer Institute, dunlapj@ohsu.edu.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dunlap
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis* / Q000235:genetics; D017381:Spliceosomes; D055815:Young Adult
keywords: Gene mutations; Leukemic transformation; Molecular hematopathology; Myelodysplastic syndrome; Myeloproliferative neoplasms