title: Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome.
abstract: The distinction between acquired aplastic anemia (AA) and hypocellular myelodysplastic syndrome (hMDS) is often difficult, especially nonsevere AA. We postulated that somatic mutations are present in a subset of AA, and predict malignant transformation. From our database, we identified 150 AA patients with no morphological evidence of MDS, who had stored bone marrow (BM) and constitutional DNA. We excluded Fanconi anemia, mutations of telomere maintenance, and a family history of BM failure (BMF) or cancer. The initial cohort of 57 patients was screened for 835 known genes associated with BMF and myeloid cancer; a second cohort of 93 patients was screened for mutations in ASXL1, DNMT3A, BCOR, TET2, and MPL. Somatic mutations were detected in 19% of AA, and included ASXL1 (n = 12), DNMT3A (n = 8) and BCOR (n = 6). Patients with somatic mutations had a longer disease duration (37 vs 8 months, P < .04), and shorter telomere lengths (median length, 0.9 vs 1.1, P < .001), compared with patients without mutations. Somatic mutations in AA patients with a disease duration of >6 months were associated with a 40% risk of transformation to MDS (P < .0002). Nearly one-fifth of AA patients harbor mutations in genes typically seen in myeloid malignancies that predicted for later transformation to MDS.
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, United Kingdom; and Department of Haematology, King's College Hospital, London, United Kingdom.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Kulasekararaj
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, United Kingdom; and Department of Haematology, King's College Hospital, London, United Kingdom.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, United Kingdom; and Department of Haematology, King's College Hospital, London, United Kingdom.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Smith
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, United Kingdom; and Department of Haematology, King's College Hospital, London, United Kingdom.
authors.forename: Azim M
authors.initials: AM
authors.lastname: Mohamedali
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, United Kingdom; and.
authors.forename: Syed
authors.initials: S
authors.lastname: Mian
authors.affiliation: Department of Haematology, King's College Hospital, London, United Kingdom.
authors.forename: Shreyans
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, United Kingdom; and.
authors.forename: Joop
authors.initials: J
authors.lastname: Gaken
authors.affiliation: Department of Haematology, King's College Hospital, London, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Czepulkowski
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, United Kingdom; and Department of Haematology, King's College Hospital, London, United Kingdom.
authors.forename: Judith C W
authors.initials: JC
authors.lastname: Marsh
authors.affiliation: Department of Haematological Medicine, King's College London School of Medicine, London, United Kingdom; and Department of Haematology, King's College Hospital, London, United Kingdom.
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000741:Anemia, Aplastic / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D059785:Karyotype; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors; D016615:Telomere / Q000235:genetics; D055815:Young Adult
chemical_list: C473949:ASXL1 protein, human; C411984:BCOR protein, human; C000717967:DNMT3A protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A