title: Single nucleotide polymorphism array analysis of bone marrow failure patients reveals characteristic patterns of genetic changes.
abstract: The bone marrow failure syndromes (BMFS) are a heterogeneous group of rare blood disorders characterized by inadequate haematopoiesis, clonal evolution, and increased risk of leukaemia. Single nucleotide polymorphism arrays (SNP-A) have been proposed as a tool for surveillance of clonal evolution in BMFS. To better understand the natural history of BMFS and to assess the clinical utility of SNP-A in these disorders, we analysed 124 SNP-A from a comprehensively characterized cohort of 91 patients at our BMFS centre. SNP-A were correlated with medical histories, haematopathology, cytogenetic and molecular data. To assess clonal evolution, longitudinal analysis of SNP-A was performed in 25 patients. We found that acquired copy number-neutral loss of heterozygosity (CN-LOH) was significantly more frequent in acquired aplastic anaemia (aAA) than in other BMFS (odds ratio 12·2, P < 0·01). Homozygosity by descent was most common in congenital BMFS, frequently unmasking autosomal recessive mutations. Copy number variants (CNVs) were frequently polymorphic, and we identified CNVs enriched in neutropenia and aAA. Our results suggest that acquired CN-LOH is a general phenomenon in aAA that is probably mechanistically and prognostically distinct from typical CN-LOH of myeloid malignancies. Our analysis of clinical utility of SNP-A shows the highest yield of detecting new clonal haematopoiesis at diagnosis and at relapse.
authors.affiliation: Division of Hematology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Babushok
authors.forename: Hongbo M
authors.initials: HM
authors.lastname: Xie
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Roth
authors.forename: Nieves
authors.initials: N
authors.lastname: Perdigones
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Olson
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Cockroft
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.forename: Juan C
authors.initials: JC
authors.lastname: Perin
authors.forename: Yimei
authors.initials: Y
authors.lastname: Li
authors.forename: Michele E
authors.initials: ME
authors.lastname: Paessler
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Podsakoff
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Mason
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Biegel
authors.forename: Monica
authors.initials: M
authors.lastname: Bessler
mesh_terms: D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic; D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology*; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012189:Retrospective Studies; D055815:Young Adult
keywords: aplastic anaemia; bone marrow failure; chromosomal rearrangements; clonal evolution; cytogenetic diagnosis