title: Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia.
abstract: Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells. One frequent acquired abnormality is copy-number neutral loss of heterozygosity on chromosome 6p (6p CN-LOH) involving the human leukocyte antigen (HLA) locus. We hypothesized that because 6p CN-LOH clones may arise from selective pressure to escape immune surveillance through deletion of HLA alleles, the development of 6p CN-LOH may affect response to IST. We used single nucleotide polymorphism array genotyping and targeted next-generation sequencing of HLA alleles to assess frequency of 6p CN-LOH, identity of HLA alleles lost through 6p CN-LOH, and impact of 6p CN-LOH on response to IST. 6p CN-LOH clones were present in 11.3% of patients, remained stable over time, and were not associated with development of MDS-defining cytogenetic abnormalities. Notably, no patient with 6p CN-LOH treated with IST achieved a complete response. In summary, clonal 6p CN-LOH in aAA defines a unique subgroup of patients that may provide insights into hematopoietic clonal evolution.
authors.affiliation: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Marisol
authors.initials: M
authors.lastname: Betensky
authors.affiliation: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Babushok
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Roth
authors.affiliation: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Mason
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Biegel
authors.affiliation: Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Busse
authors.affiliation: Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Curt
authors.initials: C
authors.lastname: Lind
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Papazoglou
authors.affiliation: Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Monos
authors.affiliation: Office of Clinical and Translational Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Podsakoff
authors.affiliation: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Bessler
authors.affiliation: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: olsont@email.chop.edu.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Olson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6; D060965:Clonal Evolution; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
keywords: Aplastic anemia; clonal evolution; single nucleotide polymorphism array