Single nucleotide polymorphism array analysis of bone marrow failure patients reveals characteristic patterns of genetic changes
Corresponding Author
Daria V. Babushok
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
Correspondence: Daria Babushok, MD, PhD, Division of Hematology, Department of Medicine, Hospital of the University of Pennsylvania, 3615 Civic Center Blvd, ARC 302, Philadelphia, PA 19104, USA.
E-mail: [email protected]
Search for more papers by this authorHongbo M. Xie
Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorJacquelyn J. Roth
Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorNieves Perdigones
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorTimothy S. Olson
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorJoshua D. Cockroft
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorXiaowu Gai
Center for Biomedical Informatics, Stritch School of Medicine at the Loyola University Chicago, Maywood, IL, USA
Search for more papers by this authorJuan C. Perin
Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorYimei Li
Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorMichele E. Paessler
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorHakon Hakonarson
Center for Applied Genomics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorGregory M. Podsakoff
Center for Cellular and Molecular Therapeutics, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorPhilip J. Mason
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorJaclyn A. Biegel
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Search for more papers by this authorMonica Bessler
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
Search for more papers by this authorCorresponding Author
Daria V. Babushok
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
Correspondence: Daria Babushok, MD, PhD, Division of Hematology, Department of Medicine, Hospital of the University of Pennsylvania, 3615 Civic Center Blvd, ARC 302, Philadelphia, PA 19104, USA.
E-mail: [email protected]
Search for more papers by this authorHongbo M. Xie
Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorJacquelyn J. Roth
Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorNieves Perdigones
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorTimothy S. Olson
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorJoshua D. Cockroft
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorXiaowu Gai
Center for Biomedical Informatics, Stritch School of Medicine at the Loyola University Chicago, Maywood, IL, USA
Search for more papers by this authorJuan C. Perin
Center for Biomedical Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorYimei Li
Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorMichele E. Paessler
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorHakon Hakonarson
Center for Applied Genomics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorGregory M. Podsakoff
Center for Cellular and Molecular Therapeutics, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorPhilip J. Mason
Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Search for more papers by this authorJaclyn A. Biegel
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Search for more papers by this authorMonica Bessler
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
Search for more papers by this authorSummary
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.
Supporting Information
| Filename | Description |
|---|---|
| bjh12603-sup-0001-SupportingMethods-TextS1-FigS1-S2.pdfapplication/PDF, 597.8 KB | Supporting Methods. CN-LOH prediction. Text S1. Case descriptions. Fig S1. Expansion of monosomy 21 clone causing RUNX1 haploinsufficiency in a patient with congenital thrombocytopenia and congenital anomalies. Fig S2. Flow diagram for candidate gene analysis. |
| bjh12603-sup-0002-TableSI-SVI.pdfapplication/PDF, 659.9 KB | Table SI. Breakdown of SNP-A genotyping by diagnosis, number of arrays and the SNP-A platform Table SII. Inherited regions of extended homozygosity in BMFS Table SIII. (A) Enrichment analysis of copy number variants in neutropenia NOS patients compared to normal controls (Quad 610 SNP Array, Caucasian). (B) Enrichment analysis of copy number variants in acquired aplastic anaemia patients compared to normal controls (Quad 610 SNP Array, Caucasian). (C) Enrichment analysis of copy number variants in neutropenia NOS patients compared to normal controls (Omni1-Quad SNP Array, Caucasian). (D) Enrichment analysis of copy number variants in acquired aplastic anaemia patients compared to normal controls (Omni1-Quad SNP Array, Caucasian). Table SIV. Targeted analysis of genes implicated in BMFS and hematologic malignancies. Table SV. Comparison of clinical information provided by SNP array and metaphase cytogenetics. Table SVI. Comparison of acquired CN-LOH frequencies in aAA versus non-aAA BMFS in published studies of SNP-A genotyping in BMFS. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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