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Detection of genome-wide copy number variants in myeloid malignancies using next-generation sequencing
  1. Wei Shen1,2,
  2. Christian N Paxton1,
  3. Philippe Szankasi1,
  4. Maria Longhurst1,
  5. Jonathan A Schumacher1,
  6. Kimberly A Frizzell1,
  7. Shelly M Sorrells1,
  8. Adam L Clayton1,
  9. Rakhi P Jattani1,
  10. Jay L Patel1,2,
  11. Reha Toydemir1,2,
  12. Todd W Kelley1,2,
  13. Xinjie Xu1,2
  1. 1 ARUP Laboratories, Salt Lake City, Utah, USA
  2. 2 Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA
  1. Correspondence to Dr Xinjie Xu, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84108, USA; xinjie.xu{at}


Aims Genetic abnormalities, including copy number variants (CNV), copy number neutral loss of heterozygosity (CN-LOH) and gene mutations, underlie the pathogenesis of myeloid malignancies and serve as important diagnostic, prognostic and/or therapeutic markers. Currently, multiple testing strategies are required for comprehensive genetic testing in myeloid malignancies. The aim of this proof-of-principle study was to investigate the feasibility of combining detection of genome-wide large CNVs, CN-LOH and targeted gene mutations into a single assay using next-generation sequencing (NGS).

Methods For genome-wide CNV detection, we designed a single nucleotide polymorphism (SNP) sequencing backbone with 22 762 SNP regions evenly distributed across the entire genome. For targeted mutation detection, 62 frequently mutated genes in myeloid malignancies were targeted. We combined this SNP sequencing backbone with a targeted mutation panel, and sequenced 9 healthy individuals and 16 patients with myeloid malignancies using NGS.

Results We detected 52 somatic CNVs, 11 instances of CN-LOH and 39 oncogenic mutations in the 16 patients with myeloid malignancies, and none in the 9 healthy individuals. All CNVs and CN-LOH were confirmed by SNP microarray analysis.

Conclusions We describe a genome-wide SNP sequencing backbone which allows for sensitive detection of genome-wide CNVs and CN-LOH using NGS. This proof-of-principle study has demonstrated that this strategy can provide more comprehensive genetic profiling for patients with myeloid malignancies using a single assay.

  • leukaemia
  • chromosomes
  • molecular oncology

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  • WS and CNP contributed equally.

  • Handling editor Mary Frances McMullin.

  • Contributors WS, CNP, XX and TWK designed the study, analysed and interpreted the data, and wrote the manuscript. CNP and ML performed sequencing and SNP microarray experiments. JAS, KAF, SMS, ALC, RPJ, JLP and RT contributed to the study design, participated in the interpretation of the data and critically revised the manuscript.

  • Competing interests None declared.

  • Ethics approval This study was conducted in accordance with protocols approved by the University of Utah Institutional Review Board and the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.