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Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation

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Abstract

Leukemia in dogs is a heterogeneous disease with survival ranging from days to years, depending on the subtype. Strides have been made in both human and canine leukemia to improve classification and understanding of pathogenesis through immunophenotyping, yet classification and choosing appropriate therapy remains challenging. In this study, we assessed 123 cases of canine leukemia (28 ALLs, 24 AMLs, 25 B-CLLs, and 46 T-CLLs) using high-resolution oligonucleotide array comparative genomic hybridization (oaCGH) to detect DNA copy number alterations (CNAs). For the first time, such data were used to identify recurrent CNAs and inclusive genes that may be potential drivers of subtype-specific pathogenesis. We performed predictive modeling to identify CNAs that could reliably differentiate acute subtypes (ALL vs. AML) and chronic subtypes (B-CLL vs. T-CLL) and used this model to differentiate cases with up to 83.3 and 95.8 % precision, respectively, based on CNAs at only one to three genomic regions. In addition, CGH datasets for canine and human leukemia were compared to reveal evolutionarily conserved copy number changes between species, including the shared gain of HSA 21q in ALL and ∼25 Mb of shared gain of HSA 12 and loss of HSA 13q14 in CLL. These findings support the use of canine leukemia as a relevant in vivo model for human leukemia and justify the need to further explore the conserved genomic regions of interest for their clinical impact.

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Abbreviations

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

BAC:

Bacterial artificial chromosome

CFA:

Canis familiaris

CLL:

Chronic lymphocytic leukemia

CML:

Chronic myeloid leukemia

CMML:

Chronic myelomonocytic leukemia

CMoL:

Chronic monocytic leukemia

CNA:

Copy number aberration

CNV:

Copy number variant

FISH:

Fluorescence in situ hybridization

GISTIC:

Genomic Identification of Significant Targets in Cancer

HSA:

Homo sapiens

LSA:

Lymphosarcoma

oaCGH:

Oligonucleotide array comparative genomic hybridization

SNP:

Single nucleotide polymorphism

TZL:

T zone lymphoma

WBC:

White blood cell

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Acknowledgments

This study was funded largely by a grant from the AKC Canine Health Foundation (#01843 awarded to MB), with additional support from an Ontario Veterinary College Pet Trust (awarded to DB, MB) and the NCSU Cancer Genomics Fund (MB). We gratefully acknowledge additional support from the Skippy Frank Fund for Life Sciences and Translational Research/ Rockefeller Philanthropy Advisors (awarded to MB/JS). SCR was supported in part by an NCSU Comparative Biomedical Science DVM-PhD training fellowship and NIH T35 training grant. We thank Jaime Modiano for providing some of the case materials, Rachael Thomas for assistance in recoding the canine data into “virtual” human data, and Siddharth Roy for valuable contributions toward calculating the shared regions for the predictive modeling feature selection.

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Authors and Affiliations

  1. Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA

    Sarah C. Roode & Matthew Breen

  2. Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA

    Daniel Rotroff & Alison Motsinger-Reif

  3. Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Science, Colorado State University, Fort Collins, CO, USA

    Anne C. Avery

  4. Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA

    Steven E. Suter

  5. Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, USA

    Steven E. Suter, Alison Motsinger-Reif & Matthew Breen

  6. Cancer Genetics Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Steven E. Suter & Matthew Breen

  7. Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada

    Dorothee Bienzle

  8. Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    Joshua D. Schiffman

  9. Department of Oncological Sciences, Center for Children’s Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Joshua D. Schiffman

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  1. Sarah C. Roode
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  2. Daniel Rotroff
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  3. Anne C. Avery
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  4. Steven E. Suter
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  5. Dorothee Bienzle
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  7. Alison Motsinger-Reif
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  8. Matthew Breen
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Correspondence to Matthew Breen.

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Roode, S.C., Rotroff, D., Avery, A.C. et al. Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation. Chromosome Res 23, 681–708 (2015). https://doi.org/10.1007/s10577-015-9475-7

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