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Influence of genetic background on tumor karyotypes: Evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma

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Abstract

Recurrent chromosomal aberrations in solid tumors can reveal the genetic pathways involved in the evolution of a malignancy and in some cases predict biological behavior. However, the role of individual genetic backgrounds in shaping karyotypes of sporadic tumors is unknown. The genetic structure of purebred dog breeds, coupled with their susceptibility to spontaneous cancers, provides a robust model with which to address this question. We tested the hypothesis that there is an association between breed and the distribution of genomic copy number imbalances in naturally occurring canine tumors through assessment of a cohort of Golden Retrievers and Rottweilers diagnosed with spontaneous appendicular osteosarcoma. Our findings reveal significant correlations between breed and tumor karyotypes that are independent of gender, age at diagnosis, and histological classification. These data indicate for the first time that individual genetic backgrounds, as defined by breed in dogs, influence tumor karyotypes in a cancer with extensive genomic instability.

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Abbreviations

aCGH:

array comparative genomic hybridization

BAC:

bacterial artificial chromosome

CFA:

Canis familiaris

CNA:

copy number aberration

DAPI:

4′,6-diamidino-2-phenylindole

FISH:

fluorescence in-situ hybridization

HSA:

Homo sapiens

OSA:

osteosarcoma

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Acknowledgements

This work was supported by a grant from the American Kennel Club Canine Health Foundation awarded to M.B./J.M. (CHF 2254), and by charitable donations from individuals, the Starlight Fund, and the Kate Koogler Canine Cancer Research Fund. We thank Eric Seiser for assistance with statistical analysis. We thank all the owners, breeders and veterinarians who contributed samples and data to this study.

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Authors and Affiliations

  1. Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC, 27606, USA

    Rachael Thomas, Pei-Chien Tsai & Matthew Breen

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

    Rachael Thomas & Matthew Breen

  3. Department of Statistics, College of Agriculture and Life Sciences, North Carolina State University, Raleigh, NC, USA

    Huixia J. Wang

  4. Microarray Facility, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    Cordelia F. Langford

  5. Integrated Department of Immunology, University of Colorado, Denver, CO, USA

    Susan P. Fosmire, Cristan M. Jubala & Jaime F. Modiano

  6. Idexx Veterinary Services, Broomfield, CO, USA

    David M. Getzy

  7. Department of Biostatistics, University of Alabama Birmingham, Birmingham, AL, USA

    Gary R. Cutter

  8. University of Colorado Cancer Center, Aurora, CO, USA

    Jaime F. Modiano

  9. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, 1365 Gortner Ave., St Paul, MN, 55108, USA

    Jaime F. Modiano

  10. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Jaime F. Modiano

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  1. Rachael Thomas
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  2. Huixia J. Wang
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  3. Pei-Chien Tsai
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  4. Cordelia F. Langford
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  5. Susan P. Fosmire
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  6. Cristan M. Jubala
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  7. David M. Getzy
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  9. Jaime F. Modiano
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  10. Matthew Breen
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Corresponding authors

Correspondence to Jaime F. Modiano or Matthew Breen.

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Responsible Editor: Fengtang Yang.

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Supplementary Table S1

Microarray-based comparative genomic hybridization (aCGH) analysis of 38 cases of canine appendicular osteosarcoma. Each case was evaluated using a genomic microarray comprising a panel of cytogenetically validated dog bacterial artificial chromosome (BAC) clones. The BAC address of each clone is listed in column one. The chromosome to which each clone maps is provided in column two and column three indicates the nucleotide position of the midpoint of the clone on the corresponding chromosome within the canine genome sequence assembly (CanFam v2.0). A subset of BAC clones are known to contain cancer-associated genes of specific interest (Thomas et al. 2003; for these clones the gene symbol is indicated in parentheses after the corresponding clone address).

Signalment data for the 38 dog osteosarcoma cases analyzed in this study are shown in the first four rows, indicating the patient ID (row 1), gender (M = male, F = female; row 2) and breed (Rott= Rottweiler, GR= Golden retriever; row 3), and the histological subtype of the tumor (OST = osteoblastic, CHO = chondroblastic, FIB = fibroblastic; row 4). aCGH-derived genomic copy number data for each locus are then provided below the corresponding case, and represent the log2 ratio of tumor:reference DNA. Loci with a log2 ratio ≤ −0.234 indicate genomic loss in the tumor, and are shaded red. Loci with a log2 ratio ≥ 0.201 indicate genomic gain in the tumor, and are shaded green. Values between these limits indicate balanced copy number status in the tumor, and are shaded yellow.

Thomas R, Bridge W, Benke K, Breen M (2003) Isolation and chromosomal assignment of canine genomic BAC clones representing 25 cancer-related genes. Cytogenet Genome Res 102:249–253 (XLS 155 KB)

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Thomas, R., Wang, H.J., Tsai, PC. et al. Influence of genetic background on tumor karyotypes: Evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma. Chromosome Res 17, 365–377 (2009). https://doi.org/10.1007/s10577-009-9028-z

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