Genome-wide association analysis of canine T zone lymphoma identifies link to hypothyroidism and a shared association with mast-cell tumors

BMC Genomics. 2020 Jul 6;21(1):464. doi: 10.1186/s12864-020-06872-9.

Abstract

Background: T zone lymphoma (TZL), a histologic variant of peripheral T cell lymphoma, represents about 12% of all canine lymphomas. Golden Retrievers appear predisposed, representing over 40% of TZL cases. Prior research found that asymptomatic aged Golden Retrievers frequently have populations of T zone-like cells (phenotypically identical to TZL) of undetermined significance (TZUS), potentially representing a pre-clinical state. These findings suggest a genetic risk factor for this disease and caused us to investigate potential genes of interest using a genome-wide association study of privately-owned U.S. Golden Retrievers.

Results: Dogs were categorized as TZL (n = 95), TZUS (n = 142), or control (n = 101) using flow cytometry and genotyped using the Illumina CanineHD BeadChip. Using a mixed linear model adjusting for population stratification, we found association with genome-wide significance in regions on chromosomes 8 and 14. The chromosome 14 peak included four SNPs (Odds Ratio = 1.18-1.19, p = .3 × 10- 5-5.1 × 10- 5) near three hyaluronidase genes (SPAM1, HYAL4, and HYALP1). Targeted resequencing of this region using a custom sequence capture array identified missense mutations in all three genes; the variant in SPAM1 was predicted to be damaging. These mutations were also associated with risk for mast cell tumors among Golden Retrievers in an unrelated study. The chromosome 8 peak contained 7 SNPs (Odds Ratio = 1.24-1.42, p = 2.7 × 10- 7-7.5 × 10- 5) near genes involved in thyroid hormone regulation (DIO2 and TSHR). A prior study from our laboratory found hypothyroidism is inversely associated with TZL risk. No coding mutations were found with targeted resequencing but identified variants may play a regulatory role for all or some of the genes.

Conclusions: The pathogenesis of canine TZL may be related to hyaluronan breakdown and subsequent production of pro-inflammatory and pro-oncogenic byproducts. The association on chromosome 8 may indicate thyroid hormone is involved in TZL development, consistent with findings from a previous study evaluating epidemiologic risk factors for TZL. Future work is needed to elucidate these mechanisms.

Keywords: Dog; Epidemiology; Genetics; Leukemia; Lymphoma.

MeSH terms

  • Animals
  • Chromosomes, Mammalian
  • Dog Diseases / genetics*
  • Dogs
  • Genome-Wide Association Study
  • Hypothyroidism / veterinary*
  • Lymphoma, T-Cell, Peripheral / genetics
  • Lymphoma, T-Cell, Peripheral / veterinary*
  • Mast Cells*
  • Neoplasms, Connective Tissue / genetics
  • Neoplasms, Connective Tissue / veterinary
  • Polymorphism, Single Nucleotide
  • Receptors, Thyrotropin / genetics

Substances

  • Receptors, Thyrotropin