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BMC Genomics DOI:10.1186/s12864-020-06872-9

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

Publication TypeJournal Article
Year of Publication2020
AuthorsLabadie, JD, Elvers, I, Feigelson, HSpencer, Magzamen, S, Yoshimoto, J, Dossey, J, Burnett, R, Avery, AC
JournalBMC Genomics
Volume21
Issue1
Pages464
Date Published2020 Jul 06
ISSN1471-2164
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 × 10-5.1 × 10) 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 × 10-7.5 × 10) 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.

DOI10.1186/s12864-020-06872-9
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/32631225?dopt=Abstract

Alternate JournalBMC Genomics
PubMed ID32631225
Grant ListDGE-1450032 / / National Science Foundation /
T32CA094880 / CA / NCI NIH HHS / United States