Genome-wide analyses for osteosarcoma in leonberger dogs reveal the CDKN2A/B gene locus as a major risk locus

Anna Letko; Katie M. Minor; Elaine M. Norton; Voichita D. Marinescu; Michaela Drögemüller; Emma Ivansson; Kate Megquier; Hyun Ji Noh; Mike Starkey; Steven G. Friedenberg; Kerstin Lindblad-Toh; James R. Mickelson; Cord Drögemüller

doi:10.3390/genes12121964

Genome-wide analyses for osteosarcoma in leonberger dogs reveal the CDKN2A/B gene locus as a major risk locus

Anna Letko, Katie M. Minor, Elaine M. Norton, Voichita D. Marinescu, Michaela Drögemüller, Emma Ivansson, Kate Megquier, Hyun Ji Noh, Mike Starkey, Steven G. Friedenberg, Kerstin Lindblad-Toh, James R. Mickelson, Cord Drögemüller

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Abstract

Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large-to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density im-puted SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h² SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10⁻⁴) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h² SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA.

Original language	English (US)
Article number	1964
Journal	Genes
Volume	12
Issue number	12
DOIs	https://doi.org/10.3390/genes12121964
State	Published - Dec 2021

Bibliographical note

Funding Information:
This research was supported in part by a gift from the Leonberger Health Foundation and by a European Research Council grant. K.M. was supported by the National Cancer Institute of the National Institutes of Health under Award Number F32CA247088. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The data handling was partially enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppmax partially funded by the Swedish Research Council through grant agreement no. 2018-05973. K.L.T is funded by a Distinguished Professorship from the Swedish Research Council and the National Cancer Institute Award Number 1R01CA225755-01A1. Partial support for S.G.F. was provided by a National Institutes of Health ORIP K01 Mentored Research Scientist Development Award (K01-OD027058).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Animal model
Bone cancer
CDKN2A/B
Canis familiaris
Leonberger
Osteosarcoma

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/genes12121964

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Letko, A., Minor, K. M., Norton, E. M., Marinescu, V. D., Drögemüller, M., Ivansson, E., Megquier, K., Noh, H. J., Starkey, M., Friedenberg, S. G., Lindblad-Toh, K., Mickelson, J. R., & Drögemüller, C. (2021). Genome-wide analyses for osteosarcoma in leonberger dogs reveal the CDKN2A/B gene locus as a major risk locus. Genes, 12(12), Article 1964. https://doi.org/10.3390/genes12121964

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title = "Genome-wide analyses for osteosarcoma in leonberger dogs reveal the CDKN2A/B gene locus as a major risk locus",

abstract = "Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large-to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density im-puted SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2 SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10−4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2 SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA.",

keywords = "Animal model, Bone cancer, CDKN2A/B, Canis familiaris, Leonberger, Osteosarcoma",

author = "Anna Letko and Minor, {Katie M.} and Norton, {Elaine M.} and Marinescu, {Voichita D.} and Michaela Dr{\"o}gem{\"u}ller and Emma Ivansson and Kate Megquier and Noh, {Hyun Ji} and Mike Starkey and Friedenberg, {Steven G.} and Kerstin Lindblad-Toh and Mickelson, {James R.} and Cord Dr{\"o}gem{\"u}ller",

note = "Funding Information: This research was supported in part by a gift from the Leonberger Health Foundation and by a European Research Council grant. K.M. was supported by the National Cancer Institute of the National Institutes of Health under Award Number F32CA247088. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The data handling was partially enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppmax partially funded by the Swedish Research Council through grant agreement no. 2018-05973. K.L.T is funded by a Distinguished Professorship from the Swedish Research Council and the National Cancer Institute Award Number 1R01CA225755-01A1. Partial support for S.G.F. was provided by a National Institutes of Health ORIP K01 Mentored Research Scientist Development Award (K01-OD027058). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = dec,

doi = "10.3390/genes12121964",

language = "English (US)",

volume = "12",

journal = "Genes",

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T1 - Genome-wide analyses for osteosarcoma in leonberger dogs reveal the CDKN2A/B gene locus as a major risk locus

AU - Letko, Anna

AU - Minor, Katie M.

AU - Norton, Elaine M.

AU - Marinescu, Voichita D.

AU - Drögemüller, Michaela

AU - Ivansson, Emma

AU - Megquier, Kate

AU - Noh, Hyun Ji

AU - Starkey, Mike

AU - Friedenberg, Steven G.

AU - Lindblad-Toh, Kerstin

AU - Mickelson, James R.

AU - Drögemüller, Cord

N1 - Funding Information: This research was supported in part by a gift from the Leonberger Health Foundation and by a European Research Council grant. K.M. was supported by the National Cancer Institute of the National Institutes of Health under Award Number F32CA247088. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The data handling was partially enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppmax partially funded by the Swedish Research Council through grant agreement no. 2018-05973. K.L.T is funded by a Distinguished Professorship from the Swedish Research Council and the National Cancer Institute Award Number 1R01CA225755-01A1. Partial support for S.G.F. was provided by a National Institutes of Health ORIP K01 Mentored Research Scientist Development Award (K01-OD027058). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/12

Y1 - 2021/12

N2 - Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large-to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density im-puted SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2 SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10−4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2 SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA.

AB - Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large-to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density im-puted SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2 SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10−4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2 SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA.

KW - Animal model

KW - Bone cancer

KW - CDKN2A/B

KW - Canis familiaris

KW - Leonberger

KW - Osteosarcoma

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ER -

Genome-wide analyses for osteosarcoma in leonberger dogs reveal the CDKN2A/B gene locus as a major risk locus

Abstract

Bibliographical note

Keywords

UN SDGs

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