Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus.

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

doi:10.3390/genes12121964

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 imputed 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 (h2SNP) 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 h2SNP 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.

Highlights

Osteosarcoma (OSA) is the most common primary form of bone cancer in children and adolescents but is a rare cancer overall [1,2]
Polygenic OSA risk may be high enough to appear Mendelian in certain dog breeds [31]
There are several dog breeds that are known to have a genetic predisposition to OSA, but for which

Summary

Introduction

Osteosarcoma (OSA) is the most common primary form of bone cancer in children and adolescents but is a rare cancer overall [1,2]. Structural variants are the driving mutagenesis events in pediatric osteosarcoma for which a complex karyotype is the hallmark [3]. Phenomena such as chromothripsis and kataegis, most often with somatic copy-number alterations in key oncogenes and tumor-suppressor genes have been found [2]. Rare familial sporadic forms of OSA have been reported to be caused by pathogenic variants in genes such as CHEK2, RB1, and TP53 (OMIM 259500) with an essential function in cell survival pathways that play a role in genome stability (RB1, TP53, CDK4, MDM2, ATRX) [2]. The etiology of most human OSA is not yet known, the list of potential driving genes is growing, and it remains unclear whether genetic alterations in TP53 or other genes are the cause or consequence of chromothripsis [2]

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