Risk-modeling of dog osteosarcoma genome scans shows individuals with Mendelian-level polygenic risk are common

Isain Zapata,Elise M Fiala,Jennie L Rowell,Carlos E Alvarez,Sara Zaldivar-Lopez,Luis E Moraes,C Guillermo Couto

doi:10.1186/s12864-019-5531-6

Isain Zapata, Elise M Fiala + Show 5 more

Open Access

https://doi.org/10.1186/s12864-019-5531-6

Copy DOI

Abstract

BackgroundDespite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar to the human condition, except for being highly heritable and having a dramatically higher incidence. Here we reanalyze published genome scans of osteosarcoma in three frequently-affected dog breeds and report entirely new understandings with immediate translational indications.ResultsFirst, meta-analysis revealed association near FGF9, which has strong biological and therapeutic relevance. Secondly, risk-modeling by multiple logistic regression shows 22 of the 34 associated loci contribute to risk and eight have large effect sizes. We validated the Greyhound stepwise model in our own, independent, case-control cohort. Lastly, we updated the gene annotation from approximately 50 genes to 175, and prioritized those using cross-species genomics data. Mostly positional evidence suggests 13 genes are likely to be associated with mapped risk (including MTMR9, EWSR1 retrogene, TANGO2 and FGF9). Previous annotation included seven of those 13 and prioritized four by pathway enrichment. Ten of our 13 priority genes are in loci that contribute to risk modeling and thus can be studied epidemiologically and translationally in pet dogs. Other new candidates include MYCN, SVIL and MIR100HG.ConclusionsPolygenic osteosarcoma-risk commonly rises to Mendelian-levels in some dog breeds. This justifies caninized animal models and targeted clinical trials in pet dogs (e.g., using CDK4/6 and FGFR1/2 inhibitors).

Highlights

Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years
Interbreed meta-analysis We conducted a meta-analysis of Karlsson, Lindblad-Toh et al.’s osteosarcoma Genome wide association studies (GWAS)’s in three breeds [18] by adding an Intersection Union Test (IUT) to the individual genome wide association studies (GWAS’s)
Its use is growing in diverse types of genome wide genetics, including for identification of pleiotropy across GWAS’s [20,21,22]

Summary

Introduction

Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar to the human condition, except for being highly heritable and having a dramatically higher incidence. We reanalyze published genome scans of osteosarcoma in three frequently-affected dog breeds and report entirely new understandings with immediate translational indications. Osteosarcoma is the most common pediatric and adult cancer of the bone in humans and dogs [1,2,3]. Animal models of human disease are necessary for dissection of pathological mechanisms and development of therapies [9]. Aside from experimental studies, dog models [10] are similar to human biomedical subjects, but without most of the ethical and legal limitations [4, 9]. Dogs are outbred and tend to live in human environments, receive health care and live to old age

Objectives

Methods

Results

Discussion

Conclusion