Genetic variation near GRB10 associated with bone growth and osteosarcoma risk in canine and human populations

Abstract

Background: Canine and human osteosarcoma are similar in clinical presentation and tumor genomics. Giant breed dogs experience elevated osteosarcoma incidence, and taller stature remains a consistent risk factor for human osteosarcoma. Whether evolutionarily conserved genes contribute to both human and canine osteosarcoma predisposition merits evaluation.

Methods: A multi-center sample of childhood osteosarcoma patients and controls underwent genome-wide genotyping and imputation. Ancestry-adjusted SNP associations were calculated within each dataset using logistic regression, then meta-analyzed across the three datasets, totaling 1091 patients and 3026 controls. Ten regions previously associated with canine osteosarcoma risk were mapped to the human genome, spanning ∼6 Mb. We prioritized association testing of 5985 human SNPs mapping to candidate osteosarcoma risk regions detected in Irish wolfhounds, the largest dog breed studied. Secondary analyses explored 6289 additional human SNPs mapping to candidate osteosarcoma risk regions identified in Rottweilers and greyhounds.

Results: Fourteen SNPs were associated with human osteosarcoma risk after adjustment for multiple comparisons, all within a 42 kb region of human Chromosome 7p12.1. The lead variant was rs17454681 (OR=1.25, 95 %CI: 1.12-1.39; P=4.1×10^-5), and independent risk variants were not observed in conditional analyses. While the associated region spanned 2.1 Mb and contained eight genes in Irish wolfhounds, associations were localized to a 50-fold smaller region of the human genome and strongly implicate GRB10 (growth factor receptor-bound protein 10) in canine and human osteosarcoma predisposition. PheWAS analysis in UK Biobank data identified noteworthy associations of the rs17454681 risk allele with varied measures of height and pubertal timing.

Conclusions: Our comparative oncology analysis identified a novel human osteosarcoma risk allele near GRB10, a growth inhibitor that suppresses activated receptor tyrosine kinases including IGF1R, PDGFRB, and EGFR. Epidemiologists may benefit from leveraging cross-species comparisons to identify haplotypes in highly susceptible but genetically homogenous populations of domesticated animals, then fine-mapping these associations in diverse human populations.

Keywords: Comparative oncology; Genome-wide association study; Growth factor receptor bound protein 10; Insulin-like growth factor receptor; Osteosarcoma.

FIGURE 1.

Association of SNPs with childhood osteosarcoma risk in a region of chromosome 7p12.1 (1091 cases, 3026 controls), orthologous to a region previously associated with OS risk in Irish wolfhounds. The lead variant, rs17454681 (purple diamond), is ~63kb upstream of GRB10 (growth factor receptor-bound protein 10). Other SNPs are displayed by color, showing their extent of genetic linkage with rs17454681. Recombination rate, genetic position (37/hg19), and the locations of nearby genes are indicated.

FIGURE 2.

Mixed-effects meta-analysis of the association between rs17454681 and osteosarcoma risk in three datasets, stratified by biological sex. The T allele is associated with OS risk among females (OR=1.33; 95%CI: 1.11–1.55) and among males (OR=1.18; 95%CI: 1.01–1.35), with differences in the magnitude of effect across strata of sex not reaching statistical significance (P=0.29).