Osteosarcoma is the most common malignant bone tumor in dogs and, like its human orthologue, is characterized by aggressive local behavior and high metastatic rates. The Scottish deerhound is a breed of dog with a >15% incidence of osteosarcoma and represents an excellent spontaneously occurring large-animal model of the human disease. We modeled the transmission of the osteosarcoma phenotype in a population of over 1000 related deerhounds ascertained as part of a prospective health study. Variance component analysis, segregation analysis, and linear modeling were performed to evaluate heritability, to infer the presumptive transmission model, and to identify covariate effects for this phenotype within the breed, respectively. Based on variance component analysis, heritability (h2) was estimated to be 0.69. Six transmission models were analyzed by segregation analysis; based on Akaike's information criteria, the most parsimonious model was the Mendelian major gene model with dominant expression. Linear modeling identified gender and genotype as significant predictors of disease outcome. Importantly, duration of gonadal hormone exposure, weight, and height at maturity were not significant predictors of outcome. Inheritance of the putative high-risk allele was thus associated with >75% risk of disease occurrence compared to the <5% baseline risk. These results support the hypothesis that a major gene with a dominant effect explains most of the osteosarcoma phenotype within the Scottish deerhound.
BackgroundOsteosarcoma is the most common neoplastic disease in Scottish Deerhounds. For Deerhounds, a 2007 population-based study concluded that a single dominant genetic factor largely governed disease risk. For Greyhounds, Rottweilers, and Irish Wolfhounds, a 2013 genome-wide association study found multiple genetic markers in each breed, with each marker only weakly associated with the disease.We obtained from two breeders the pedigrees, age (if alive) or age at death, and osteosarcoma status for two families of Scottish Deerhounds, designated Cohorts K and T. A dog was considered unaffected only if it was osteosarcoma-free and at least 8.5 years old. We analyzed the data in two ways, by assuming either a single recessive genetic factor or a single dominant genetic factor with high penetrance.ResultsCohort K contained 54 evaluable dogs representing 12 litters. Cohort T contained 56 evaluable dogs representing eight litters. Osteosarcoma seemed clearly heritable in both cohorts; however, having a parent with osteosarcoma raised a pup’s risk of developing osteosarcoma to 38% for Cohort K but 78% for Cohort T, suggesting the possibility of different genetic risk factors in each cohort. In Cohort K, osteosarcoma inheritance fit well with a single, recessive, autosomal risk factor, although we could not rule out the possibility of a single dominant risk factor with incomplete penetrance. In Cohort T, inheritance could be explained well by a single, dominant, autosomal risk factor but was inconsistent with recessive expression.ConclusionsInheritance of osteosarcoma in two Scottish Deerhound families could be explained well by a single genetic risk factor residing on an autosome, consistent with a 2007 report. In one family, inheritance was consistent with dominant expression, as previously reported. In the other family, inheritance fit better with recessive expression, although the possibility of a dominant genetic factor influenced by one or more other genetic factors could not be ruled out. In either case, the results suggest that there may be at least two different genetic risk factors for osteosarcoma in Deerhounds.
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