Background: Although increased height has been associated with osteosarcoma risk in previous epidemiologic studies, the relative contribution of stature during different developmental time-points remains unclear. Furthermore, how genetic determinants of height impact osteosarcoma etiology remains unexplored. Genetic variants associated with stature in previous genome-wide association studies may be biomarkers of osteosarcoma risk. Methods: We tested the associations between osteosarcoma risk and polygenic scores for adult height (416 variants), childhood height, (six variants), and birth length (five variants) in 864 osteosarcoma patients and 1879 controls of European ancestry. Results: Each standard deviation increase in the polygenic score for adult height, corresponding to a 1.7-cm increase in stature, was associated with a 1.10-fold increase in risk of osteosarcoma (95% CI: 1.01–1.19, P= 0.027). Each standard deviation increase in the polygenic score for childhood height, corresponding to a 0.5-cm increase in stature, was associated with a 1.10-fold increase in risk of osteosarcoma (95% CI: 1.01–1.20, P= 0.023). The polygenic score for birth length was not associated with osteosarcoma risk (P=0.11). When adult and childhood height scores were modeled together, they were independently associated with osteosarcoma risk (P=0.037 and 0.043, respectively). An eQTL for CILP2 (cartilage intermediate layer protein 2), rs8103992, was significantly associated with osteosarcoma risk after adjustment for multiple comparisons (OR=1.35, 95% CI: 1.16–1.56, P=7.93×10−5, Padjusted=0.034). Conclusions: Genetic propensity to taller adult and childhood height attainments contributed independently to osteosarcoma risk in our data. These results suggest that the biological pathways affecting normal bone growth may be involved in osteosarcoma etiology.
Osteosarcoma, a malignant primary bone tumor most commonly diagnosed in children and adolescents, has a poorly understood genetic etiology. Genome-wide association studies (GWAS) and candidate-gene analyses have identified putative risk variants in subjects of European ancestry. However, despite higher incidence among African-American and Hispanic children, little is known regarding common heritable variation that contributes to osteosarcoma incidence and clinical presentation across racial/ethnic groups. In a multi-ethnic sample of non-Hispanic white, Hispanic, African-American and Asian/Pacific Islander children (537 cases, 2165 controls), we performed association analyses assessing previously-reported loci for osteosarcoma risk and metastasis, including meta-analysis across racial/ethnic groups. We also assessed a previously described association between genetic predisposition to longer leukocyte telomere length (LTL) and osteosarcoma risk in this independent multi-ethnic dataset. In our sample, we were unable to replicate previously-reported loci for osteosarcoma risk or metastasis detected in GWAS of European-ancestry individuals in either ethnicity-stratified analyses or meta-analysis across ethnic groups. Our analyses did confirm that genetic predisposition to longer LTL is a risk factor for
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