Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma

Abstract

Introduction: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma.

Methods: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene.

Results: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10^-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma.

Conclusion: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.

Keywords: Birthweight; Genetic risk score; Height; Osteosarcoma; Puberty timing.

Figure 1.

Scatter plot illustrating the correlation between A) GRS for birthweight and measured birthweight, and B) GRS for height and measured height. A subset of set 1 cases (n=143) with detailed data on measured birthweight and height were used in the analysis.

Figure 2.

Risk of osteosarcoma associated with genetically inferred birthweight, A) as a continuous measure, overall cases and by available case clinical characteristics and by presence of pathogenic/likely pathogenic (P/LP) cancer susceptibility gene (CSG) variants in the cases, and B) categorized into quartiles. For Figure 1A, odds ratios are per standard deviation increase in the GRS for birthweight comparing cases versus controls. For Figure 1B, the birthweight GRS was divided into quartiles and analyzed with the lowest quartile as the reference group. For tumor location, appendicular included extremities, shoulder, and pelvic girdle; axial included skull, mandible, vertebral column, and thorax. For age of diagnosis, cases were stratified based whether they were diagnosed during average puberty ages for girls (10-16 years) and boys (12-18 years) versus outside of average puberty ages. ‘Conventional’ histology included osteoblastic, chondroblast, and fibroblastic. ‘Other’ was made up of all other histologic subtypes. Overall cases and sex-specific associations were based on a fixed effects meta-analysis of the two case-control sets (n=1039); other stratified analyses were restricted to cases with available clinical data (case-control set 1, n=968).

Figure 2.

Risk of osteosarcoma associated with genetically inferred birthweight, A) as a continuous measure, overall cases and by available case clinical characteristics and by presence of pathogenic/likely pathogenic (P/LP) cancer susceptibility gene (CSG) variants in the cases, and B) categorized into quartiles. For Figure 1A, odds ratios are per standard deviation increase in the GRS for birthweight comparing cases versus controls. For Figure 1B, the birthweight GRS was divided into quartiles and analyzed with the lowest quartile as the reference group. For tumor location, appendicular included extremities, shoulder, and pelvic girdle; axial included skull, mandible, vertebral column, and thorax. For age of diagnosis, cases were stratified based whether they were diagnosed during average puberty ages for girls (10-16 years) and boys (12-18 years) versus outside of average puberty ages. ‘Conventional’ histology included osteoblastic, chondroblast, and fibroblastic. ‘Other’ was made up of all other histologic subtypes. Overall cases and sex-specific associations were based on a fixed effects meta-analysis of the two case-control sets (n=1039); other stratified analyses were restricted to cases with available clinical data (case-control set 1, n=968).

Figure 3.

Risk of osteosarcoma associated with genetically inferred A) height, B) female age of menarche, and C) male puberty timing, as a continuous measure, overall cases and by available case clinical characteristics and presence of pathogenic/likely pathogenic (P/LP) cancer susceptibility gene (CSG) variants in the cases. Odds ratios are per standard deviation increase in the GRS for corresponding characteristic comparing cases versus controls. For tumor location, appendicular included extremities, shoulder, and pelvic girdle; axial included skull, mandible, vertebral column, and thorax. For age of diagnosis, cases were stratified based whether they were diagnosed during average puberty ages for girls (10-16 years) and boys (12-18 years) versus outside of average puberty ages. ‘Conventional’ histology included osteoblastic, chondroblast, and fibroblastic. ‘Other’ was made up of all other histologic subtypes. Overall cases and sex-specific associations were based on a fixed effects meta-analysis of the two case-control sets (n=1039); other stratified analyses were restricted to cases with available clinical data (case-control set 1, n=968).

Figure 3.

Risk of osteosarcoma associated with genetically inferred A) height, B) female age of menarche, and C) male puberty timing, as a continuous measure, overall cases and by available case clinical characteristics and presence of pathogenic/likely pathogenic (P/LP) cancer susceptibility gene (CSG) variants in the cases. Odds ratios are per standard deviation increase in the GRS for corresponding characteristic comparing cases versus controls. For tumor location, appendicular included extremities, shoulder, and pelvic girdle; axial included skull, mandible, vertebral column, and thorax. For age of diagnosis, cases were stratified based whether they were diagnosed during average puberty ages for girls (10-16 years) and boys (12-18 years) versus outside of average puberty ages. ‘Conventional’ histology included osteoblastic, chondroblast, and fibroblastic. ‘Other’ was made up of all other histologic subtypes. Overall cases and sex-specific associations were based on a fixed effects meta-analysis of the two case-control sets (n=1039); other stratified analyses were restricted to cases with available clinical data (case-control set 1, n=968).

Figure 3.

Risk of osteosarcoma associated with genetically inferred A) height, B) female age of menarche, and C) male puberty timing, as a continuous measure, overall cases and by available case clinical characteristics and presence of pathogenic/likely pathogenic (P/LP) cancer susceptibility gene (CSG) variants in the cases. Odds ratios are per standard deviation increase in the GRS for corresponding characteristic comparing cases versus controls. For tumor location, appendicular included extremities, shoulder, and pelvic girdle; axial included skull, mandible, vertebral column, and thorax. For age of diagnosis, cases were stratified based whether they were diagnosed during average puberty ages for girls (10-16 years) and boys (12-18 years) versus outside of average puberty ages. ‘Conventional’ histology included osteoblastic, chondroblast, and fibroblastic. ‘Other’ was made up of all other histologic subtypes. Overall cases and sex-specific associations were based on a fixed effects meta-analysis of the two case-control sets (n=1039); other stratified analyses were restricted to cases with available clinical data (case-control set 1, n=968).