Insulin growth factor-1 (IGF-1) plays important roles in
carcinogenesis. Previous studies have linked circulating
IGF-1 and its main
binding protein,
insulin-like growth factor-binding protein-3 (IGFBP-3), to
cancer risks. However, no study has been conducted in
soft tissue sarcoma (STS). In this study, we investigated the relationship of genetically predicted circulating
IGF-1 and
IGFBP-3 with STS risks. Recent large genome-wide association studies (GWAS) have identified 413 single nucleotide polymorphisms (SNPs) associated with
IGF-1 and 4 SNPs associated with
IGFBP-3. We genotyped these SNPs in 821 patients and 851 healthy controls. We constructed weighted
genetic risk scores (GRS) to predict circulating
IGF-1 and
IGFBP-3. We determined the associations of individual SNPs and GRS with the risks of STS using multivariate logistic regression analysis. We found high genetically predicted circulating
IGF-1 and
IGFBP-3 were both associated with increased STS risks. Dichotomized at the median values of
IGF-1 and
IGFBP-3 in controls, individuals with high level of
IGF-1 exhibited a 27% increased risk of STS (odds ratio [OR]=1.27, 95% confidence interval [CI]=1.04-1.54, P=0.017), whereas the OR for high
IGFBP-3 was 1.45 (95% CI=1.20-1.77, P<0.001). Interestingly, the significant association between
IGFBP-3 and STS risk was only evident in women (OR=1.88, 95% CI=1.42-2.49, P<0.001), but not in men (OR=1.00, 95% CI=0.75-1.33, P=0.992). In stratified analyses by major STS subtypes, the strongest associations were observed in
angiosarcoma for
IGF-1,
leiomyosarcoma for
IGFBP-3, and
gastrointestinal stromal tumors for
IGFBP-3 in women. In conclusion, high circulating
IGF-1 and
IGFBP-3 levels were both associated with increased STS risks.