The association between sex and most childhood cancers is not mediated by birthweight

Background: Male sex is associated with an increased risk of childhood cancer as is high birthweight. Given that sex determination precedes birthweight we conducted a mediation analysis to estimate the direct effect of sex in association with childhood cancer tumor type with birthweight as the mediator. Methods: Cases (n = 12,632) and controls (n = 64,439) (ages 0–14 years) were identified from population-based cancer and birth registries in Minnesota, New York, and Washington states (1970–2014). An inverse odds weighting (IOW) mediation analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) as the measure of association between sex and cancer. Results: A significant indirect effect was observed for sex and lymphoid leukemia, mediated by birthweight (indirectOR: 1.03; 95% CI: 1.02–1.04). We observed significant direct effects for male sex and lymphoid leukemia (directOR: 1.16; 95% CI: 1.08–1.25), Hodgkin lymphoma (directOR: 1.48; 95% CI: 1.22–1.81), Burkitt lymphoma (directOR: 5.02; 95% CI: 3.40–7.42), other non-Hodgkin lymphoma (directOR: 1.42; 95% CI: 1.18–1.70), intracranial embryonal tumors (directOR: 1.49; 95% CI: 1.26–1.76), hepatoblastoma (directOR: 1.90; 95% CI: 1.40–2.59), and rhabdomyosarcoma (directOR: 1.47; 95% CI: 1.19–1.81). There were also inverse associations for extracranial GCTs (directOR: 0.41; 95% CI: 0.26–0.63) and thyroid carcinoma (directOR: 0.35; 95% CI: 0.25–0.50). Conclusion: Significant direct effects for sex and numerous childhood cancer types suggests sex-specific factors such as differences in gene expression from the autosomes or the X chromosome, rather than birthweight, may underlie sex differences in tumor risk.