Case-parent analysis of variation in pubertal hormone genes and pediatric osteosarcoma: a Children's Oncology Group (COG) study

Abstract

Osteosarcoma (OS) is a rare malignant bone tumor with an overall incidence rate of 4.6 cases per million children aged 0-19 years in the United States. While the etiology of OS is largely unknown, its distinctive age-incidence pattern suggests that growth and development is crucial in genesis. Prior studies have suggested that variants in genes in the estrogen metabolism (ESTR) and insulin-like growth factor/growth hormone (IGF/GH) pathways are associated with OS. We examined 798 single nucleotide polymorphisms (SNPs) in 42 genes from these pathways in a case-parent study (229 complete triads and 56 dyads) using buccal cell samples. Relative risks (RR) and 95% confidence intervals (CI) associated with transmitting one or two copies of the variant were estimated using log-linear models. After Bonferroni correction, 1 SNP within the ESTR pathway (rs1415270: RR = 0.50 and 8.37 for 1 and 2 vs. 0 copies, respectively; p = 0.010), and two SNPs in the IGF/GH pathway (rs1003737: RR = 0.91 and 0.0001 for 1 and 2 vs. 0 copies, respectively; p <0.0001 and rs2575352: RR = 2.62 and 0.22 for 1 and 2 vs. 0 copies; p < 0.0001) were significantly associated with OS incidence. These results confirm previous findings that variation in the estrogen metabolism and bone growth pathways influence OS risk and further support a biologically and epidemiologically plausible role in OS development.

Keywords: Osteosarcoma; case-parent study; estrogen metabolism pathway; growth and development; insulin-like growth factor pathway.

Figure 1

Flow chart describing the identification and enrollment of the cases that make up the study population from the initial population of childhood osteosarcoma cases treated at Children’s Oncology Group institutions during the eligibility period. Patient Identification, Contact, Consent, Enrollment, and Participation in a case-parent study of childhood osteosarcoma; April 1, 2007-March 31, 2010.

Figure 2

This figure depicts both the uncorrected p-values and the p-values after correction for multiple testing for each of the SNPs analyzed in the two pathways. We present the p-values (corrected and uncorrected) on the -log scale and provide a horizontal line so that the reader can easily see the threshold necessary for significance in this analysis. P-values for each SNP by pathway before and after Bonferroni correction^a α = 0.05. Inset box indicates pathway symbol, results for 798 SNPs in 42 candidate genes (29 ESTR and 13 IGF/GH). Dashed line represents significance threshold for α.