Abstract 2860: Identification of genes associated with osteosarcoma using a genetic pathway approach
Authors: Mirabello Lisa , Berndt Sonja L. , Burdett Laurie , Chowdhury Salma , Teshome Kedest , Uzoka Arinze , Hutchinson Amy , Douglass Chester , Hayes Richard B. , Hoover Robert N. , Savage Sharon A. ,   National Osteosarcoma Etiology Study Group.
Published: February 2011

Abstract
Osteosarcoma (OS) is a primary bone malignancy that typically occurs in adolescents and young adults. Epidemiologic studies suggest that OS is positively correlated with tall stature and high birth weight. It is common in hereditary retinoblastoma and Li-Fraumeni syndrome. A limited number of pilot studies suggest that single nucleotide polymorphisms (SNPs) in IGF2R, TP53, and VDR may also be associated with OS. Despite these findings, OS etiology is not well understood. Since it occurs during a period of rapid bone growth, genes important in growth and puberty are biologically plausible modifiers of OS risk. Genes in DNA repair and tumor suppressor pathways may also contribute to OS pathogenesis because of their function in critical cellular processes and known contributions to carcinogenesis.
We evaluated these hypotheses in an OS association study of candidate genes from the following pathways: growth, hormones/hormone metabolism, bone formation, tumor suppressor, and DNA repair. The study consisted of 99 OS cases from the hospital-based prospective case-control U.S. Bone Disease and Injury Study of Osteosarcoma (BDISO). Controls (n=1430) included cancer-free individuals from BDISO (n=65) and the Prostate, Lung, Colorectal, and Ovarian screening trial (n=1365). All participants were whites from the continental US. We evaluated 4507 tag-SNPs across 282 candidate genes using a Custom Infinium® BeadChip (iSelect)™. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the association between OS risk and each SNP, adjusting for potential confounders, using PLINK. Bonferroni corrections (Padj, per gene) were conducted for correction of multiple statistical tests.
Significant SNPs after correction with an additive model included 2 SNPs in Growth Hormone 1 (GH1) (OR 0.56, 95% CI 0.39-0.82, and OR 1.55, 95% CI 1.16-2.06, Padj &lt;0.009), one SNP in FGFR3 (OR 1.47, 95% CI 1.1-1.97, Padj =0.016), IGFBP3 (OR 5.19, 95% CI 1.18-14.89, Padj =0.033), and FGF2 (OR 2.0, 95% CI 1.29-3.10, Padj =0.038), all involved in growth. Six SNPs in the DNA repair gene TDP1 were significant (top SNP: OR 2.59, 95% CI 1.61-4.19, Padj =0.002). Seven SNPs in HSD17B2 (androgen/estrogen metabolism) were also significant after correction by gene, and 2 were significant after correction for all SNPs in this pathway (OR 24.2, 95% CI 5.68-103, Padj = 0.001, and OR 14.8, 95% CI 4.20-52.2, Padj =0.002).
Our results suggest that several SNPs in biologically plausible pathways important in growth, hormone metabolism, and DNA repair are associated with OS, even with conservative statistical corrections. The study is limited by the number of OS cases, but the inclusion of 14 controls per case improved the statistical power to identify SNPs with strong effects. Larger studies of genetic variants in OS and functional studies of the SNPs identified here are required to confirm the significance of our findings.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2860.