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Int J Mol Epidemiol Genet 2012;3(4):286-293

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

Jessica RB Musselman, Tracy L Bergemann, Julie A Ross, Charles Sklar, Kevin AT Silverstein, Erica K
Langer, Sharon A Savage, Rajaram Nagarajan, Mark Krailo, David Malkin, Logan G Spector

Division of Pediatric Epidemiology and Clinical Research, University of Minnesota, Minneapolis MN 55455;
Medtronic, Mounds View, MN 55112; University of Minnesota Masonic Cancer Center, Minneapolis MN 55455;
Memorial Sloan-Kettering Cancer Center, New York City, New York 10065; Supercomputing Institute for Advanced
Computational Research University of Minnesota, 55455; Clinical Genetics Branch, Division of Cancer
Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20852; Division
of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati OH 45229; Department of Preventive
Medicine, University of Southern California, Los Angeles CA 90089; Division of Hematology/Oncology, Department
of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto CA M5G 1X8

Received August 21, 2012; Accepted October 19, 2012; Epub November 15, 2012; Published November 30, 2012

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 ageincidence
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.(IJMEG1208003).

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

Address all correspondence to:
Logan G Spector
Division of Pediatric Epidemiology and Clinical Research
University of Minnesota Cancer Center
420 Delaware Street SE, MMC 715
Minneapolis, MN 55455.
Phone: (612)624-3912; Fax: (612) 624-7147
E-mail: spector@umn.edu