Since osteogenic sarcoma (OS), the most common primary malignant bone tumor, most commonly occurs during the adolescent growth spurt, we hypothesized that common genetic variants in genes of the insulin growth factor, IGF, pathway could be associated with OS. IGF1, IGF2, their receptors, (IGF1R and IGF2R) and binding proteins stimulate mitogenesis, regulate growth and development in utero as well as up to and including adolescence. Circulating levels of IGF1 have been associated with the risk for developing prostate, breast, colorectal and lung cancer. IGF2 appears to over-expressed in most tumor cell lines. In 1995, the National Cancer Institute and the Harvard School of Dental Medicine initiated a prospective case control study of the epidemiology of OS. Blood samples were collected from OS cases (n=124) and two sets of hospital-based controls, individuals with non-malignant bone diseases (ortho controls, n=87) and individuals with non-OS bone tumors (tumor controls, n=77). Twenty-four single nucleotide polymorphisms (SNPs) in the following six genes were genotyped by Taqman assays at the NCI’s Core Genotyping Facility (http://snp500cancer.nci.nih.gov); Growth Hormone Receptor (GHR, 2 synonymous [S], 1 nonsynonymous [NS]), IGF1 (2 intervening sequence SNPS [IVS]), IGF1R (1S, 4 IVS, 1 3’ utr), IGF2 (2 IVS), IGF2R (4 S, 1NS, 1 IVS), IGFALS (3 S) and IGFBP3 (1NS, 1 IVS). Contingency tables were used to analyze the case-control data assuming additive, dominant and recessive genetic models using SAS (v8.02). Haplotypes were constructed and a case-control permutation test performed using PHASE v2.1. Two of the IGF2R SNPs (S in exon 16 and IVS16) were significantly associated with OS cases compared to ortho controls; p=0.008 and p=0.003, respectively, as well as the OS cases compared to tumor controls; p=0.04 and p=0.03, respectively. Haplotypes for IGF2R based on six SNPs were analyzed and the overall test was significant for cases vs. ortho (p=0.01) and for ortho vs tumor (p=0.01) and when all three were input in the case control format, p=0.03. The IGF1R SNP in the 3’ UTR was also significant when OS cases were compared to tumor controls (p=0.003). This preliminary study suggests that variants in the IGF pathway, specifically, IGF1R and IGF2R could be associated with OS. Further study of genetic variation in these genes and other genes important for growth and development in OS is warranted.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]