As part of a prospective case-control study of osteogenic sarcoma (OS) initiated in 1995 between the NCI and the Harvard Dental School (the Bone Disease and Injury Study of Osteosarcoma [BDISO]), investigators in the Clinical Genetics Branch have studied genetic variation in many genes potentially important in growth pathways. They identified a small haplotype block that was associated with two-fold increase in risk of OS in the IGF2R gene. This region (around exon 16) consisted of CpG islands, and functional analysis of the SNPs in this block suggested that a SNP associated with OS risk results in differential methylation at that SNP site.
Although most cases of OS are sporadic, it is also a prototypic syndrome-related malignancy in the Li-Fraumeni syndrome; germline TP53 mutations are the primary genetic basis for this rare disorder. Therefore, we investigated the role of germline genetic variation in TP53 as risk factors for sporadic OS. Although our data did not indicate a strong link between variation in TP53 and OS risk, they did provide preliminary evidence suggesting an increased risk of OS associated with TP53 variants IVS2+38 and Pro72Arg. While this was a small study, genetic variation across the TP53 gene was thoroughly investigated. Genetic variants in telomere maintenance genes are the focus of ongoing analysis. Preliminary data suggest a possible protective effect associated with specific variants in several different telomere pathway genes.
A formal meta-analysis of this plus other published osteogenic sarcoma case-control studies is now underway, under the leadership of CGB investigators. It will focus on a pooled analysis of birth weight, birth length and height as OS risk factors.
As a follow-up to these pilot observations, subjects from the BDISO OS case-control study were genotyped as part of DCEG's Rare Cancer iSelect project. Comprehensive analysis of more than 25,000 variants in several hundred carcinogenesis-related candidate genes and pathways is being conducted. Increased statistical power will be achieved through pooling of control subjects obtained from other DCEG studies, after careful correction for population stratification. Analysis of these data is currently underway.