Genetic Modifiers of Osteogenic Sarcoma

We have a major interest aimed at identifying genetic modifiers of OS risk, building upon pilot observations made by Dr. Savage in the Bone Disease and Injury Study of Osteosarcoma. Analysis of 11 growth-related genes identified a functional single nucleotide polymorphism (SNP) in IGF2R that was associated with an odds ratio = 2.0. Selected TP53 SNPs were associated with 6- to 8-fold increases in OS risk, and a reduced risk (i.e., a protective effect) was observed for specific haplotypes in the telomere genes TERF1, POT1 and TEP1. A collaboration has been established with the Children's Oncology Group to extend these observations into a larger series of OS cases and controls.

Osteogenic Sarcoma (OS) Case-Control Study - BDISO:

As part of a prospective case-control study of OS initiated in 1995 between the NCI and Harvard Dental School (the Bone Disease and Injury Study of Osteosarcoma; BDISO), we have studied genetic variation in many genes potentially important in growth pathways. We 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; germ-line TP53 mutations are the primary genetic basis for this rare disorder. Therefore, we investigated the role of germ-line 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.

Osteogenic Sarcoma Case-Control Study - Children's Oncology Group:

A collaboration has been established with the US Children's Oncology Group (COG), the NCI-sponsored clinical trials cooperative group that treats the vast majority of children diagnosed with cancer in this country. We have initiated a study of germline genetic variation and OS risk, using 900 OS cases from which COG has collected and stored germline DNA samples. Controls will be selected from prior and ongoing DCEG studies, genetically matched to avoid bias related to population stratification. This study has evolved from one in which htSNPS from a ~100 biologically-plausible candidate genes (including those identified in our earlier work) implicated in growth, height, hormone synthesis and metabolism, bone formation, tumor suppression, cell cycle regulation, chromosome stability, telomere maintenance, DNA repair and ribosomal metabolism would be genotyped, into a full-scale genomewide association study (see below).

Osteogenic Sarcoma Genomewide Association Study:

The retrospective, candidate gene association study now underway in collaboration with the COG has grown and matured into an international genomewide association study (GWAS). In part, this has been facilitated by rapid decreases in the per subject costs for large-scale genotyping, and the increasing sophistication of genotyping platforms, which now include more than 1,000,000 SNPs and a similar number of copy number variants (CNVs). The COG samples comprise the cornerstone of a large, international effort, led by the NCI, which will undertake a genome-wide association study of OS. Identifying international investigators willing to contribute their OS-related samples and data will be critical to assembling the very large number of samples required to identify and validate candidate SNPs using a GWAS strategy. This process has begun.

Prospective Study of Genetic Variants as OS Risk Factors (COG):

We are currently collaborating with COG investigators from the University of Minnesota, in the implementation and conduct of prospective specimen collection from newly-diagnosed OS patients now enrolling on various COG protocols. Epidemiologic data are also being collected. This project is employing a parent/affected offspring ("trio") design, and data collection is now underway.

Descriptive Epidemiology of Osteogenic Sarcoma via Population-Based Registries:

Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents, but there is also a second incidence peak among individuals aged > 60 years. Most osteosarcoma epidemiology studies have been embedded in large analyses of bone tumors in general, all histologic subtypes combined, or focused on cases occurring in adolescence. Detailed descriptions of osteosarcoma incidence and survival in particular, with direct comparisons among patients of all ages and ethnicities, are not available. We have completed and published several analyses of US (SEER) and international cancer registry data, to more fully characterize the descriptive epidemiology of osteogenic sarcoma.

Frequency, incidence, and survival rates for 3,482 patients with osteosarcoma from the National Cancer Institute's population-based Surveillance, Epidemiology, and End Results (SEER) Program diagnosed between 1973 and 2004 were investigated by age, race, sex, pathology subtype, stage, and anatomic site. There were large differences in incidence and survival rates by age. There was a high percentage of osteosarcoma with Paget disease and osteosarcoma as a second or later cancer among the elderly. Tumor site differences among age groups were noted. Survival rates varied by anatomic site and disease stage, and did not improve significantly from 1984 to 2004. In this comprehensive, population-based description of osteosarcoma, we identified important differences in incidence, survival, pathologic subtype, and anatomic site among age groups, and quantified the impact of osteosarcoma in patients with Paget disease or as a second cancer on incidence and mortality rates. These findings may have implications in understanding osteosarcoma biology and epidemiology.

Osteosarcoma incidence rates in the United States peak in adolescence and in the elderly. The international patterns of osteosarcoma incidence in children have been described, whereas those for young, middle age or elderly adults have not. Using the Cancer Incidence in Five Continents, International Agency for Cancer Research database we compared incidence rates for children and adolescents (age 0-24 years), the middle age group (25-59 years) and elderly (> or = 60 years) persons by world regions and individual countries. Overall, worldwide osteosarcoma incidence rates were quite similar in the younger age groups. The greatest variation in incidence rates was observed in the elderly.

Study-Related Publications