Analysis of genes critical for growth regulation identifies Insulin-like Growth Factor 2 Receptor variations with possible functional significance as risk factors for osteosarcoma.
BACKGROUND
Osteosarcoma, the most common malignant primary bone tumor, typically occurs during the adolescent growth spurt. Germ-line genetic variation in genes critical in growth regulation could confer altered risk of osteosarcoma.


METHODS
Fifty-two common single nucleotide polymorphisms (SNP) in 13 genes were genotyped in a prospective case-control study of osteosarcoma (104 osteosarcoma cases and 74 orthopedic controls). Genotype data analyzed with contingency tables suggested the strongest association with insulin-like growth factor 2 receptor (IGF2R) SNPs. Additional SNPs were genotyped to capture IGF2R common haplotypes and resequencing was done across the IGF2R block associated with osteosarcoma risk. Percentage methylation was determined by pyrosequencing of the IGF2R variant allele located in a CpG island.


RESULTS
IGF2R Ex16+88G>A (rs998075) and IVS16+15C>T (rs998074) SNPs were associated with increased risk for osteosarcoma compared with orthopedic controls (haplotype odds ratio, 2.04; 95% confidence interval, 1.29-3.24). Follow-up genotyping showed that IGF2R IVS15+213C>T was also associated with increased osteosarcoma risk. Resequence analysis identified two additional SNPs linked to the risk-associated SNPs; linkage disequilibrium was strongest in a 1-kb pair region around them. The Ex16+88G>A SNP is located within a CpG island and alters methylation at that site.


CONCLUSIONS
This pilot study of germ-line genetic variation in growth pathway genes and osteosarcoma identified a haplotype block in IGF2R associated with increased risk of osteosarcoma. The presence of a SNP in this block results in loss of methylation at a CpG island, providing corroborative evidence of a possible functional variant. Our analysis of the IGF2R haplotype structure will be applicable to future studies of IGF2R and disease risk.
Section of Genomic Variation, Pediatric Oncology Branch, National Cancer Institute, 6120 Executive Boulevard, EPS/7018, Rockville, MD 20852, USA. savagesh@mail.nih.gov
Sharon A
SA
Savage
Karen
K
Woodson
Elyse
E
Walk
William
W
Modi
Jason
J
Liao
Chester
C
Douglass
Robert N
RN
Hoover
Stephen J
SJ
Chanock
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001859:Bone Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D018899:CpG Islands / Q000235:genetics; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008745:Methylation; D008875:Middle Aged; D012516:Osteosarcoma / Q000235:genetics*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D012307:Risk Factors
D017527:Receptor, IGF Type 2