Osteosarcoma: Genetics of Inherited Susceptibility

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumour that typically occurs in adolescents and young adults. OS incidence has been related to growth and height, age, gender, ethnicity, certain inherited cancer predisposition syndromes, abnormal bone growth and therapeutic radiation. However, most cases are sporadic (not associated with an inherited syndrome) and no specific genetic or environmental predisposing factor has been identified. A common genetic susceptibility locus has not been found. Germline genetics refers to deoxyribonucleic acid (DNA) sequence changes that are inherited and present in all cells of the body versus an acquired or somatic mutation. Germline candidate gene association studies have identified several common single nucleotide polymorphisms (SNPs) associated with risk of OS, including genes important in growth, cell cycle checkpoint control and tumour immunity. Recently, the first genome‐wide association study was conducted and further expands our understanding of the germline genetics of OS. Key Concepts: Epidemiologic studies have provided many important clues about the aetiology of OS, including an association with bone growth, which have directed much of the search for candidate genes associated with risk of OS. OS is associated with several rare inherited cancer predisposition syndromes (Li–Fraumeni syndrome, hereditary bilateral retinoblastoma, Bloom, Werner, Rothmund Thomson syndromes, and Diamond–Blackfan anemia) that are caused by highly penetrant germline mutations. These syndromes are not a common cause of OS. Candidate gene association studies have suggested several polymorphisms associated with risk of OS; SNP associations in the following candidate genes have been replicated in two or more studies: IGF2R , FGFR3 , MDM2 , TGFBR1 and CTLA‐4 . An agnostic genome‐wide association study has found two novel loci associated with risk of OS: GRM4 gene and the 2p25.2 chromosomal region. Studies are needed to expand these genetic association findings to more ethnic groups and in larger samples sizes to determine if these are stable associations.