Abstract 4871: Whole-exome sequencing identifies a high frequency of germline deleterious variants in cancer predisposition genes in individuals with osteosarcoma

In children and adolescents, osteosarcoma (OS) is the most common malignant bone tumor. OS occurs in certain cancer predisposition syndromes at a higher than expected frequency. However, outside of these rare syndromes, OS is significantly more common and its genetic etiology remains poorly understood. We conducted an evaluation of rare exonic variants in 545 unselected OS cases compared with 1061 cancer-free controls using whole-exome sequencing of blood or buccal cell DNA to estimate the prevalence and burden of rare deleterious germline variants. We assessed potentially pathogenic rare variants in 126 established cancer predisposing genes (CPG) and known somatically mutated genes. We also surveyed the exome for genes with a higher burden of rare variants in 342 EUR cases with 994 EUR controls sequenced at the same time. Rare genetic variants, defined by a MAF