Age-dependent chromosomal instability in osteosarcoma: younger patients exhibit paradoxically higher genomic damage

Osteosarcoma is an aggressive bone malignancy with peak incidence during adolescence and a secondary peak in older adults. While the disease is characterized by extreme chromosomal instability, the relationship between patient age and genomic damage has not been systematically quantified. Here, using two independent cohorts totaling 589 osteosarcoma samples, we demonstrate a paradoxical inverse relationship between age and chromosomal instability. In the discovery cohort (n = 460, Foundation Medicine), younger patients (≤ 25 years) exhibited significantly higher loss of heterozygosity (LOH: 16.52% vs 12.70%, p = 0.0002) compared to older patients (> 40 years). This finding was validated in an independent cohort (n = 129, MSK-IMPACT) using fraction genome altered (FGA: 36.5% vs 26.5%, p = 0.028). The age-instability correlation was continuous and negative in both cohorts (r=-0.15 to -0.25, p < 0.01). Notably, chromosomal instability did not differ between primary and metastatic tumors, suggesting metastatic competence is established early rather than acquired through additional genomic damage. These findings challenge conventional cancer models where genomic damage accumulates with age and support the chromothripsis hypothesis for adolescent osteosarcoma, wherein catastrophic chromosomal shattering during rapid bone growth drives tumorigenesis. Our results suggest that adolescent and adult osteosarcomas may represent biologically distinct entities requiring different therapeutic strategies.