Analysis of a large osteosarcoma sequencing data set elucidates patterns of genomic alterations

Genomic complexity and small case numbers make statistically robust assessment of mutational patterns in osteosarcoma difficult. The authors analyzed a large cohort of targeted next-generation sequencing data from osteosarcoma cases from young patients submitted for clinical testing to Foundation Medicine.

The osteosarcoma cohort included 653 patients: 109 pediatric (males, <13 years old; females, <12 years old), 246 adolescent (males, 13-17 years old; females, 12-17 years old), and 298 young adult (males and females, 18-40 years old). Sequencing from osteosarcoma cases was compared to a pan-cancer cohort comprising 37,947 patients ≤40 years old.

Genes commonly altered and significantly enriched (p < .0001) for alterations in osteosarcoma compared to other cancers were TP53 (55%), RB1 (22%), GID4 (26%), MYC (17%), and CCND3 (16%). Less commonly altered genes also significantly enriched (p < .0001) for alterations in osteosarcoma included AURKB (odds ratio [OR], 28.0), NCOR1 (OR, 8.2), and BCL2L2 (OR, 8.9). Fisher exact tests demonstrated mutual exclusivity between MDM2 amplification and TP53 inactivation and between RB1 inactivation and CDK4 amplification or CDKN2A/B deletion. Chi-square tests and binomial regression revealed statistically significant differences in genomic events by age, including frequent amplification of CDK4 and MDM2 in young adults and MYC, CCND3, and CCNE1 in pediatric and adolescent cases.

Novel findings from this statistically rigorous analysis of a large patient population include: identifying genes of interest in osteosarcoma that are more often altered when compared to other cancers; identifying MYC and CCND3 amplification as significantly more prevalent in osteosarcoma diagnosed in childhood; and proving mutual exclusivity and co-occurrence with statistical robustness.