Genomic Insights into High-Grade Infarct-Associated Bone Sarcomas.

Sarcomas rarely develop in bones previously compromised by infarcts. These infarct-associated sarcomas often present as undifferentiated pleomorphic sarcomas (UPS), and their genetic characteristics are poorly understood. High-grade spindle cell/UPS of bone are typically treated with a combination of surgery and chemotherapy, similar to osteosarcoma. We conducted a detailed clinicopathologic and genomic analysis of six cases of intraosseous sarcomas arising from histologically and radiographically confirmed bone infarcts. We analyzed 523 genes for sequence-level mutations using next-generation sequencing with the TruSight Oncology 500 panel and utilized whole-genome SNP Microarray (OncoScan CNV) to detect copy number alterations and loss of heterozygosity (LOH). Genomic instability was assessed through Homologous Recombination Deficiency (HRD) metrics, incorporating LOH, telomeric allelic imbalance, and large-scale state transitions. FISH and immunohistochemistry validated the findings. The cohort included three men and three women, with a median age of 70, and tumors located in the femur and tibia. Five of the six patients developed distant metastases. Treatment involved surgery and chemotherapy or immune checkpoint inhibitors. Genomic analysis revealed significant complexity and high HRD scores, ranging from 32 to 57 (with a cut-off of 32). Chromosome 12 alterations, including segmental amplification or chromothripsis, were observed in four cases. Notably, MDM2 amplification, confirmed by FISH, was detected in two cases. Homozygous deletion of CDKN2A/B was observed in all six cases. Tumor mutational burden (TMB) levels ranged from 2.4 to 7.9 mutations per megabase. Notable pathogenic mutations included H3-3A mutations (p.G35R and p.G35W), and mutations in HRAS, DNMT3A, NF2, PIK3CA, POLE, and TP53, each in one case. These results suggest that high-grade infarct-associated sarcomas of bone, while sharing high levels of structural variations with osteosarcoma, may exhibit potentially less frequent TP53 mutations and more common CDKN2A/B deletions. This points to the possibility that the mutation spectrum and disrupted pathways could be distinct from conventional osteosarcoma.