Abstract：
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 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 6 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 single nucleotide polymorphism 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. Fluorescence in situ hybridization and immunohistochemistry validated the findings. The cohort included 3 men and 3 women, with a median age of 70 years, and tumors located in the femur and tibia. Five of the 6 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 cutoff of 32). Chromosome 12 alterations, including segmental amplification or chromothripsis, were observed in 4 cases. Notably, MDM2 amplification, confirmed by fluorescence in situ hybridization, was detected in 2 cases. Homozygous deletion of CDKN2A/B was observed in all six cases. Tumor mutational burden 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, whereas 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.
摘要：
肉瘤很少在先前因梗塞而受损的骨骼中发展。这些梗死相关肉瘤通常表现为未分化多形性肉瘤（UPS），他们的遗传特征知之甚少。骨的高级梭形细胞/UPS通常采用手术和化疗的组合治疗，类似于骨肉瘤。我们对6例由组织学和影像学证实的骨梗塞引起的骨内肉瘤进行了详细的临床病理和基因组分析。我们使用TruSightOncology500小组的下一代测序分析了523个基因的序列水平突变，并利用全基因组SNP微阵列（OncoScanCNV）检测拷贝数改变和杂合性丢失（LOH）。基因组不稳定性通过同源重组缺陷（HRD）指标进行评估，合并LOH，端粒等位基因失衡，和大规模的状态转换。FISH和免疫组织化学验证了这些发现。这群人包括三名男性和三名女性，平均年龄为70岁，肿瘤位于股骨和胫骨。六名患者中有五名发生了远处转移。治疗包括手术和化疗或免疫检查点抑制剂。基因组分析显示出显著的复杂性和高HRD分数，范围从32到57（截止为32）。12号染色体改变，包括节段扩增或染色体增生，在四个病例中观察到。值得注意的是,MDM2扩增，由FISH确认，在两起案件中被发现。在所有6例病例中均观察到CDKN2A/B的纯合缺失。肿瘤突变负荷(TMB)水平范围为每兆碱基2.4至7.9个突变。值得注意的致病性突变包括H3-3A突变（p。G35Randp.G35W),和HRAS的突变，DNMT3A,NF2,PIK3CA,POLE,和TP53，每个都在一个案例中。这些结果表明，高级别梗死相关骨肉瘤，同时与骨肉瘤共享高水平的结构变异，可能表现出可能不太频繁的TP53突变和更常见的CDKN2A/B缺失。这表明突变谱和破坏的途径可能与常规骨肉瘤不同。
