高级梗死相关骨肉瘤的基因组学见解

IF 7.1 1区 医学 Q1 PATHOLOGY Modern Pathology Pub Date : 2024-07-20 DOI:10.1016/j.modpat.2024.100572
Tatiana Tvrdik , Sandra Gjorgova Gjeorgjievski , Philip Wong , Shervin Oskouei , William Read , Armita Bahrami
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引用次数: 0

摘要

肉瘤很少发生在因梗塞而受损的骨骼中。这些与梗塞相关的肉瘤通常表现为未分化多形性肉瘤(UPS),其遗传特征尚不清楚。骨的高级别纺锤形细胞/多形性肉瘤通常采用手术和化疗相结合的方法进行治疗,这与骨肉瘤的治疗方法类似。我们对经组织学和放射学证实的骨梗塞引起的六例骨内肉瘤进行了详细的临床病理和基因组分析。我们利用新一代测序技术TruSight Oncology 500面板分析了523个基因的序列级突变,并利用全基因组SNP芯片(OncoScan CNV)检测拷贝数改变和杂合性缺失(LOH)。基因组不稳定性通过同源重组缺陷(HRD)指标进行评估,其中包括异质性缺失、端粒等位基因不平衡和大规模状态转换。FISH和免疫组化验证了研究结果。研究对象包括三名男性和三名女性,中位年龄为70岁,肿瘤位于股骨和胫骨。六名患者中有五名出现了远处转移。治疗包括手术、化疗或免疫检查点抑制剂。基因组分析表明,肿瘤具有明显的复杂性,HRD评分较高,从32分到57分不等(以32分为临界值)。在四例病例中观察到了染色体12的改变,包括节段性扩增或染色体三分裂。值得注意的是,在两个病例中发现了经 FISH 证实的 MDM2 扩增。在所有六个病例中都观察到了 CDKN2A/B 的同基因缺失。肿瘤突变负荷(TMB)水平从每兆位碱基 2.4 个突变到 7.9 个突变不等。显著的致病突变包括H3-3A突变(p.G35R和p.G35W),以及HRAS、DNMT3A、NF2、PIK3CA、POLE和TP53的突变,每种突变都出现在一个病例中。这些结果表明,高级别梗死相关性骨肉瘤虽然与骨肉瘤具有高度的结构变异,但可能表现出较少见的TP53突变和较常见的CDKN2A/B缺失。这表明,骨肉瘤的突变谱和紊乱途径可能与传统骨肉瘤不同。
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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 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.

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来源期刊
Modern Pathology
Modern Pathology 医学-病理学
CiteScore
14.30
自引率
2.70%
发文量
174
审稿时长
18 days
期刊介绍: Modern Pathology, an international journal under the ownership of The United States & Canadian Academy of Pathology (USCAP), serves as an authoritative platform for publishing top-tier clinical and translational research studies in pathology. Original manuscripts are the primary focus of Modern Pathology, complemented by impactful editorials, reviews, and practice guidelines covering all facets of precision diagnostics in human pathology. The journal's scope includes advancements in molecular diagnostics and genomic classifications of diseases, breakthroughs in immune-oncology, computational science, applied bioinformatics, and digital pathology.
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