Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California.
Clin Cancer Res. 2023 Nov 14;29(22):4669-4678. doi: 10.1158/1078-0432.CCR-23-0876.
Ultra-rare sarcomas (URS) comprise a group of orphan diseases with an incidence of ≤1/1,000,000 people per year. We aimed to assess clinically actionable genomic alterations in URS.
Data were extracted from the GENIE database using cBioPortal. OncoKB was used to assess for clinical actionability of mutations. Tumor mutational burden (TMB) was inferred from clinical sequencing data.
Soft tissue (ST) URS made up 23.5% of ST sarcoma cases, and bone URS made up 16.5% of bone sarcoma cases. The most commonly mutated gene in all four groups was TP53. The most common fusions involved EWSR1. The most common copy-number variations included deletions of CDKN2A and CDKN2B and amplifications of MDM2 and CDK4. TMB was generally low across all four categories of sarcoma, though there was considerable heterogeneity, with 3.8% of ST URS and 0.55% of bone URS having high TMB. We find Level 1 alterations (FDA-recognized biomarker predictive of response to an FDA-approved drug) in 10.0% of ST URS compared with 7.1% of ST non-URS, 1.1% of bone URS, and 4.5% of bone non-URS. Level 1-3 alterations (also include alterations for which there are standard-of-care drugs or clinical evidence supporting a drug) were seen in 27.8% of ST URS, 25.2% of ST non-URS, 20.9% of bone URS, and 17.4% of bone non-URS.
Clinically actionable genomic alterations are seen in a substantial fraction of URS. Clinical sequencing in advanced URS has the potential to guide the treatment of a significant portion of patients with URS.
超罕见肉瘤（URS）属于一组孤儿病，发病率为每年每 100 万人中≤1 例。我们旨在评估 URS 中具有临床可操作性的基因组改变。
使用 cBioPortal 从 GENIE 数据库中提取数据。OncoKB 用于评估突变的临床可操作性。肿瘤突变负荷（TMB）由临床测序数据推断。
软组织（ST）URS 占 ST 肉瘤病例的 23.5%，骨 URS 占骨肉瘤病例的 16.5%。所有四个组中最常突变的基因均为 TP53。最常见的融合涉及 EWSR1。最常见的拷贝数变异包括 CDKN2A 和 CDKN2B 的缺失以及 MDM2 和 CDK4 的扩增。所有四种肉瘤类型的 TMB 通常都较低，但存在很大的异质性，3.8%的 ST URS 和 0.55%的骨 URS 具有高 TMB。我们发现 10.0%的 ST URS 存在 1 级改变（FDA 认可的生物标志物，预测对 FDA 批准药物的反应），而 ST 非 URS 为 7.1%，骨 URS 为 1.1%，骨非 URS 为 4.5%。ST URS 为 27.8%，ST 非 URS 为 25.2%，骨 URS 为 20.9%，骨非 URS 为 17.4%，存在 1-3 级改变（还包括有标准治疗药物或支持药物的临床证据的改变）。
在相当一部分 URS 中存在具有临床可操作性的基因组改变。在晚期 URS 中进行临床测序有可能指导治疗 URS 患者的很大一部分患者。
