Saoud Carla, Dermawan Josephine K, Arora Kanika, Tap William D, Reed Damon, Slotkin Emily K, Wexler Leonard H, Murciano-Goroff Yonina R, Latham Alicia, Mandelker Diana L, Antonescu Cristina R
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
NPJ Precis Oncol. 2025 May 7;9(1):133. doi: 10.1038/s41698-025-00925-6.
Translocation-associated sarcomas (TAS) are rare, phenotypically heterogeneous, with predisposition for young adults. We aimed to investigate the clinical impact of germline pathogenic/likely pathogenic (P/LP) variants in a diverse group of TAS and to conduct a comprehensive comparative analysis of clinicopathologic features, genomic alterations, and survival outcomes. A retrospective cohort of 426 TAS patients with both tumor and germline DNA sequencing was investigated for clinical actionability of P/LP variants, and potential impact on current screening guidelines and clinical interventions. Twenty-eight patients (6.6%) carried Tier 1 germline P/LP variants (moderate to high penetrance autosomal dominant (AD) variants), while 27 (6.3%) patients carried Tier 2 variants (monoallelic autosomal recessive or low penetrance AD variants). Compared to Tier 2, Tier 1 patients were more commonly of European ancestry and had a higher frequency of first- and second-degree relatives with cancer history. Notably, the frequency of both tiers variants was lower among pediatric patients compared to older patients and differed across TAS histologies, with the highest observed in solitary fibrous tumors. All germline P/LP variants were monoallelic, dispersed across multiple genes, and enriched in DNA damage repair pathways. There was no association between the germline P/LP variants and somatic genomic profile, nor any survival impact when stratified by histotype. Our findings highlight the incidence of clinically significant germline P/LP variants in TAS is lower in pediatric patients, questioning current sarcoma genetic screening guidelines and supporting germline testing for all TAS patients. Significant interventions were triggered in 46% of Tier 1 (n = 13), including platinum-based chemotherapy and PARP inhibitors in two BRCA1/2 patients.
易位相关肉瘤（TAS）较为罕见，表型具有异质性，好发于年轻人。我们旨在研究不同类型TAS中胚系致病性/可能致病性（P/LP）变异的临床影响，并对临床病理特征、基因组改变和生存结果进行全面的比较分析。对426例同时进行肿瘤和胚系DNA测序的TAS患者的回顾性队列进行研究，以评估P/LP变异的临床可操作性，以及对当前筛查指南和临床干预的潜在影响。28例患者（6.6%）携带1级胚系P/LP变异（中度至高外显率常染色体显性（AD）变异），而27例（6.3%）患者携带2级变异（单等位基因常染色体隐性或低外显率AD变异）。与2级患者相比，1级患者更常见于欧洲血统，且一级和二级亲属有癌症病史的频率更高。值得注意的是，与老年患者相比，儿科患者中这两级变异的频率较低，并且在不同的TAS组织学类型中有所不同，在孤立性纤维瘤中观察到的频率最高。所有胚系P/LP变异均为单等位基因，分散在多个基因中，并富集于DNA损伤修复途径。胚系P/LP变异与体细胞基因组谱之间没有关联，按组织学类型分层时也没有生存影响。我们的研究结果表明，儿科患者中TAS具有临床意义的胚系P/LP变异的发生率较低，这对当前的肉瘤基因筛查指南提出了质疑，并支持对所有TAS患者进行胚系检测。46%的1级患者（n = 13）触发了重大干预措施，包括两名BRCA1/2患者接受铂类化疗和PARP抑制剂治疗。
