Background: The etiology of most mesenchymal tumors is unknown, and knowledge about syndromes with an increased risk of tumors in bone or soft tissue is sparse. Methods: We present a prospective germline analysis of 312 patients with tumors suspected of being sarcomas at a tertiary sarcoma center. Germline and tumor whole genome sequencing, tumor transcriptome, and methylome analyses were performed. Results: Germline pathogenic or likely pathogenic variants associated with an increased risk of tumors were detected in 24 patients (8%), of which 11 (4%) harbored a detectable second hit in the tumor. Second hits were confirmed in genes with (NF1,RB1,TP53,EXT2, andSDHC) and without (ATM,CDC73,MLH1,MSH6,POLG, andKCNQ1) known association with mesenchymal tumor predisposition. Sarcomas from two Lynch syndrome patients showed mismatch repair deficiency, predicting a treatment response to immune checkpoint inhibitors (Level 1 biomarker according to the FDA (Federal Drug Administration) and ESMO (European Society for Medical Oncology)). None of the threeCHEK2carriers had a second hit in the tumor, suggesting a weak link to sarcoma. Conclusions: We conclude that second-hit analyses can be used in standard of care to identify syndrome-related tumors. This approach can help distinguish true manifestations of tumor syndromes from unrelated germline findings and enhance the understanding of germline predisposition in soft tissue tumors. Prospective screening using germline whole genome sequencing should be considered when comprehensive somatic sequencing is introduced into clinical practice.
背景：大多数间叶组织肿瘤的病因尚不明确，且关于骨骼或软组织肿瘤风险增加的综合征知识较为匮乏。方法：本研究在一家三级肉瘤中心对312例疑似肉瘤患者进行了前瞻性种系分析，实施了种系与肿瘤全基因组测序、肿瘤转录组及甲基化组分析。结果：在24例患者（8%）中检测到与肿瘤风险增加相关的种系致病性或可能致病性变异，其中11例（4%）在肿瘤中存在可检测的二次打击。二次打击在已知与间叶组织肿瘤易感性相关的基因（NF1、RB1、TP53、EXT2和SDHC）及尚无明确关联的基因（ATM、CDC73、MLH1、MSH6、POLG和KCNQ1）中均得到确认。两名林奇综合征患者的肉瘤显示错配修复缺陷，预示其对免疫检查点抑制剂具有治疗反应（根据美国食品药品监督管理局和欧洲肿瘤内科学会标准，该标志物为1级生物标志物）。三名CHEK2携带者均未在肿瘤中发现二次打击，提示其与肉瘤的关联较弱。结论：我们认为二次打击分析可作为标准诊疗手段用于识别综合征相关肿瘤。该方法有助于区分肿瘤综合征的真实表现与无关的种系发现，并增进对软组织肿瘤种系易感性的理解。当全面体细胞测序引入临床实践时，应考虑采用种系全基因组测序进行前瞻性筛查。
Prospective Screening of Cancer Syndromes in Patients with Mesenchymal Tumors
肿瘤(癌症)患者之家