肉瘤是一种罕见而多样的癌症群，主要发生在年轻人身上，然而大多数情况下，其潜在遗传基因原因仍不清楚。本研究使用具有113个或126个癌症易感基因（CPG）的多基因面板对177名患有软组织或骨肉瘤的儿童、青少年和年轻成年人的生殖DNA进行了测试，以描述有致病/可能致病变异（GPV）的基因型的普遍性。随后，对部分肿瘤进行杂合性缺失（LOH）评估测试，以研究这些变异的临床和分子意义。结果显示，38名患者（21.5%）的GPV检测为阳性（其中儿童为15.8%，青少年和年轻成年人为21.6%），其中有15.2%出现了主导型CPG变异。这些变异发现在先前与患肉瘤风险有关的基因（TP53、RB1、NF1、EXT1/2）中，但也出现在风险仍在出现/有限的基因（ERCC2、TSC2和BRCA2）以及未知的基因（PALB2、RAD50、FANCM等）中。GPV检出率在肉瘤亚型间的变化为0%至33%，GPV携带者患有多个原发肿瘤的可能性较非携带者更高（21.1%×6.5%；p=0.012）。在GPV携带者的肿瘤中，野生型等位基因的丧失检出率为48%，大部分检出于明确定与肉瘤风险相关的基因中。我们的研究结果揭示，许多年轻肉瘤患者携带CPG中的GPV，凸显了建立适当的遗传筛查策略以及针对这类个体及其家庭的紧迫性。©作者（或其雇主）2023。在CC BY-NC下允许再次使用。不允许商业再利用。由BMJ出版。

Sarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases.Germline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants.GPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53, RB1, NF1, EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2, TSC2 and BRCA2) or unknown (PALB2, RAD50, FANCM and others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk.Our findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.