自从引入配对肿瘤-种系测序以来，种系数据已在儿科肿瘤学中广泛使用。为了指导癌症易感综合征 (CPS) 诊断的最佳实践，我们旨在评估所有癌症儿童中广泛种系分析与基于临床选择的基因检测的诊断率。在这项前瞻性诊断研究中，所有儿童（0- 2020 年 6 月 1 日至 2022 年 7 月 31 日期间，在荷兰国家中心马克西玛公主儿科肿瘤中心（荷兰乌得勒支）接受新诊断肿瘤治疗的 19 年）患者接受了两种方法来识别 CPS。在表型驱动的方法中，儿科肿瘤学家使用麦吉尔互动儿科肿瘤遗传学指南工具来选择儿童转诊给临床遗传学家并进行基因检测。采用与表型无关的方法，向所有儿童提供 CPS 基因组测序（143 个基因）。在拒绝接受 CPS 基因组研究的儿童中，病理学家仍将分析 49 个 CPS 基因作为常规诊断的一部分。在肿瘤诊断前发现患有致病性 CPS 的儿童被排除在外。主要目的是比较两种方法之间诊断为 CPS 的患者数量和类型。 1052 名儿童符合本研究的资格，其中 733 名 (70%) 完成了表型驱动方法并接受了表型不可知的 CPS 基因面板测序（143 个基因 n=600；49 个基因 n=133）。在 53 名儿童中，确定了 CPS：14 名（26%）仅通过表型驱动方法诊断，22 名（42%）仅通过 CPS 基因测序诊断，17 名（32%）通过两种方法诊断。在 53 名儿童中，有 27 名 (51%) 被认为是导致儿童肿瘤的原因。表型驱动的方法仅漏掉了 27 种致病 CPS 中的一种 (4%)，并且仅通过与表型无关的 CPS 基因测序来识别。在 26 名 (49%) 儿童中，确定了因果关系不确定的 CPS，其中包括 14 名成人发病的 CPS。因果关系不确定的 CPS 主要通过表型不可知的方法检测（26 个中的 21 个 [81%]）。表型驱动的基因检测和表型不可知的 CPS 基因组测序是互补的。表型驱动的方法确定了最致病的 CPS。 CPS 基因组测序发现了其他 CPS，其中许多具有不确定的因果关系，但有些具有临床实用性。我们建议对所有患有肿瘤的儿童进行 CPS 的临床评估。所有 CPS 基因的表型不可知测试最好仅在研究环境中进行，并应与咨询相结合。Stichting Kinderen Kankervrij。版权所有 © 2024 Elsevier Ltd。保留所有权利，包括文本和数据挖掘、人工智能培训和类似技术的权利。

Germline data have become widely available in paediatric oncology since the introduction of paired tumour-germline sequencing. To guide best practice in cancer predisposition syndrome (CPS) diagnostics, we aimed to assess the diagnostic yield of extensive germline analysis compared with clinical selection-based genetic testing among all children with cancer.In this prospective diagnostic study, all children (aged 0-19 years) with newly diagnosed neoplasms treated in the Netherlands national centre, the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands), between June 1, 2020, and July 31, 2022, were offered two approaches to identify CPSs. In a phenotype-driven approach, paediatric oncologists used the McGill Interactive Pediatric OncoGenetic Guidelines tool to select children for referral to a clinical geneticist, and for genetic testing. In a phenotype-agnostic approach, CPS gene panel sequencing (143 genes) was offered to all children. In children declining the research CPS gene panel, 49 CPS genes were still analysed as part of routine diagnostics by the pathologist. Children with a causative CPS identified before neoplasm diagnosis were excluded. The primary objective was to compare the number and type of patients diagnosed with a CPS between the two approaches.1052 children were eligible for this study, of whom 733 (70%) completed both the phenotype-driven approach and received phenotype-agnostic CPS gene panel sequencing (143 genes n=600; 49 genes n=133). In 53 children, a CPS was identified: 14 (26%) were diagnosed by the phenotype-driven approach only, 22 (42%) by CPS gene sequencing only, and 17 (32%) by both approaches. In 27 (51%) of the 53 children, the identified CPS was considered causative for the child's neoplasm. Only one (4%) of the 27 causative CPSs was missed by the phenotype-driven approach and was identified solely by phenotype-agnostic CPS gene sequencing. In 26 (49%) children, a CPS with uncertain causality was identified, including 14 adult-onset CPSs. The CPSs with uncertain causality were mainly detected by the phenotype-agnostic approach (21 [81%] of 26).Phenotype-driven genetic testing and phenotype-agnostic CPS gene panel sequencing were complementary. The phenotype-driven approach identified the most causative CPSs. CPS gene panel sequencing identified additional CPSs, many of those with uncertain causality, but some with clinical utility. We advise clinical evaluation for CPSs in all children with neoplasms. Phenotype-agnostic testing of all CPS genes is preferably conducted only in research settings and should be paired with counseling.Stichting Kinderen Kankervrij.Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.