儿童癌症易感性 (ChiCaP) 综合征越来越被认为是儿童癌症发展的促成因素。然而，由于种系检测的可用性存在差异，许多患有 ChiCaP 的儿童今天可能未被发现。我们报告了全国性前瞻性 ChiCaP 研究的结果，该研究调查了种系全基因组测序 (gWGS) 与肿瘤测序和系统表型分析相结合对实体瘤儿童的诊断率和临床影响。对 309 名诊断为 CNS 的儿童进行了 gWGS（ n = 123, 40%) 或颅外 (n = 186, 60%) 实体瘤，并分析 189 个已知癌症易感基因的致病变异。 74% (227/309) 的患者可以获得肿瘤测序数据。此外，对 95% (293/309) 的患者进行了潜在易感性的标准化临床评估。ChiCaP 诊断的患病率为 11% (35/309)，其中 69% (24/35) 在纳入时未知（诊断率 8%，24/298）。在 19/21 (90%) 的肿瘤中观察到二次打击和/或相关突变特征，并提供了丰富的信息数据。 ChiCaP 诊断在视网膜母细胞瘤 (50%, 6/12) 和高级别星形细胞瘤 (37%, 6/16) 患者以及具有非癌症相关特征的患者 (23%, 20/88) 中更为普遍≥2 个阳性 ChiCaP 标准 (28%, 22/79)。 80% (28/35) 的患者 ChiCaP 诊断为常染色体显性遗传，但 64% (18/28) 的患者为新发确诊。 35 项 ChiCaP 研究结果导致了量身定制的监测（86%，30/35）和治疗建议（31%，11/35）。总体而言，我们的结果表明，系统表型分析与基于基因组学的 ChiCaP 诊断相结合，可治疗患有实体瘤的儿童在大规模临床实践中是可行的，并且可以严格指导相当大比例患者的个性化护理。该研究得到了瑞典儿童癌症基金会以及卫生和社会事务部的支持。© 2024 作者。

Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.© 2024 The Author(s).