■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,由于种系测试的可变可用性,许多患有ChiCaP的儿童今天可能未被发现。我们报告了全国性和前瞻性ChiCaP研究的结果,该研究调查了在实体肿瘤儿童中整合种系全基因组测序(gWGS)与肿瘤测序和系统表型的诊断产量和临床影响。
■对309名诊断为中枢神经系统(n=123,40%)或颅外(n=186,60%)实体瘤的儿童进行了gWGS,并分析了189个已知的癌症易感基因中的致病变异。肿瘤测序数据可用于74%(227/309)的患者。此外,95%(293/309)的患者对潜在易感性进行了标准化临床评估.
■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)。在具有信息数据的19/21(90%)肿瘤中观察到第二次命中和/或相关突变特征。ChiCaP诊断在视网膜母细胞瘤患者中更为普遍(50%,6/12)和高级星形细胞瘤(37%,6/16),在那些具有非癌症相关特征的人群中(23%,20/88),和≥2个阳性ChiCaP标准(28%,22/79).ChiCaP诊断为80%(28/35)的患者常染色体显性遗传,但仍在64%(18/28)中确认从头。35项ChiCaP调查结果导致了量身定制的监测(86%,30/35)和治疗建议(31%,11/35).
■总的来说,我们的结果表明,系统的表型,与基于基因组学的ChiCaP诊断相结合,在大规模临床实践中是可行的,并且在相当大比例的患者中指导个性化护理.
■这项研究得到了瑞典儿童癌症基金会和卫生与社会事务部的支持。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: The
study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.