Children's Cancer Research Unit, Kids Research and Discipline of Child and Adolescent Health, University of Sydney, Westmead, New South Wales, Australia.
Eye & Developmental Genetics Research Group, The Children's Hospital at Westmead and Children's Medical Research Institute, Westmead, New South Wales, Australia.
J Med Genet. 2018 Dec;55(12):785-793. doi: 10.1136/jmedgenet-2018-105488. Epub 2018 Oct 4.
Genetic predisposition is an important underlying cause of childhood cancer, although the proportion of patients with childhood cancer carrying predisposing pathogenic germline variants is uncertain. This review considers the pathogenic or likely pathogenic germline variants reported by six studies that used next-generation sequencing to investigate genetic predisposition in selected cohorts of patients with childhood cancer and used incompletely overlapping gene sets for analysis and interpretation. These six studies reported that 8.5%-35.5% of patients with childhood cancer carried clinically relevant germline variants. Analysis of 52 autosomal dominant cancer predisposition genes assumed common to all six studies showed that 5.5%-25.8% of patients with childhood cancer carried pathogenic or likely pathogenic germline variants in at least one of these genes. When only non-central nervous system solid tumours (excluding adrenocortical carcinomas) were considered, 8.5%-10.3% of the patients carried pathogenic or likely pathogenic germline variants in at least one of 52 autosomal dominant cancer predisposition genes. There was a lack of concordance between the genotype and phenotype in 33.3%-57.1% of the patients reported with pathogenic or likely pathogenic germline variants, most of which represented variants in autosomal dominant cancer predisposition genes associated with adult onset cancers. In summary, germline genetic testing in patients with childhood cancer requires clear definition of phenotypes and genes considered for interpretation, with potential to inform and broaden childhood cancer predisposition syndromes.
遗传易感性是儿童癌症的一个重要潜在原因，尽管携带致病种系变异体的儿童癌症患者比例尚不确定。这篇综述考虑了六项研究报告的致病性或可能致病性的种系变异体，这些研究使用下一代测序技术对儿童癌症的选定队列患者进行了遗传易感性研究，并使用不完全重叠的基因集进行分析和解释。这六项研究报告称，8.5%-35.5%的儿童癌症患者携带具有临床意义的种系变异体。对 52 个常染色体显性癌症易感基因的分析表明，所有六项研究共有的基因，5.5%-25.8%的儿童癌症患者至少有一种基因携带致病性或可能致病性的种系变异体。当仅考虑非中枢神经系统实体瘤（不包括肾上腺皮质癌）时，8.5%-10.3%的患者在至少一个 52 个常染色体显性癌症易感基因中携带致病性或可能致病性的种系变异体。在报告的携带致病性或可能致病性种系变异体的患者中，33.3%-57.1%的基因型与表型之间缺乏一致性，其中大多数是与成人发病癌症相关的常染色体显性癌症易感基因的变异体。总之，儿童癌症患者的种系基因检测需要明确定义解释所考虑的表型和基因，这有可能为儿童癌症易感性综合征提供信息和扩展。
