Although cancer is rare in children and adolescents, it remains a leading cause of death within this age range, and genetic predisposition is the main known risk factor. Since the discovery of retinoblastoma-predisposing RB1 pathogenic germline variants in 1985, several additional high-penetrance cancer predisposition genes (CPGs) have been identified. Although few clinically recognizable genetic conditions display moderate cancer phenotypes, burden testing has revealed low-to-moderate penetrance CPGs. In addition to germline pathogenic variants in CPGs, postzygotic somatic mosaic CPG pathogenic variants acquired during embryonic development are increasingly recognized as factors that predispose children and adolescents to malignancies. Genome-wide association studies of various childhood and adolescent cancer types have identified some common low-risk cancer susceptibility alleles. Although the clinical utility of polygenic risk scores is currently limited in children and adolescents, polygenic risk scores developed for adults can predict subsequent cancer risks in childhood and adolescent cancer survivors. In this Review, I describe our current knowledge of genetic predisposition to childhood and adolescent cancers. Survival rates in children and adolescents with cancer and CPGs are often poor, necessitating better integration of genomic testing into clinical care to improve cancer prevention, surveillance and therapies.

尽管癌症在儿童和青少年中很少见，但它仍然是该年龄段的主要死亡原因，遗传易感性是已知的主要危险因素。自 1985 年发现易患视网膜母细胞瘤的 RB1 致病性种系变异以来，已经确定了几个额外的高外显率癌症易感基因 （CPG）。尽管很少有临床可识别的遗传病表现出中度癌症表型，但负荷试验显示低至中度外显率 CPG。除了 CPG 中的种系致病性变异外，在胚胎发育过程中获得的合子后体细胞嵌合 CPG 致病性变异也越来越被认为是使儿童和青少年易患恶性肿瘤的因素。各种儿童和青少年癌症类型的全基因组关联研究已经确定了一些常见的低风险癌症易感性等位基因。尽管目前多基因风险评分在儿童和青少年中的临床应用有限，但为成人开发的多基因风险评分可以预测儿童和青少年癌症幸存者的后续癌症风险。在这篇综述中，我描述了我们目前对儿童和青少年癌症遗传易感性的了解。患有癌症和 CPG 的儿童和青少年的存活率通常很差，因此需要更好地将基因组检测整合到临床护理中，以改善癌症预防、监测和治疗。