Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children^1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma³. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MB_SHH)_. ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MB_SHH. Parent–offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype⁴ and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U₃₄) position^5,6. Tumours from patients with ELP1-associated MB_SHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems^7,8,9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

癌症基因组学揭示了许多导致人类恶性肿瘤的基因和核心分子过程，但许多罕见癌症的遗传和分子基础仍不清楚。遗传易感性占儿童癌症诊断的 5% 至 10% ^1,2 ，而与已知体细胞驱动事件配合的遗传事件却知之甚少。最近在 5% 的恶性脑肿瘤髓母细胞瘤患者中发现了已确定的癌症易感基因中的致病性种系变异³ 。在这里，通过分析所有蛋白质编码基因，我们在 14% 的髓母细胞瘤亚组 Sonic Hedgehog (MB _SHH ) 儿科患者中识别并复制了ELP1 的罕见种系功能丧失变异_。 ELP1是最常见的髓母细胞瘤易感基因，使 MB _SHH儿科患者的遗传易感性患病率增加至 40%。亲子和谱系分析确定了两个有儿科髓母细胞瘤病史的家庭。 ELP1相关的髓母细胞瘤仅限于分子SHHα亚型⁴ ，其特征是由于染色体臂9q的体细胞丢失而导致ELP1普遍双等位基因失活。大多数ELP1相关髓母细胞瘤也表现出PTCH1的体细胞改变，这表明种系ELP1功能丧失变异与 SHH 信号传导的组成性激活相结合，使个体易于发生肿瘤发展。 ELP1 是进化上保守的 Elongator 复合体中最大的亚基，它通过摆动 (U ₃₄ ) 位点^5,6处的 tRNA 修饰来催化翻译延伸。 ELP1相关 MB _SHH患者的肿瘤特征为不稳定的 Elongator 复合物、Elongator 依赖性 tRNA 修饰的丧失、密码子依赖性翻译重编程以及未折叠蛋白反应的诱导，这与 Elongator 缺陷导致的蛋白质稳态丧失一致。模型系统^7,8,9 。因此，蛋白质组不稳定性的遗传倾向可能是小儿脑癌发病机制的决定因素。这些结果支持对蛋白质稳态在其他癌症类型中的作用以及治疗干扰潜力的研究。