PURPOSE The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete. METHODS Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series. RESULTS We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors. CONCLUSION Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MBSHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.

中文翻译：

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种系 GPR161 突变易患小儿成神经管细胞瘤

目的 遗传性肿瘤易感性的鉴定通常会导致管理的变化和对高危个体的监测增加；然而，对于许多罕见的实体，我们对遗传倾向的了解​​并不完整。方法 对患有儿童髓母细胞瘤（最常见的儿童恶性脑肿瘤之一）的家庭进行调查，以确定易感的生殖系突变。初步发现扩展到来自国际多中心队列的 1,044 例髓母细胞瘤病例的基因组和表观基因组，包括回顾性和前瞻性临床研究以及患者系列。结果 我们在 6 名婴儿型髓母细胞瘤患者（中位年龄 1.5 岁）中发现了 G 蛋白偶联受体 161 (GPR161) 基因中的杂合种系突变。GPR161 突变与声波刺猬成神经管细胞瘤 (MBSHH) 亚组完全相关，占我们队列中婴儿 MBSHH 病例的 5%。分子肿瘤分析显示，在所有受影响的 MBSHH 肿瘤中，GPR161 的杂合性丢失，体细胞拷贝数分布不典型，并且没有额外的体细胞驱动事件。对 226 个 MBSHH 肿瘤的分析显示，染色体 1q 杂合性的体细胞拷贝中性丢失是 GPR161 缺陷的标志特征，也是受影响的 MBSHH 肿瘤中 GPR161 双等位基因失活的主要机制。结论在此，我们描述了一种由生殖系 GPR161 突变引起并以婴儿 MBSHH 为特征的新型脑肿瘤易感综合征。需要更多的研究来确定与种系 GPR161 突变相关的潜在更广泛的肿瘤谱。