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Germline Elongator mutations in Sonic Hedgehog medulloblastoma

机译：声波刺猬髓母细胞瘤的生殖系延伸子突变

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摘要

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 medulloblastoma~(3). 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 subtype~(4)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 (U_(34)) 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~(7-9). 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.
机译：癌症基因组学已经揭示了许多导致人类恶性肿瘤的基因和核心分子过程，但是许多罕见癌症的遗传和分子基础仍然不清楚。遗传易感性占儿童癌症诊断的5-10％〜（1,2），与已知的体细胞驱动程序事件协同作用的遗传事件知之甚少。最近已经在5％的恶性脑肿瘤髓母细胞瘤患者中发现了已建立的癌症易感基因中的致病种系变异（3）。在这里，通过分析所有蛋白质编码基因，我们在髓母细胞瘤亚群Sonic Hedgehog（MB_（SHH））_（。）ELP1最多的小儿患者中，在14％的儿科患者中跨ELP1鉴定并复制了罕见的种系功能丧失变异。常见的髓母细胞瘤易感基因，并将小儿MB_（SHH）患者的遗传易感性增加到40％。父母-后代和家系分析确定了两个有小儿髓母细胞瘤历史的家族。与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，导致ELP1的普遍双等位基因失活。大多数与ELP1相关的髓母细胞瘤在PTCH1中也表现出体细胞改变，这表明种系ELP1功能丧失型变体与SHH信号的组成性激活相结合，使个体易于发生肿瘤。 ELP1是进化保守的Elongator复合物中最大的亚基，它通过在（U_（34））位置〜（5,6）处的tRNA修饰催化翻译延伸。与ELP1相关的MB_（SHH）患者的肿瘤的特征是不稳定的Elongator复合物，Elongator依赖的tRNA修饰缺失，密码子依赖的翻译重编程和未折叠的蛋白应答诱导，与Elongator导致的蛋白质稳态失衡相一致模型系统的不足〜（7-9）。因此，蛋白质组不稳定的遗传易感性可能是小儿脑癌发病机理的决定性因素。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的潜力的研究。

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    《Nature》 |2020年第7803期|396-401|共6页
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    European Molecular Biology Laboratory (EMBL) Genome Biology Unit;

    Department of Oncology Division of Neuro-Oncology St Jude Children's Research Hospital;

    Department of Developmental Neurobiology St Jude Children's Research Hospital;

    Université Paris Sud Université Paris-Saclay;

    Institute for Molecular Bioscience University of Queensland;

    Department of Oncology Division of Cancer Predisposition St Jude Children's Research Hospital;

    Omics IT and Data Management Core Facility (W610) German Cancer Research Center (DKFZ);

    Hopp Children's Cancer Center Heidelberg (KiTZ)|Division of Pediatric Neurooncology German Consortium for Translational Cancer Research (DKTK) German Cancer Research Center (DKFZ);

    Hopp Children's Cancer Center Heidelberg (KiTZ)|Division of Pediatric Neurooncology German Consortium for Translational Cancer Research (DKTK) German Cancer Research Center (DKFZ)|Princess Máxima Center for Pediatric Oncology;

    Hopp Children's Cancer Center Heidelberg (KiTZ)|Pediatric Glioma Research Group German Cancer Research Center (DKFZ);

    Cancer Center Administration St Jude Children's Research Hospital;

    Department of Pathology St Jude Children's Research Hospital;

    Hartwell Center St Jude Children's Research Hospital;

    Institut Curie PSL Research University Centre de Recherche Laboratoire de Spectrométrie de Masse Protéomique;

    Department of Computational Biology St Jude Children's Research Hospital;

    Division of Pediatric Hematology-Oncology University of Texas Southwestern Medical School;

    Department of Pediatric Hematology and Oncology Children's Hospitals and Clinics of Minnesota Minnesota;

    Department of Neurology and Neurological Sciences Stanford University;

    Texas Children's Cancer Center Baylor College of Medicine;

    Department of Neurosciences University of California San Diego and Rady Children's Hospital|Department of Pediatrics University of California San Diego and Rady Children's Hospital;

    Department of Paediatric and Adolescent Oncology/Haematology Perth Children's Hospital and Brain Tumour Research Programme Telethon Kids Institute;

    Arnold Palmer Hospital Center for Children's Cancer;

    Gustave Roussy Université Paris-Saclay Department of Pediatric and Adolescent Oncology;

    Department of Pediatric Hematology and Oncology University Medical Center Hamburg-Eppendorf;

    The Cancer Registry of Norway Majorstuen;

    Department of Research Cancer Registry of Norway Institute of Population-Based Cancer Research;

    Institute of Environmental Medicine Karolinska Institutet;

    Department of Pediatrics University of Gothenburg The Queen Silvia Children's Hospital;

    Section of Environment and Radiation International Agency for Research on Cancer (IARC);

    Oncology Clinic Finsen Centre Rigshospitalet University of Copenhagen|Danish Cancer Society Research Center Danish Cancer Society;

    Department of Epidemiology and Public Health Swiss Tropical and Public Health Institute University of Basel;

    Swiss Childhood Cancer Registry Institute of Social and Preventive Medicine University of Bern;

    Swiss Childhood Cancer Registry Institute of Social and Preventive Medicine University of Bern|Department of Paediatric Haematology and Oncology University Children's Hospital;

    University Children's Hospital of Zurich;

    Department of Pediatric Oncology Hematology and Clinical Immunology Medical Faculty University Hospital Düsseldorf;

    Department of Pediatric Neurosurgery Necker Hospital Université de Paris;

    Hopp Children's Cancer Center Heidelberg (KiTZ)|Division of Pediatric Neurooncology German Consortium for Translational Cancer Research (DKTK) German Cancer Research Center (DKFZ)|Department of Pediatric Hematology and Oncology Heidelberg University Hospital;

    Hopp Children's Cancer Center Heidelberg (KiTZ)|Department of Pediatric Hematology and Oncology Heidelberg University Hospital|Clinical Cooperation Unit Pediatric Oncology German Cancer Research Center (DKFZ);

    Department of Neuropathology Burdenko Neurosurgical Institute;

    Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ)|Department of Neuropathology University Hospital;

    Division of Molecular Genetics German Consortium for Translational Cancer Research (DKTK) German Cancer Research Center Heidelberg (DKFZ);

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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