小柯机器人

Sonic Hedgehog型髓母细胞瘤存在Elongator复合物生殖突变
2020-04-02 17:23

德国海德尔堡儿童癌症研究中心Stefan M. Pfister、美国圣朱迪儿童研究医院Paul A. Northcott、德国欧洲分子生物学实验室Jan O. Korbel等研究人员合作有了新发现。他们揭示了Sonic Hedgehog型髓母细胞瘤中Elongator复合物的生殖突变。这一研究成果于2020年4月1日在线发表在《自然》杂志上。

通过分析所有蛋白质编码基因,研究人员在14%的髓母细胞瘤亚型Sonic Hedgehog(MBSHH)儿童患者中鉴定并验证ELP1基因的罕见功能丧失生殖变异体。ELP1是最常见的髓母细胞瘤易感基因,在MBSHH的小儿患者中,遗传易感性的患病率增加到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,其特征是由于染色体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是进化上保守的Elongator复合物的最大亚基,它通过在摆动(U34)位置处的tRNA修饰催化翻译延伸。
 
ELP1相关MBSHH患者的肿瘤的特征是不稳定的Elongator复合物、Elongator依赖性tRNA修饰缺失、密码子依赖性翻译重编程以及未折叠蛋白应答的产生,这与模型系统中Elongator缺乏引起的蛋白质稳态丧失相一致。因此,蛋白质组不稳定的遗传易感性可能是小儿脑癌发病的决定性因素。这些结果表明,应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开展研究。
 
据了解,癌症基因组学已经揭示了许多促进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的5-10%,而与已知体细胞驱动程序事件协同作用的遗传事件则知之甚少。最近,已知癌症易感基因的致病生殖变异在5%的恶性脑肿瘤髓母细胞瘤患者中被发现。
 
附:英文原文

Title: Germline Elongator mutations in Sonic Hedgehog medulloblastoma

Author: SebastianM. Waszak, GilesW, Robinson, Brian L. Gudenas, Kyle S. Smith, Antoine Forget, Marija Kojic, Jesus Garcia-Lopez, Jennifer Hadley, Kayla V. Hamilton, Emilie Indersie, Ivo Buchhalter, Jules Kerssemakers, Natalie Jger, Tanvi Sharma, Tobias Rausch, Marcel Kool, Dominik Sturm, David T. W. Jones, Aksana Vasilyeva, Ruth G. Tatevossian, Geoffrey Neale, Brangre Lombard, Damarys Loew, Joy Nakitandwe, Michael Rusch, Daniel C. Bowers, Anne Bendel, Sonia Partap, Murali Chintagumpala, John Crawford, Nicholas G. Gottardo, Amy Smith, Christelle Dufour, Stefan Rutkowski, Tone Eggen, Finn Wesenberg, Kristina Kjaerheim, Maria Feychting, Birgitta Lannering, Joachim Schz, Christoffer Johansen, Tina V. Andersen, Martin Rsli, Claudia E. Kuehni, Michael Grotzer, Marc Remke, Stphanie Puget, Kristian W. Pajtler, Till Milde, Olaf Witt, Marina Ryzhova, Andrey Korshunov, Brent A. Orr, David W. Ellison, Laurence Brugieres, Peter Lichter, Kim E. Nichols, Amar Gajjar, Brandon J. Wainwright, Olivier Ayrault, Jan O. Korbel, Paul A. Northcott, Stefan M. Pfister

Issue&Volume: 2020-04-01

Abstract: 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 children1,2, 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 (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. 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) position5,6. Tumours from patients with ELP1-associated MBSHH 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 systems7,8,9. 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.

DOI: 10.1038/s41586-020-2164-5

Source: https://www.nature.com/articles/s41586-020-2164-5

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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