Sonic Hedgehog型髓母細胞瘤存在Elongator複合物生殖突變
作者：
小柯機器人發布時間：2020/4/5 17:23:33
德國海德爾堡兒童癌症研究中心Stefan M. Pfister、美國聖朱迪兒童研究醫院Paul A. Northcott、德國歐洲分子生物學實驗室Jan O. Korbel等研究人員合作有了新發現。他們揭示了Sonic Hedgehog型髓母細胞瘤中Elongator複合物的生殖突變。這一研究成果於2020年4月1日在線發表在《自然》雜誌上。
通過分析所有蛋白質編碼基因，研究人員在14%的髓母細胞瘤亞型Sonic Hedgehog（MBSHH）兒童患者中鑑定並驗證ELP1基因的罕見功能喪失生殖變異體。ELP1是最常見的髓母細胞瘤易感基因，在MBSHH的小兒患者中，遺傳易感性的患病率增加到40％。父母-後代和家系分析確定了兩個有小兒髓母細胞瘤歷史的家族。
與ELP1相關的髓母細胞瘤僅限於分子SHHα亞型，其特徵是由於染色體9q的體細胞丟失，導致ELP1的普遍雙等位基因失活。大多數與ELP1相關的髓母細胞瘤在PTCH1中也表現出體細胞改變，這表明種系ELP1功能喪失型變體與SHH信號的組成性激活相結合，使個體易於發生腫瘤。 ELP1是進化上保守的Elongator複合物的最大亞基，它通過在擺動（U34）位置處的tRNA修飾催化翻譯延伸。
ELP1相關MBSHH患者的腫瘤的特徵是不穩定的Elongator複合物、Elongator依賴性tRNA修飾缺失、密碼子依賴性翻譯重編程以及未摺疊蛋白應答的產生，這與模型系統中Elongator缺乏引起的蛋白質穩態喪失相一致。因此，蛋白質組不穩定的遺傳易感性可能是小兒腦癌發病的決定性因素。這些結果表明，應對蛋白質穩態在其他癌症類型中的作用以及治療幹擾的潛力開展研究。
據了解，癌症基因組學已經揭示了許多促進人類惡性腫瘤的基因和核心分子過程，但是許多罕見癌症的遺傳和分子基礎仍然不清楚。遺傳易感性佔兒童癌症的5-10％，而與已知體細胞驅動程序事件協同作用的遺傳事件則知之甚少。最近，已知癌症易感基因的致病生殖變異在5％的惡性腦腫瘤髓母細胞瘤患者中被發現。
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