Sonic Hedgehog 髓母细胞瘤的胚系延长突变
- 作者列表："Waszak, Sebastian M.","Robinson, Giles W,","Gudenas, Brian L.","Smith, Kyle S.","Forget, Antoine","Kojic, Marija","Garcia-Lopez, Jesus","Hadley, Jennifer","Hamilton, Kayla V.","Indersie, Emilie","Buchhalter, Ivo","Kerssemakers, Jules","Jäger, Natalie","Sharma, Tanvi","Rausch, Tobias","Kool, Marcel","Sturm, Dominik","Jones, David T. W.","Vasilyeva, Aksana","Tatevossian, Ruth G.","Neale, Geoffrey","Lombard, Bérangère","Loew, Damarys","Nakitandwe, Joy","Rusch, Michael","Bowers, Daniel C.","Bendel, Anne","Partap, Sonia","Chintagumpala, Murali","Crawford, John","Gottardo, Nicholas G.","Smith, Amy","Dufour, Christelle","Rutkowski, Stefan","Eggen, Tone","Wesenberg, Finn","Kjaerheim, Kristina","Feychting, Maria","Lannering, Birgitta","Schüz, Joachim","Johansen, Christoffer","Andersen, Tina V.","Röösli, Martin","Kuehni, Claudia E.","Grotzer, Michael","Remke, Marc","Puget, Stéphanie","Pajtler, Kristian W.","Milde, Till","Witt, Olaf","Ryzhova, Marina","Korshunov, Andrey","Orr, Brent A.","Ellison, David W.","Brugiere
Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma. 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.
延长体复合体基因 ELP1 的生殖系突变使个体易患儿童髓母细胞瘤。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 ~ 10% ^ 1,2，与已知躯体驱动事件协同作用的遗传事件知之甚少。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生殖系变异 ^ 3。在此，通过分析所有蛋白编码基因，我们在 14% 的髓母细胞瘤亚群 Sonic Hedgehog (MB_SHH)_ 的儿科患者中鉴定并复制了 ELP1 中罕见的生殖系功能缺失变异。ELP1 是最常见的髓母细胞瘤倾向基因，在 MB_SHH 患儿中遗传倾向的患病率增加到 40%。亲子和系谱分析确定了两个有儿童髓母细胞瘤病史的家庭。ELP1 相关的髓母细胞瘤仅限于分子 shh α 亚型 ^ 4，其特征是由于染色体臂 9q 的体细胞缺失导致 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，这表明生殖系 ELP1 功能缺失变异体结合 SHH 信号的组成性激活使个体易于肿瘤发展。ELP1 是进化上保守的延长子复合物的最大亚基，通过摆动 (U_34) 位置 ^ 5,6 的 tRNA 修饰催化翻译延伸。ELP1 相关 MB_SHH 患者的肿瘤特征为不稳定的延长子复合物、延长子依赖性 tRNA 修饰的缺失、密码子依赖性翻译重编程和未折叠蛋白反应的诱导。与模型系统中由于伸长器缺陷导致的蛋白质稳态丧失一致 ^ 7-9。因此，蛋白质组不稳定性的遗传易感性可能是儿科脑癌发病机制的决定因素。这些结果支持研究蛋白质稳态在其他癌症类型中的作用和潜在的治疗干扰。
METHODS:PURPOSE:To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS:Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS:The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION:The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.
METHODS:BACKGROUND:Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population. METHODS:Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained. The patients' age, gender, ethnicity, Karnofsky Performance Scale (KPS) score, ability to perform activities of daily living (ADLs), tumor location and biomarkers status were recorded. Data were analyzed using chi-square and Mann-Whitney U tests, Kaplan-Meier estimates and log-rank test. RESULTS:181 patients were selected (56 with grade III gliomas, 125 with grade IV gliomas). In the grade III group, 55% had MGMT promoter methylation, 41% had 1p19q co-deletion, 35% had IDH1 mutation and none had ATRX loss. In the grade IV group, 30% had MGMT promoter methylation, 2% had 1p19q co-deletion, 15% had IDH1 mutation and 8% had ATRX loss. After adjusting for effects of age, surgery and pre-operative ADL statuses, only MGMT promoter methylation was found to be significantly associated with longer overall survival time in grade III (p = 0.024) and IV patients (p = 0.006). CONCLUSIONS:The incidences of MGMT promoter methylation and IDH1 mutation were found to be comparable to globally reported rates, but those of 1p19q co-deletion and ATRX loss seemed to be lower in our cohort. MGMT promoter methylation was associated with increased overall survival in our cohort and might serve as favorable prognostic factor.
METHODS:BACKGROUND:Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue. MAIN BODY:The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities. SHORT CONCLUSIONS:On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.