髓母细胞瘤(MB)是最常见的恶性脑肿瘤,发生在儿童时期,在成人中很少见。根据转录组概况,MB目前分为四个主要分子组,反映了相当大的生物异质性:WNT激活,SHH激活,第3组和第4组。最近,DNA甲基化分析允许鉴定与不同临床病理和分子特征相关的四个主要分子组中的其他亚组。异柠檬酸脱氢酶-1和2(IDH1和IDH2)突变已在几种肿瘤中得到描述。包括神经胶质瘤,而在MB中很少报告,也没有常规调查。通过磁共振波谱(MRS),我们明确评估了体内代谢物D-2-羟基戊二酸(2HG)的存在,IDH1和IDH2突变的标记,在成人MB的情况下。免疫表型检查和甲基化分析分配了MB的诊断,SHH-A子类,和分子测试表明存在非规范体细胞IDH1(p。R132C)突变和额外的GNAS突变,也很少用MB描述。据我们所知,这是报道的首例同时携带两种突变的MB病例.值得注意的是,肿瘤表现出异质性表型,肿瘤成分表现出神经胶质分化,具有强大的GFAP表达式,以及具有常规MB特征和选择性存在GNAS突变的组件,表明两个不同的主要肿瘤亚克隆共存。这些发现提请注意需要对MB进行更深入的遗传表征,为了深入了解他们的生物学,改善患者的分层和临床管理。此外,我们的结果强调了在非神经胶质肿瘤中进行MRS对于识别IDH突变的重要性.使用通量分子谱分析和先进的医学成像肯定会增加具有罕见分子改变的肿瘤实体被识别的频率。这些发现是否具有任何特定的治疗意义或预后相关性需要进一步研究。
Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adults. Based on transcriptome profile, MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate dehydrogenase-1 and 2 (IDH1 and IDH2) mutations have been described in several tumors, including gliomas, while in MB are rarely reported and not routinely investigated. By means of magnetic resonance spectroscopy (MRS), we unequivocally assessed the presence the oncometabolite D-2-hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutations, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also rarely described in MB. To the best of our knowledge, this is the first reported case of MB simultaneously harboring both mutations. Of note, tumor exhibited a heterogeneous phenotype with a tumor component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting co-existence of two different major tumor subclones. These findings drew attention to the need for a deeper genetic characterization of MB, in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, our results underlined the importance of performing MRS for the identification of IDH mutations in non-glial tumors. The use of throughput molecular profiling analysis and advanced medical imaging will certainly increase the frequency with which tumor entities with rare molecular alterations will be identified. Whether these findings have any specific therapeutic implications or prognostic relevance requires further investigations.