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Clinical and mutational profiles of adult medulloblastoma groups
Acta Neuropathologica Communications ( IF 7.1 ) Pub Date : 2020-11-10 , DOI: 10.1186/s40478-020-01066-6
Gabriel Chun-Hei Wong 1 , Kay Ka-Wai Li 1 , Wei-Wei Wang 2 , Anthony Pak-Yin Liu 3 , Queenie Junqi Huang 1 , Aden Ka-Yin Chan 1 , Manix Fung-Man Poon 1 , Nellie Yuk-Fei Chung 1 , Queenie Hoi-Wing Wong 1 , Hong Chen 4 , Danny Tat Ming Chan 5 , Xian-Zhi Liu 6 , Ying Mao 7 , Zhen-Yu Zhang 6 , Zhi-Feng Shi 7 , Ho-Keung Ng 1
Affiliation  

Adult medulloblastomas are clinically and molecularly understudied due to their rarity. We performed molecular grouping, targeted sequencing, and TERT promoter Sanger sequencing on a cohort of 99 adult medulloblastomas. SHH made up 50% of the cohort, whereas Group 3 (13%) was present in comparable proportion to WNT (19%) and Group 4 (18%). In contrast to paediatric medulloblastomas, molecular groups had no prognostic impact in our adult cohort (p = 0.877). Most frequently mutated genes were TERT (including promoter mutations, mutated in 36% cases), chromatin modifiers KMT2D (31%) and KMT2C (30%), TCF4 (31%), PTCH1 (27%) and DDX3X (24%). Adult WNT patients showed enrichment of TP53 mutations (6/15 WNT cases), and 3/6 TP53-mutant WNT tumours were of large cell/anaplastic histology. Adult SHH medulloblastomas had frequent upstream pathway alterations (PTCH1 and SMO mutations) and few downstream alterations (SUFU mutations, MYCN amplifications). TERT promoter mutations were found in 72% of adult SHH patients, and were restricted to this group. Adult Group 3 tumours lacked hallmark MYC amplifications, but had recurrent mutations in KBTBD4 and NOTCH1. Adult Group 4 tumours harboured recurrent mutations in TCF4 and chromatin modifier genes. Overall, amplifications of MYC and MYCN were rare (3%). Since molecular groups were not prognostic, alternative prognostic markers are needed for adult medulloblastoma. KMT2C mutations were frequently found across molecular groups and were associated with poor survival (p = 0.002). Multivariate analysis identified histological type (p = 0.026), metastasis (p = 0.031) and KMT2C mutational status (p = 0.046) as independent prognosticators in our cohort. In summary, we identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their risk stratification and treatment.

中文翻译:

成人髓母细胞瘤组的临床和突变谱

由于其罕见,成人髓母细胞瘤在临床和分子上的研究不足。我们对 99 例成人髓母细胞瘤进行了分子分组、靶向测序和 TERT 启动子 Sanger 测序。SHH 占队列的 50%,而第 3 组(13%)与 WNT(19%)和第 4 组(18%)的比例相当。与小儿髓母细胞瘤相比,分子组对我们的成人队列没有预后影响(p = 0.877)。最常见的突变基因是 TERT(包括启动子突变,在 36% 的病例中发生突变)、染色质修饰因子 KMT2D(31%)和 KMT2C(30%)、TCF4(31%)、PTCH1(27%)和 DDX3X(24%)。成人 WNT 患者表现出 TP53 突变的富集(6/15 WNT 病例),3/6 TP53 突变的 WNT 肿瘤具有大细胞/间变性组织学。成人 SHH 髓母细胞瘤具有频繁的上游通路改变(PTCH1 和 SMO 突变)和很少的下游改变(SUFU 突变、MYCN 扩增)。在 72% 的成年 SHH 患者中发现了 TERT 启动子突变,并且仅限于这一组。成人第 3 组肿瘤缺乏标志性的 MYC 扩增,但在 KBTBD4 和 NOTCH1 中有反复突变。成人第 4 组肿瘤在 TCF4 和染色质修饰基因中具有复发性突变。总体而言,MYC 和 MYCN 的扩增很少见 (3%)。由于分子组不具有预后意义,因此成人髓母细胞瘤需要替代的预后标志物。KMT2C 突变经常在分子组中发现,并且与较差的存活率相关(p = 0.002)。多变量分析确定了组织学类型 (p = 0.026)、转移 (p = 0. 031) 和 KMT2C 突变状态 (p = 0.046) 作为我们队列中的独立预后因素。总之,我们确定了成人髓母细胞瘤的不同临床和突变特征,这些特征将为它们的风险分层和治疗提供信息。
更新日期:2020-11-12
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