Journal Article

Clinical and mutational profiles of adult medulloblastoma groups

Chan, Danny Tat Ming, Liu, Anthony Pak-Yin, Mao, Ying, Chan, Aden Ka-Yin, Chen, Hong, Shi, Zhi-Feng, Liu, Xian-Zhi, Ng, Ho-Keung, Li, Kay Ka-Wai, Chung, Nellie Yuk-Fei, Poon, Manix Fung-Man, Wang, Wei-Wei, Wong, Gabriel Chun-Hei, Zhang, Zhen-Yu, Wong, Queenie Hoi-Wing, Huang, Queenie Junqi

2020

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Nature Publishing Group,BMC
• Subject: Adult medulloblastoma / Adults / Biomedical and Life Sciences / Biomedicine / Brain cancer / Cancer metastasis / Chemotherapy / Chromatin / Deoxyribonucleic acid / DNA / DNA sequencing / Ethics / Gene mutation / Genes / Genetic aspects / Genomes / KMT2C / Medulloblastoma / Metastasis / Molecular group / Mutation / MYC / Neurology / Neurosciences / Pathology / Pediatrics / Radiation therapy / Targeted sequencing / TP53 / Tumor proteins / Tumors