Abstract
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.
Highlights
Medulloblastoma is one of the most common malignant brain tumours in children [52]
In this study, we showed that molecular groups have no prognostic significance in adult medulloblastomas
When examining the mutational profiles of adult WNT medulloblastomas, we discovered a high frequency of TP53 mutations, compared to paediatric WNT
Summary
Medulloblastoma is one of the most common malignant brain tumours in children [52]. Medulloblastomas are classified into four major molecular groups (WNTactivated, SHH-activated, Group 3, and Group 4) with distinct clinical, genetic and transcriptomic profiles [23, 32, 39, 67]. WNT medulloblastoma patients have the best 5-year overall survival rate of over 90%, while Group 3 patients have the worst 5-year overall survival rate of merely 50% [30]. Clinical trials are investigating the reduction of irradiation dose to low-risk WNT patients (NCT01878617, NCT02724579, NCT02066220). Medulloblastomas account for less than 1% of central nervous system (CNS) tumours [52]. Due to their rarity, prospective trials on adult medulloblastomas are limited [40]. The management of adult medulloblastomas is adapted from paediatric protocols, often resulting in dose-limiting toxicities [12]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.