Clinical and mutational profiles of adult medulloblastoma groups

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.

Clinical Neuropathological Conference: There’s a Child in All of Us

“…The SHH subtype can make up to 50% of all adult medulloblastoma as suggested in a recently published analysis. 4 However, in all reported medulloblastoma cases in the literature of patients above the age of 60, only four tumours were molecularly subtyped according to the 2016 WHO CNS tumour classification; all tumours were found to be type 4 (non WNT/non-SHH).…”

Adult Medulloblastoma: Updates on Current Management and Future Perspectives

“…MB molecularly defined in adults [ 11 , 24 , 46 , 47 ] shows a predominance of SHH-MB, typically TP53-wildtype [ 37 ], while SHH TP53-mutant MB cases seem to occur predominantly in children and adolescents. The frequency of WNT-MB is similar to that published for children (15% vs. 10%), and non-WNT/non-SHH-MB is relatively rare (2.6%) in adults compared to childhood MB (25%) [ 37 , 46 , 47 ]. The group of non-WNT/non-SHH-MBs in adults nearly consists of Group 4 tumors only [ 11 , 24 , 48 ].…”

“…TERT promoter mutations have been reported in most adult MBs, but only rarely in childhood MB [ 34 , 46 , 55 ].…”

Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes

“…Moreover, in the typical pediatric cancers including Wilms tumor [104][105][106], neuroblastoma [104,107,108] and pediatric hepatoblastoma [104,[109][110][111] somatic KMT2D variants only (very) infrequently occur. In contrast, in other cancers including, amongst others, pediatric-and adult diffuse large B-cell lymphoma (DLBCL) (20-35%) [11,15,112,113], adult follicular lymphoma (70-90%) [14,15], nodal marginal zone lymphoma (≈20-30%) [114][115][116], (non)small cell lung cancer/lung squamous cell carcinoma (≈20-30%) [11,65,117], upper tract urothelial carcinoma/bladder cancer (≈25-45%) [11,[118][119][120], esophageal (squamous cell) carcinoma (≈10-25%) [11,121,122] and pediatric-and adult medulloblastoma (overall ≈5-30%, large differences between individual molecular subgroups) [123][124][125] somatic KMT2D variants are (highly) recurrent but these cancers have not been reported in patients with KS (yet). However, with a lack of longitudinal studies it remains unclear whether KS patients reach the ages at which many of tumor types are most prevalent.…”