Subgroup and subtype-specific outcomes in adult medulloblastoma

Hallie Coltin, Lakshmikirupa Sundaresan, Kyle S. Smith, Patryk Skowron, Luca Massimi, Charles G. Eberhart, Karisa C. Schreck, Nalin Gupta, William A. Weiss, Daniela Tirapelli, Carlos Carlotti, Kay K.W. Li, Marina Ryzhova, Andrey Golanov, Olga Zheludkova, Oksana Absalyamova, Konstantin Okonechnikov, Damian Stichel, Andreas von Deimling, Caterina GianniniScott Raskin, Erwin G. Van Meir, Jennifer A. Chan, Daniel Fults, Lola B. Chambless, Seung Ki Kim, Alexandre Vasiljevic, Cecile Faure-Conter, Rajeev Vibhakar, Shin Jung, Sarah Leary, Jaume Mora, Roger E. McLendon, Ian F. Pollack, Peter Hauser, Wieslawa A. Grajkowska, Joshua B. Rubin, Marie Lise C. van Veelen, Pim J. French, Johan M. Kros, Linda M. Liau, Stefan M. Pfister, Marcel Kool, Noriyuki Kijima, Michael D. Taylor, Roger J. Packer, Paul A. Northcott, Andrey Korshunov, Vijay Ramaswamy*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)


Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0–86.5), 61.9% (51.6–74.2), 80.0% (95% CI 51.6–100.0), and 44.9% (95% CI 28.6–70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1–7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3–9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1–4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1–6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1–0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

Original languageEnglish
Pages (from-to)859-871
Number of pages13
JournalActa Neuropathologica
Issue number5
Early online date18 Aug 2021
Publication statusPublished - Nov 2021

Bibliographical note

HC was supported by a Garron Family Cancer Centre Research Fellowship. MDT is supported by operating funds from the National Institutes for Health (5R01CA159859-08 and R01NS106155-01) and the Pediatric Brain Tumor Foundation. V.R. and M.D.T. are supported by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team translational research grant (SU2C-AACR-DT1113). VR is supported by operating funds from the Canadian Institutes for Health Research, the Canadian Cancer Society Research Institute, the C.R. Younger Foundation, the Garron Family Cancer Centre, Meagan’s Walk, b.r.a.i.n.child and Nelina’s Hope. This study was partially funded with support provided by the Government of Ontario, Ministry of Research, Innovation and Science, and the Princess Margaret Cancer Foundation and support from the Princess Margaret Cancer Centre-OICR Translational Genomics Laboratory. EGVM is supported by operating funds from the National Institutes of Health (R01NS096236 and R01CA235162).

© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.


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