1. Subgroup and subtype‑specifc outcomes in adult medulloblastoma
- Author
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Konstantin Okonechnikov, Charles G. Eberhart, Roger E. McLendon, Ian F. Pollack, Stefan M. Pfister, Kyle S. Smith, Shin Jung, Noriyuki Kijima, Alexandre Vasiljevic, Karisa C. Schreck, Oksana Absalyamova, Paul A. Northcott, Daniela Pretti da Cunha Tirapelli, Rajeev Vibhakar, Sarah Leary, Olga Zheludkova, Kay K.W. Li, Lakshmikirupa Sundaresan, Seung-Ki Kim, Hallie Coltin, Jaume Mora, Erwin G. Van Meir, Wiesława Grajkowska, Marcel Kool, Daniel W. Fults, Pim J. French, Caterina Giannini, Andreas von Deimling, Jennifer A. Chan, Andrey Golanov, Linda M. Liau, Scott Raskin, Michael D. Taylor, Joshua B. Rubin, Cécile Faure-Conter, Roger J. Packer, Luca Massimi, William A. Weiss, Peter Hauser, Andrey Korshunov, Lola B. Chambless, Patryk Skowron, Carlos Gilberto Carlotti, Vijay Ramaswamy, Marie Lise C. van Veelen, Marina Ryzhova, Damian Stichel, Nalin Gupta, Johan M. Kros, Coltin H., Sundaresan L., Smith K.S., Skowron P., Massimi L., Eberhart C.G., Schreck K.C., Gupta N., Weiss W.A., Tirapelli D., Carlotti C., Li K.K.W., Ryzhova M., Golanov A., Zheludkova O., Absalyamova O., Okonechnikov K., Stichel D., von Deimling A., Giannini C., Raskin S., Van Meir E.G., Chan J.A., Fults D., Chambless L.B., Kim S.-K., Vasiljevic A., Faure-Conter C., Vibhakar R., Jung S., Leary S., Mora J., McLendon R.E., Pollack I.F., Hauser P., Grajkowska W.A., Rubin J.B., van Veelen M.-L.C., French P.J., Kros J.M., Liau L.M., Pfister S.M., Kool M., Kijima N., Taylor M.D., Packer R.J., Northcott P.A., Korshunov A., Ramaswamy V., Neurosurgery, Neurology, and Pathology
- Subjects
Male ,Oncology ,Adult ,medicine.medical_specialty ,Adult Medulloblastoma ,Adolescent ,medicine.medical_treatment ,DNA methylation profiling ,Pathology and Forensic Medicine ,Cohort Studies ,Young Adult ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Risk Factors ,GLI2 ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Medulloblastoma ,Sonic hedgehog ,Cerebellar Neoplasms ,Risk stratification ,Chemotherapy ,biology ,business.industry ,Molecular groups ,medicine.disease ,Molecular group ,NEOPLASIAS CEREBRAIS ,Progression-Free Survival ,3. Good health ,Radiation therapy ,PTCH1 ,030220 oncology & carcinogenesis ,Cohort ,biology.protein ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2021