| Literature DB >> 30019219 |
Florence M G Cavalli1, Jens-Martin Hübner2,3,4, Tanvi Sharma2,3,4, Betty Luu1, Martin Sill3, Michal Zapotocky5, Stephen C Mack6, Hendrik Witt2,3,7, Tong Lin8, David J H Shih9, Ben Ho5, Mariarita Santi10, Lyndsey Emery11, Juliette Hukin12, Christopher Dunham13, Roger E McLendon14, Eric S Lipp14, Sridharan Gururangan15, Andrew Grossbach16, Pim French17, Johan M Kros17, Marie-Lise C van Veelen17, Amulya A Nageswara Rao18, Caterina Giannini19, Sarah Leary20, Shin Jung21, Claudia C Faria22, Jaume Mora23, Ulrich Schüller24, Marta M Alonso25, Jennifer A Chan26, Almos Klekner27, Lola B Chambless28, Eugene I Hwang29, Maura Massimino30, Charles G Eberhart31, Matthias A Karajannis32, Benjamin Lu33, Linda M Liau34, Massimo Zollo35, Veronica Ferrucci35, Carlos Carlotti36, Daniela P C Tirapelli36, Uri Tabori5, Eric Bouffet5, Marina Ryzhova37, David W Ellison38, Thomas E Merchant39, Mark R Gilbert40, Terri S Armstrong40, Andrey Korshunov41, Stefan M Pfister2,3,7, Michael D Taylor1,42, Kenneth Aldape43, Kristian W Pajtler2,3,7, Marcel Kool44,45, Vijay Ramaswamy46,47.
Abstract
Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.Entities:
Keywords: Clustering; Ependymoma; PFA; PFB; Posterior fossa; Subgrouping
Mesh：
Year: 2018 PMID： 30019219 PMCID： PMC6373486 DOI： 10.1007/s00401-018-1888-x
Source DB: PubMed Journal: Acta Neuropathol ISSN： 0001-6322 Impact factor: 17.088