期刊
ACTA NEUROPATHOLOGICA
卷 136, 期 2, 页码 227-237出版社
SPRINGER
DOI: 10.1007/s00401-018-1888-x
关键词
Ependymoma; Posterior fossa; Subgrouping; PFB; PFA; Clustering
资金
- Canadian Institutes of Health Research
- American Brain Tumor Association
- Garron Family Cancer Center
- Meagan's Walk
- Brain Tumor Foundation of Canada
- Collaborative Ependymoma Research Network (CERN) basic science fellowship
- Stephen Buttrum Brain Tumor Research Fellowship - Brain Tumor Foundation of Canada
- Garron Family Cancer Center Fellowship
- Meagan's Walk Neuro-Oncology Fellowship
- Restracomp from Research Training Center at The Hospital for Sick Children
- Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children
- University of Toronto
- National Institutes of Health [R01CA159859, R01CA148699]
- Pediatric Brain Tumor Foundation
- NIH/NCI Cancer Center Support Grant [P30 CA008748]
- CERN Research Fellowship
- b.r.a.i.n.child
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据