Atypical neurofibromas reveal distinct epigenetic features with proximity to benign peripheral nerve sheath tumor entities

周围神经鞘恶性肿瘤 表观遗传学 CDKN2A 病理 神经纤维瘤病 恶性转化 神经纤维瘤 生物 DNA甲基化 癌症研究 医学 内科学 癌症 基因 基因表达 生物化学
作者
Catena Kresbach,Matthias Dottermusch,Alicia Eckhardt,Inka Ristow,Petros Paplomatas,Lea Altendorf,Annika K. Wefers,Michael Bockmayr,Sarra Belakhoua,Ivy Tran,Lara Pohl,Sina Neyazi,Helena Bode,Said Farschtschi,Lennart Well,Reinhard E. Friedrich,David L. Reuss,Matija Snuderl,Christian Hagel,Victor‐Felix Mautner,Ulrich Schüller
出处
期刊:Neuro-oncology [Oxford University Press]
卷期号:25 (9): 1644-1655 被引量:11
标识
DOI:10.1093/neuonc/noad053
摘要

Abstract Background Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST. Methods We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors. Results Unsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions. Conclusions Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes.
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