Impact of the methylation classifier and ancillary methods on CNS tumor diagnostics. Issue 4 (23rd September 2021)

• Record Type: Journal Article
• Authors: Wu, Zhichao; Abdullaev, Zied; Pratt, Drew; Chung, Hye-Jung; Skarshaug, Shannon; Zgonc, Valerie; Perry, Candice; Pack, Svetlana; Saidkhodjaeva, Lola; Nagaraj, Sushma; Tyagi, Manoj; Gangalapudi, Vineela; Valdez, Kristin; Turakulov, Rust; Xi, Liqiang; Raffeld, Mark; Papanicolau-Sengos, Antonios; O'Donnell, Kayla; Newford, Michael; Gilbert, Mark R; Sahm, Felix; Suwala, Abigail K; von Deimling, Andreas; Mamatjan, Yasin; Karimi, Shirin; Nassiri, Farshad; Zadeh, Gelareh; Ruppin, Eytan; Quezado, Martha; Aldape, Kenneth
• Is Part Of: Neuro-oncology. Volume 24:Issue 4(2022)
• Page Start: 571
• Page End: 581
• Publication Date: 2021-09-23
• Subjects: brain tumor classification -- deconvolution -- DNA methylation profile -- neuropathology -- tumor purity; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab227
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: Accurate CNS tumor diagnosis can be challenging, and methylation profiling can serve as an adjunct to classify diagnostically difficult cases. Methods: An integrated diagnostic approach was employed for a consecutive series of 1258 surgical neuropathology samples obtained primarily in a consultation practice over 2-year period. DNA methylation profiling and classification using the DKFZ/Heidelberg CNS tumor classifier was performed, as well as unsupervised analyses of methylation data. Ancillary testing, where relevant, was performed. Results: Among the received cases in consultation, a high-confidence methylation classifier score (>0.84) was reached in 66.4% of cases. The classifier impacted the diagnosis in 46.7% of these high-confidence classifier score cases, including a substantially new diagnosis in 26.9% cases. Among the 289 cases received with only a descriptive diagnosis, methylation was able to resolve approximately half (144, 49.8%) with high-confidence scores. Additional methods were able to resolve diagnostic uncertainty in 41.6% of the low-score cases. Tumor purity was significantly associated with classifier score ( P = 1.15e−11). Deconvolution demonstrated that suspected glioblastomas (GBMs) matching as control/inflammatory brain tissue could be resolved into GBM methylation profiles, which provided a proof-of-concept approach to resolve tumor classification in the setting of low tumor purity. Conclusions: This work assesses the impact of a methylation classifier and additional methods in a consultative practice by defining the proportions with concordant vs change in diagnosis in a set of diagnostically challenging CNS tumors. We address approaches to low-confidence scores and confounding issues of low tumor purity.