J Korean Med Sci.  2023 Nov;38(43):e356. 10.3346/jkms.2023.38.e356.

Brain Tumor Classification by Methylation Profile

• Park JW
• Lee K
• Kim EE
• Kim SI
• Park SH

• KMID: 2547966
• DOI: http://doi.org/10.3346/jkms.2023.38.e356

Abstract

The goal of the methylation classifier in brain tumor classification is to accurately classify tumors based on their methylation profiles. Accurate brain tumor diagnosis is the first step for healthcare professionals to predict tumor prognosis and establish personalized treatment plans for patients. The methylation classifier can be used to perform classification on tumor samples with diagnostic difficulties due to ambiguous histology or mismatch between histopathology and molecular signatures, i.e., not otherwise specified (NOS) cases or not elsewhere classified (NEC) cases, aiding in pathological decision-making. Here, the authors elucidate upon the application of a methylation classifier as a tool to mitigate the inherent complexities associated with the pathological evaluation of brain tumors, even when pathologists are experts in histopathological diagnosis and have access to enough molecular genetic information. Also, it should be emphasized that methylome cannot classify all types of brain tumors, and it often produces erroneous matches even with high matching scores, so, excessive trust is prohibited. The primary issue is the considerable difficulty in obtaining reference data regarding the methylation profile of each type of brain tumor. This challenge is further amplified when dealing with recently identified novel types or subtypes of brain tumors, as such data are not readily accessible through open databases or authors of publications. An additional obstacle arises from the fact that methylation classifiers are primarily research-based, leading to the unavailability of charging patients. It is important to note that the application of methylation classifiers may require specialized laboratory techniques and expertise in DNA methylation analysis.

Keyword

Brain Tumor; Classifications; Methylation; Bioinformatics

Figure

• 

  Fig. 1 t-SNE clustering was applied to the CNS tumor methylation data obtained from the SNUH, along with reference methylation data from the German Cancer Research Center (DKFZ). The reference data used in this study was publicly available and obtained from the GSE90496 dataset. (A) Figure illustrates the t-SNE visualization of the methylation classes of various SNUH tumors, represented by different colors, in comparison to the DKFZ reference methylation classes of brain tumors, also represented by different colors. (B) Figure depicts the visualization of the SNUH data represented by the brown color, overlaid on the reference data from DKFZ, which are represented by the gray color. (C-E) Figures exhibit the t-SNE visualization of the methylation classes of specific tumor types, namely EPN, MB, and AT/RT, respectively.t-SNE = t-distributed stochastic neighbor embedding, CNS = central nervous system, SNUH = Seoul National University Hospital, DKFZ = Deutsches Krebsforschungszentrum, MB = medulloblastoma, AT/RT = atypical teratoid/rhabdoid tumor, EPN = ependymoma, PFA/PFB = posterior fossa group A/B, SPNE = spinal ependymoma, MPE = myxopapillary ependymoma, TYR = tyrosinase-activated, MYC = MYC-activated, WNT = WNT-activated, SHH = Sonic hedgehog-activated, G3 = group 3, G4 = group 4, SHH INF = infantile sonic hedgehog-activated medulloblastoma.

• 

  Fig. 2 Examples of copy number aberration plots of four subtype of medulloblastoma generated from methylation 850K Epic microarray data. The first two plots are derived from the WNT-subtype, the next two plots are from SHH-activated group, followed by two plots from group 3, and the last two plots represent group 4 medulloblastoma.SNUH = Seoul National University Hospital, SHH = Sonic hedgehog.

• 

  Fig. 3 Examples of MGMT promoter (MGMTp) methylated status predicted by DKFZ classifier with Illumina Epic850K methylation microarray data. The cutoff of methylated and unmethylated status is the red line (score = 0.3582). The results of MGMTp status, determined through methylation-specific polymerase chain reaction, align perfectly with the findings mentioned above. (A, B) glioblastomas, (C, D) oligodendrogliomas.DKFZ = Deutsches Krebsforschungszentrum, SNUH = Seoul National University Hospital, IDH = isocitrate dehydrogenase.

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