Individual Assignment of Adult Diffuse Gliomas into the EM/PM Molecular Subtypes Using a TaqMan Low-Density Array [Human Clariom D array]

Diagnosis of glioma into the hierarchy of human brain development would greatly facilitate mechanistic studies and clinical services in combating glioma. By analysing the multi-dimension big data of glioma genome and clinical manifestations, we have recently developed an EM/PM classification scheme anchored in the brain development and glioma pathogenesis (Sun et al., PNAS 111:3538-3543, 2014). To translate the EM/PM classification into a clinical diagnostic tool, we here designed and validated a TaqMan low-density RT-PCR array (TLDA) and a support vector machine (SVM) based prediction model that enables individual diagnosis of gliomas into the EM/PM subtype with high accuracy and precision. Results of 153 individually diagnosed adult diffuse gliomas of WHO grades II-IV derived from Chinese or Swedish patients confirmed our previous data base investigations: EM and PM gliomas show distinct prognosis, occur at different ages, and harbor mutually exclusive patterns of genomic alterations detected by Sanger sequencing and shallow-coverage whole genome sequencing (WGS). Further, we show that shallow-coverage WGS enabled a systematic identification of clonal and subclonal copy number variations (CNV) in glioma genomes, and the extent and the pattern of CNV can serve as an objective marker of tumor progression in the PM gliomas harboring IDH mutations. A validation cohort that contains 31 glioma samples and 9 non-tumor brain tissues were analyzed by Human Clariom D array. Then, we assigned them into EM/PM subtypes according to the gene chip data, and compared the result with the EM/PM classification label derived from TLDA data.