IDH-wildtype Diffuse Gliomas Research Articles

GENT-23. MOLECULAR PATHOLOGICAL ANALYSIS ON IDH-WILDTYPE ADULT LOW-GRADE GLIOMAS

More than 90% of adult diffuse low-grade glioma have the IDH1/2 mutation. Diffuse astrocytoma, IDH-mutants also often harbor TP53 and ATRX mutation and oligodendroglioma have 1p/19q co-deletion. In contrast, diffuse gliomas lacking IDH mutation are rare and their molecular pathological features are not well understood. Therefore, to reveal the clinical and molecular characteristics of IDH-wildtype adult low-grade glioma, we applied multi-omics analysis to these tumors. IDH-wildtype diffuse gliomas and corresponding normal peripheral blood cells were collected from five neurosurgical facilities. Initial pathological diagnoses were made by the neuropathologist at each hospital. A few of these tumors that were detected to have IDH mutation by exome sequencing were excluded and further analyses using Illumina Infinium 450K array and RNA-sequencing were performed on the remaining 18 cases. Among these 18 cases, consensus diagnoses made by senior neuro-pathologists suggested that three cases that had KRAS, BRAF or NF1 mutation were pilocytic astrocytomas, one case with H3F3AK27M mutation was glioblastoma, and three case that had mutations in genes related to the EGFR/PI3K/PTEN signaling pathway were high-grade gliomas. All the remaining 10 tumors were from adult patients older than 20-years of age. The numbers of non-synonymous mutations in these cases varied (median 9, 0-56). The clinical features of these patients also varied greatly; some patients demonstrated a favorable prognosis with Gr.II low-grade gliomas, while other patients died within two years as do most patients with Gr.IV glioblastomas. The methylome analysis showed that these tumors had a similar methylation profile to that of mesenchymal-type glioblastoma. RNA-sequence did not detect any oncogenic fusion gene. In conclusion, IDH-wildtype diffuse gliomas seem to be a heterogeneous tumor group and their clinical courses are difficult to predict. Further molecular stratification of these tumors with advanced analytical modalities is needed.

The Evolving Role of Molecular Markers in the Diagnosis and Management of Diffuse Glioma

While the classification of diffuse gliomas has relied on the examination of morphologic features supplemented with techniques such as immunohistochemistry, there is an increasing recognition of substantial biologic diversity within morphologically defined entities. High-throughput technologies, in particular studies that integrate genome-wide data from diverse molecular platforms, increasingly identify the existence of robust and distinct glioma subtypes. While treatment advances and improvement of outcomes for patients with diffuse glioma have been modest, there may be benefit to integrate findings from biologic studies into clinical practice to enhance the precision of treatment for these diseases. Recent examples such as the identification of mutations in IDH1 and IDH2 as an early genetic event that is predominantly in lower-grade gliomas (grades 2 and 3) underscore the importance of molecular discovery leading to the ability to develop subclassifications with prognostic and potentially therapeutic implications. In contrast, glioblastoma (grade 4), the most common and aggressive glioma, typically arises without IDH mutation, supporting the need for different therapeutic approaches. Additional genomic and epigenomic signatures are generally nonoverlapping between IDH-mutant and IDH wild-type diffuse glioma, and despite comparable histopathology, IDH-mutant gliomas can be considered as biologically distinct from IDH wild-type gliomas. In this CCR Focus article, we highlight and summarize the current understanding of recent molecular findings and the relationships of these findings to clinical trials and clinical management.