Mutational landscape and clonal architecture in grade II and III gliomas

Abstract

Grade II and III gliomas are generally slowly progressing brain cancers, many of which eventually transform into more aggressive tumors. Despite recent findings of frequent mutations in IDH1 and other genes, knowledge about their pathogenesis is still incomplete. Here, combining two large sets of high-throughput sequencing data, we delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes. Grade II and III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors. Mutations showed significant positive and negative correlations and a chronological hierarchy, as inferred from different allelic burdens among coexisting mutations, suggesting that there is functional interplay between the mutations that drive clonal selection. Extensive serial and multi-regional sampling analyses further supported this finding and also identified a high degree of temporal and spatial heterogeneity generated during tumor expansion and relapse, which is likely shaped by the complex but ordered processes of multiple clonal selection and evolutionary events.

Gliomatosis cerebri: no evidence for a separate brain tumor entity

“…In this GC cohort, 10 of 25 tumors were classified as glioblastoma WHO grade IV by histological analysis while DNA methylation profiling revealed IDH wildtype glioblastoma-associated DNA methylation signatures in 12/23 evaluable tumors. Thus, similar to data recently reported for diffuse and anaplastic astrocytic gliomas [3,16,20,23], 450k beadchip-based DNA methylation profiling may lead to a refined diagnosis of GC tumors. This appears to be both biologically and clinically meaningful, since methylation profiling but not focal histology allowed for the identification of a subgroup of GC with poor prognosis.…”

Diagnostic and Prognostic Value of11C-Methionine PET for Nonenhancing Gliomas

“…Many potentially confounding factors influence PFS, such as age, extent of removal, histopathologic subtype, and molecular prognostic biomarkers, as well as adjuvant therapy. Because it has become clear that grade II and grade III gliomas exhibit different clinical courses according to their molecular subtypes, 46,47 future studies should incorporate this information when conducting survival analysis on the basis of radiologic findings. Finally, prognostic values of imaging parameters should be analyzed not only with PFS but also with overall survival, which requires further future investigation.…”

Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma

“…Importantly, they have been shown to be clonal mutations in gliomas (11) and are likely to play a role in tumor initiation (12). Using clonal pTERT mutations as the defining characteristic of a GBM tumor cell, we established a convenient PCR-based assay to systematically study clinical and molecular consequences of varying tumor purity.…”