The presence or absence of three mutations describes glioma clinical behavior better than traditional pathology

profound effect of tumor genetics on grade II glioma prognosis

Brain tumor oncologists and researchers have long defined gliomas by their physical appearance under a microscope. Along with location and size, standard pathological definitions include glioma grade (low grade - II, III, and high grade, or glioblastoma IV) and morphology (astrocytoma, oligodendroglioma, and mixed). These morphological characteristics play a large role in guiding treatment decisions: generally lower grade tumors are treated less aggressively. Recent advances in glioma diagnosis, based on tumor mutations, should result in some changes to clinical management as described below.

Recurrent genetic mutations have long been understood to drive tumorigenesis in gliomas, with historical work focusing on common mutations such as TP53 mutation, EGFR mutation and amplification, and CDKN2A deletion. These mutations were associated with clinical characteristics but did not describe tumor behavior better than pathological considerations. What has now changed is that three simple to define genetic mutations, described more recently, neatly define the clinical behavior of gliomas better than traditional pathological considerations. The first of these to be described was 1p19q co-deletions, discovered in the early 1990s by Bob Jenkins and colleagues and denoting a favorable feature with regards to survival. Second, mutations in the Krebs cycle gene IDH was discovered in 2007 by Bert Vogelstein and colleagues, using a whole genome sequencing strategy. This mutation was a serendipitous find and leads to an epigenetic defect and is also a favorable tumor feature for survival. The third mutation, in the promoter of the TERT gene, was found by Hai Yan and colleagues in 2013 who surveyed 20 different tumor types for this feature. TERT mutations by themselves denote a poor prognostic feature. Bob Jenkins at Mayo Clinic and Margaret Wrensch at UCSF with their colleagues now report remarkable clinical features by five categories of tumors based on these features, called “triple positive,” TERT and IDH mutated,” IDH mutation only,” “TERT mutation only,” and “triple negative.” Among grade III tumors, these mutations have a profound effect on survival (see Figure 1) and should be incorporated into clinical practice in the near term. Among grade IV tumors the effect is still significant though not as profound. Notably, TERT mutation only tumors, whether low grade or high, have very poor prognosis. Aggressive treatments may be indicated for this subtype, regardless of grade.

Interestingly, there are clear differences in age at onset of tumors as defined by these genetic subtypes (click on the figure below). The etiologic pathways for each subtype will likely be different, and epidemiologists can use these genetic classifications to help link genetic and environmental causes to specific glioma groups. Already, specific inborn polymorphisms are clearly linked to these subtypes: see the manuscript for details. Along with the Jenkins article (Eckel-Passow et al., DOI: 10.1056/NEJMoa1407279), a separate article was reported in the same issue in New England journal by The Cancer Genome Atlas group; see NEJM (DOI: 10.1056/NEJMoa1402121).