This article is more than 5 years old. Information may no longer be current.
Promoter mutations redefine molecular subgroups of gliomas
Click Here to Manage Email Alerts
Gliomas can be classified into five distinct categories based on the presence of IDH, 1p/19q codeletion and TERT promoter mutations, according to study results.
These categories correlated with different variables — such as age at onset, OS and associations with germline variants — and may be characterized by distinct mechanisms of pathogenesis, results showed.
It is challenging to predict the clinical behavior, response to therapy and outcomes of infiltrative gliomas, according to study background.
Daniel H. Lachance, MD, associate professor of neurology at the Mayo Clinic in Rochester, Minnesota, and colleagues sought to define five glioma molecular subgroups based on previous tumor biology studies, such as the research from The Cancer Genome Atlas Research Network that was co-published with this research in The New England Journal of Medicine (The Cancer Genome Atlas Research Network. 2015;doi:10.1056/NEJMoa1402121.).
Researchers defined the molecular subgroups according to the presence of TERT promoter mutations, IDH mutations and codeletion of chromosome arms 1p and 19q and evaluated 1,087 patients with grade II, III and IV gliomas for these molecular markers. Researchers excluded patients with grade I gliomas because they are clinically and pathologically distinct.
The analysis also included data from 11,590 controls.
Among 615 patients with grade II or III gliomas, 29% exhibited all three genetic alterations. Five percent harbored TERT and IDH mutations, whereas 45% only harbored IDH mutations and 10% harbored only TERT mutations. Seven percent of patients had triple-negative gliomas and 5% exhibited different combinations.
Among 472 patients with grade IV gliomas, 74% harbored only TERT mutations, 7% harbored only IDH mutations and 2% harbored IDH and TERT mutations. Seventeen percent of patients with grade IV gliomas did not harbor any of the alterations, whereas less than 1% possessed all three.
The researchers observed different characteristics related to mutation categories. Patients with only IDH mutations had the lowest age at diagnosis (mean age, 37 years), whereas patients with only TERT mutations had the highest age at diagnosis (mean age, 59 years). Although patients in both groups tended to have grade IV gliomas, patients with only TERT mutations tended to be significantly younger than patients with triple-negative gliomas (P < .001).
Further, patients with only IDH mutations tended to be significantly younger than patients with triple-positive gliomas, gliomas with TERT and IDH mutations and triple-negative gliomas (P < .001).
In a multivariate analysis, researchers observed that age at diagnosis (HR = 1.03; 95% CI, 1.02-1.05), grade (grade III, HR = 1.49; 95% CI, 1.03-2.15) and molecular group independently correlated with OS in patients with grade II or II gliomas. Patients with only TERT mutations had poorer OS compared with patients with triple-negative gliomas, gliomas with TERT and IDH mutations, gliomas with IDH mutations only and triple-positive gliomas. Further, patients with triple-negative gliomas had poor OS than patients with triple-positive gliomas and patients with TERT and IDH mutations.
Molecular grade was associated with OS in patients with grade IV gliomas in a univariate analysis; however, researchers did not observe a similar association in a multivariate analysis.
The researchers then evaluated associations between the five glioma groups and germline variants associated with glioma risk. The CCDC26 single-nucleotide polymorphism correlated with an increased risk for any gliomas with IDH mutation, and PHLDB1 was associated with gliomas with IDH mutations only.
TERC, TERT and RTEL1 genes demonstrated a protective effect against gliomas with only TERT mutations. The TP53 gene increased the risk for gliomas with TERT and IDH mutations.
“Our findings are going to weigh heavily on the future classification of brain tumors,” Lachance said in a press release. “The time of classifying these tumors solely according to histology as astrocytoma, oligodendroglioma or mixed oligodendroglioma could be a thing of the past. This molecular data helps us better classify glioma patients, so we can begin to understand who needs to be treated more aggressively and who might be able to avoid unnecessary therapies.”
The study findings may determine new treatments for the wide variety of gliomas, David W. Ellison, MD, PhD, chair of pathology at St. Jude Children’s Research Hospital, wrote in an accompanying editorial.
“Although recurrent genetic alterations have previously been identified among these diffuse gliomas, how best to use such information alongside clinical and pathologic variables to optimize a patient’s therapy has been contentious,” Ellison wrote. “These new data sets have the potential to inform how we define and treat the range of adult diffuse gliomas at a time when the current edition of the WHO classification of nervous-system tumors is being revised to include, for the first time, molecular information in the classification of disease.” – by Cameron Kelsall
Disclosure: Lachance reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Click Here to Manage Email Alerts