Genetically Classifying Adult Diffuse Lower-Grade Gliomas

Two large-scale analyses of genomics have characterized the details of the genetic alterations present in diffuse gliomas to help improve the diagnosis and treatment of this disease. Both studies are published in The New England Journal of Medicine. The results of both studies suggest that the genetics of these tumors likely play a larger role in clinical outcomes compared to histology.

“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 World Health Organization classification of nervous system tumors is being revised to include, for the first time, molecular information in the classification of disease,” wrote David Ellison, MD, PhD, of St. Jude Children's Research Hospital in Memphis, in an accompanying editorial.

The Cancer Genome Atlas (TCGA) group comprehensively analyzed 293 adult diffuse lower-grade gliomas including RNA and protein expression, and correlation with clinical outcomes. All samples analyzed came from patients with grade II and III tumors.¹

The pooled RNA, DNA copy number, and DNA methylation data identified three glioma subtypes. The most frequently mutated genes were all previously identified: IDH1, TP53, ATRX, CIC, FUBP1, NOTCH1, and the TERT promoter. The most frequently identified copy number variation was a deletion of chromosome 1p and 19q.

Just three aberrations-a mutation in IDH1 or IDH2 (the 1p/19q codeletion), and TP53 status were enough to classify a tumor into one of the three subtypes. One subtype lacked both an IDH1 mutation and the 1p/19q codeletion, and was found most frequently in older patients with grade III disease. The two other subtypes had IDH mutations and either a presence or absence of the 1p/19q co-deletion, and had more favorable clinical outcomes.

Almost all gliomas with an IDH1 mutation and lacking the 1p/19q codeletion also had a mutation in TP53. Most of the lower-grade gliomas that lacked an IDH mutation had genetic abnormalities and clinical behavior that was similar to primary glioblastoma. Wild-type IDH was associated with shorter median overall survival; 1.7 years compared to 8 years among those with an IDH mutation and 1p/19q codeletion. Median survival was 6.3 years among those with an IDH mutation and no 1p/19q codeletion.

Grade II gliomas are thought to progress to grade III through step-wise genetic changes, but it is unclear how to predict which grade II disease is most likely to progress nor is it easy to discern grade II from grade III disease.  Low-grade gliomas are the most common tumors of the central nervous system in young adults, and tend to begin as either diffuse or circumscribed tumors that invade healthy neural tissue.

The second study by Robert Jenkins, MD, PhD, of the Mayo Clinic in Rochester, Minn., and colleagues examined 1,087 tumors of grade II through IV. This study classified each tumor into one of five subgroups defined by three markers: IDH, TERT, and 1p/19q codeletion. The two subgroups with no IDH mutation or codeletion had copy number changes and gene mutations similar to those found in glioblastomas.²

Median overall survival among those with an IDH mutation and TERT promoter mutation, or those that were positive for all three markers was more than 10 years. Those patients who only had a TERT mutation had a median survival of just 1.3 years.

References:

• The Cancer Genome Atlas Research Network. (2015). Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. The New England Journal of Medicine.
• Eckel-Passow JE, Lachance DH, Molinaro AM, et al. (2015). Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. The New England Journal of Medicine.