Molecular classifications of low-grade gliomas proposed

By Shreeya Nanda, Senior medwireNews Reporter

Two research teams have independently proposed molecular classification systems for grade II and III glioma based on three tumour markers, with each category displaying distinct clinical features and outcomes.

According to the articles published in The New England Journal of Medicine, both groups used mutations in the IDH1 or IDH2 genes (collectively referred to as IDH) and the codeletion of chromosome arms 1p and 19q (1p/9q codeletion) as the basis of their proposed classification system.

But researcher Robert Jenkins (Mayo Clinic, Rochester, Minnesota, USA) and colleagues additionally used mutations in the promoter of the telomerase-encoding TERT gene to establish five main groups, while Daniel Brat (Emory University Hospital, Atlanta, Georgia, USA) and members of the Cancer Genome Atlas Research Network identified three subtypes.

Jenkins et al were able to assign the majority of the 1087 grade II, III or IV cases to one of five groups – triple-positive (harbouring all three alterations), TERT- and IDH-mutations, only IDH-mutations, only TERT mutations and triple-negative – with just 2.6% of cases not fitting into one of these groups.

The groups differed significantly with respect to age at diagnosis, which ranged from 37 years for patients with only IDH mutations to 59 years in those with only TERT mutations.

And among the 615 patients with infiltrative glioma of grade II or III, molecular group was independently prognostic of outcome after adjusting for age at diagnosis and grade. Patients who had only TERT mutations had the least favourable overall survival of the five groups, followed by those in the triple-negative group.

By contrast, molecular group was not associated with overall survival for the 472 grade IV glioma patients.

The authors caution that “[a]lthough the data on overall survival were robust with respect to sample size and showed consistency among data sets, they must be considered preliminary.”

Speaking to medwireNews, Robert Jenkins said that the next step is to make patients and their physicians aware of these findings.

“The data strongly suggest that many gliomas should be tested for these alterations – to help determine how the patient might be treated”, he said, adding that although targeting the 1p/19q codeletion and telomerase dysfunction is “more challenging”, the development of agents targeting the IDH mutations is underway.

Brat et al used a genome-wide approach incorporating data from multiple platforms, including DNA copy number profiling and exome, messenger RNA and microRNA sequencing, to categorise 293 patients with grade II or III glioma into three classes.

Overall survival varied substantially across the groups, at a median of 1.7, 6.3 and 8.0 years for patients with wild-type IDH, and mutated IDH without and with the 1p/19q codeletion, respectively.

And the association between the molecular groups and patient outcomes remained after adjustment for confounders such as age and extent of resection.

Noting that gliomas with wild-type IDH were molecularly and clinically similar to primary glioblastomas, Brat et al observe that “molecular classification based on IDH–1p/19q status represents an improvement in diagnostic practice because it enables the identification of a clinically aggressive form of lower-grade glioma (with wild-type IDH) in the absence of morphologic criteria for glioblastoma.”

They conclude: “Further analysis of survival data in our cohort as it matures will be required to improve risk stratification with the use of molecular markers.”

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