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Genomic data may better classify lower-grade glioma than histology

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June 30, 2015

IDH, 1p/19q and TP53 status more accurately represented three molecular classes of lower-grade gliomas than histologic class, according to study results.

Lower-grade gliomas with an IDH mutation also had codeletion of chromosome arms 1p and 19q or a TP53 mutation, whereas lower-grade gliomas without IDH mutations demonstrated molecular and clinical similarity to glioblastoma, results showed.

Diffuse low-grade and intermediate-grade gliomas — grouped together as lower-grade gliomas and classified as grade II or III by the WHO — exhibit highly variable clinical behavior inadequately predicted by histologic class, according to study background. Some lower-grade gliomas remain indolent, whereas others rapidly progress to glioblastoma.

Daniel J. Brat, MD, PhD, professor of pathology and laboratory medicine at the Winship Cancer Institute at Emory University, and colleagues from The Cancer Genome Atlas Research Network, thus, sought to determine whether integrated whole-genome molecular data could be used to identify biological disease classes that more accurately represented the clinically distinct behavior of lower-grade gliomas than histologic categories.

Previous research implicated mutations in IDH, TP53 and ATRX and 1p/19q codeletion as clinically relevant markers for lower-grade gliomas, according to the researchers.

Researchers performed genome-wide analyses of 293 previously untreated adults with lower-grade gliomas, including patients with oligodendroglioma (n = 116), astrocytoma (n = 100) and oligoastrocytoma (n = 77).

The researchers incorporated exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression and targeted protein expression in their analyses.

Overall, data from RNA, DNA copy number and DNA methylation platforms — combined with unsupervised clustering of mutations — revealed concordant classification of three unrelated and prognostically significant subtypes of lower-grade glioma that were more accurately captured by IDH, 1p/19q and TP53 status than histologic class.

The most favorable clinical outcomes occurred among patients with lower-grade gliomas harboring an IDH mutation and 1p/19q codeletion. These patients also commonly harbored CIC, FUBP1, NOTCH1 and the TERT promoter gene mutations.

Nearly all lower-grade gliomas harboring an IDH mutation without 1p/19q codeletion exhibited mutations in TP53 (94%) and ATRX inactivation (86%).

The researchers found a majority of patients with lower-grade gliomas without an IDH mutation had other genomic aberrations and clinical behavior extremely similar to primary glioblastoma.

“Mutations in the ATRX, CIC and FUBP1 have only recently been implicated in cancer pathogenesis, yet their specificity and prevalence in lower-grade glioma with an IDH mutation support central roles in oncogenesis and argue for thorough characterization of associated signaling networks to facilitate therapeutic development,” Brat and colleagues wrote. “The genetic and clinical similarities between lower-grade glioma with wild-type IDH and primary glioblastoma support the potential inclusion of this type of lower-grade glioblastoma within the broad spectrum of glioblastoma-related clinical investigation and treatment protocols. Our integrative analysis has shown that all subtypes of lower-grade glioma rely to some extent on core signaling networks that have previously been implicated in glioblastoma pathogenesis, many of which are targeted by agents that are being evaluated in clinical trials.”

In the era of precision medicine, genomic information may confer substantial benefit for the individualized treatment of lower-grade gliomas, David W. Ellison, MD, PhD, chair of pathology at St. Jude Children’s Research Hospital, wrote in an accompanying editorial.

“[This study] can justifiably claim that molecular classification captures the biologic features of glioma variants better than does histopathological evaluation, even though grade remains an independent prognostic indicator,” 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: Please see the full study for a list of all researchers’ relevant financial disclosures.

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PERSPECTIVE
Stephanie Weiss

Stephanie Weiss

This is an important study. We know there are patients with so-called low-grade gliomas that behave with the aggressiveness of a grade IV glioma (a glioblastoma), the brain tumor Ted Kennedy had. In this study, the authors looked at genome-wide profile of grade II and grade III gliomas. They found that they could use these genetic profiles to divide these tumors into three groups in terms of favorable, intermediate and poor outcomes. These groups correlated very nicely with presence or absence of previously known prognostic biomarkers — IDH mutation, TP53 status, and codeletion of 1p/19q — and were more prognostic than traditional grading.

This study confirms what clinical experts have long suspected — the genetic profile of a glioma may be more important than the classic determinant of aggressiveness, or "grade,” which is essentially what the tumor looks like under the microscope. This has enormous implications for prognosticating for newly diagnosed patients, and very likely in determining treatment in the future.

Toward that end, some on-going clinical trials have been designed to determine the optimal treatment for brain tumors that already stratify patients of a given histopathologic type by known important molecular mutations. This work suggests that perhaps the molecular signature in fact is the most important feature and therefore could have implications for future trial design.


Stephanie Weiss, MD
Fox Chase Cancer Center

Disclosure: Weiss reports no relevant financial disclosures.