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Deep, Integrated Genomic Analysis Reclassifies Lower-Grade Brain Tumors

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Key Points

  • Low-grade brain tumors have been categorized into three clusters based on their IDH1/IDH2 mutation status and codeletion of chromosome arms 1p and 19q.
  • Each molecular group includes tumors from all grades and categories of astrocytoma, oligodendrocytoma, and oligo-astrocytoma.
  • Tumors with wild-type IDHI1 and IDH2 are similar to glioblastoma (with a median survival of 18 months), and patients should receive the standard of care for glioblastoma.

Using comprehensive genomic analysis, researchers have sorted low-grade brain tumors into three categories, one of which has the molecular hallmarks and shortened survival of glioblastoma multiforme, the most lethal of brain tumors. The findings were reported at the American Association for Cancer Research (AACR) Annual Meeting 2014 in San Diego.

“The immediate clinical implication is that a group of patients with tumors previously categorized as lower grade should actually be treated as glioblastoma patients and receive that standard of care—temozolomide chemotherapy and irradiation,” said lead author Roel Verhaak, PhD, Assistant Professor of Bioinformatics and Computational Biology at The University of Texas MD Anderson Cancer Center.

“Classifying lower-grade tumors in these three molecular clusters more accurately characterizes them than current methods used to group and grade tumors,” Dr. Verhaak said.

The pivotal molecular markers that define the three tumor clusters—mutational status of the IDH1 and IDH2 genes and loss of chromosome arms 1p and 19q—are already routinely checked in clinical care, Dr. Verhaak noted, so implementing the new categories can be done relatively quickly.

Dr. Verhaak and colleagues analyzed data from The Cancer Genome Atlas (TCGA) brain tumor studies.

Lack of IDH1/2 Mutations Reduces Survival

Brain tumors arise in the glia, or supportive cells, of the brain and now are classified by their histology as well as their cell of origin—either astrocytes or oligodendrocytes.

Classified this way, grade 2 and 3 oligodendrogliomas and astrocytomas demonstrate median overall patient survival ranging from 3 to 10 years. This compares with 14 months for patients with glioblastoma multiforme, a complex and aggressive astrocytoma.

Glioblastomas make up 55% to 60% of gliomas, with lower-grade astrocytomas comprising 15% to 20% of cases; oligodendrocytes, 12% to 20%; and combination oligo-astrocytomas, 5% to 10%.

The researchers comprehensively analyzed 254 TCGA lower-grade gliomas for gene, protein, and microRNA expression, DNA methylation, and gene copy profiles to cluster cases by category. Then they conducted a “cluster of clusters” analysis that encompassed all data.

“The results overwhelmingly point to a natural grouping of lower-grade gliomas into three superclusters based on the mutational status of the IDH1 and IDH2 genes and codeletion of chromosome arms 1p and 19q,” Dr. Verhaak said.

Previous TCGA research had shown that glioblastoma patients with mutations of IDH1/IDH2 in their tumors have an improved prognosis. Dr. Verhaak said whether these mutations are markers of good prognosis or actually have a role in thwarting tumor progression is not known. Codeletion of 1p19q has been associated with increased tumor sensitivity to chemotherapy and longer survival for oligodendroglioma patients.

Each molecular group includes tumors from all grades and categories of astrocytoma, oligodendrocytoma, and oligo-astrocytoma

Three Categories of Lower-Grade Gliomas

The three molecular superclusters of lower-grade gliomas have either:

  • Wild-type IDHI1 and IDH2 (with no mutations). These tumors are similar to glioblastoma, with patients’ median survival at 18 months.
  • IDH1/IDH2 mutations and chromosome arms 1p/19q intact. These tumors have no dominant histology or grade type and are associated with a median survival of about 7 years.
  • IDH1/IDH2 mutations and codeletion of 1p/19q. This cluster was composed mainly of oligodendrogliomas (84%) and associated with median survival of about 8 years.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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