Overview: Infiltrating gliomas are shaped by their genetic evolution and microenvironment, researchers report. The findings may aid in the development of therapies to treat glioma brain tumors.
Source: University of Colorado
Researchers have found that infiltrating gliomas, a common tumor in the brain and spinal cord, are shaped by their genetic evolution and microenvironment, a finding that could lead to more targeted treatments.
“We identified epigenetic changes in recurrence that in some cases are not only prognostic, but may lead to different treatment options for the different subtypes that may improve long-term survival,” said study co-author D. Ryan Ormond, MD, PhD, member of the University of Colorado Cancer Center and associate professor of neurosurgery at the University of Colorado School of Medicine at CU Anschutz Medical Campus.
The study was published May 31 in the journal Cell†
The researchers looked at how gliomas interact with the brain, change over time, develop therapy resistance and become more invasive.
They identified three different phenotypes or observable features in glioma recurrence – neuronal, mesenchymal and proliferative. Each of them comes together with cellular, genetic and histological features that repeatedly manifest themselves. Some of these are associated with less favorable results.
In this study, scientists used participant samples from the Glioma Longitudinal Analysis Consortium or GLASS cohort, a consortium created to identify the causes of treatment resistance in glioma.
They analyzed RNA and/or DNA sequence data from tumor pairs from 304 adult patients with isocitrate dehydrogenase (IDH) wild-type and IDH mutant gliomas.
The tumors came back in specific ways depending on the IDH mutation status. The changes they experienced during the recurrence depended on how they interacted with the microenvironments they inhabited.
Researchers found that many IDH wild-type tumors were more invasive on recurrence. Their neoplastic cells showed enhanced neuronal signaling programs, suggesting a possible role for neuronal interactions in fueling tumor progression.
They also found that hypermutation, often caused by treatment with drugs such as temozolomide, along with deletion of the CDKN2A gene, which makes tumor suppressor proteins, was associated with tumor cell proliferation upon recurrence in both glioma subtypes.
In both IDH wild-type and IDH mutant tumors, the hypermutation was associated with an increased number of stem-like neoplastic cells. The growth of these cells reduced the patient’s overall survival.
Collectively, these results indicate that genetic evolution can repetitively change neoplastic glioma cells toward a more proliferative phenotype that associates with poor prognosis,” the study said.
Ormond said that therapy resistance remains a serious obstacle for patients with glioma and to improve quality of life and survival it must be overcome. These findings, he said, will allow doctors to better target the cancer with new therapies and treatments.
About this news about brain cancer and genetics research
Author: David Kelly
Source: University of Colorado
Contact: David Kelly – University of Colorado
Image: The image is in the public domain
Original research: Closed access.
†Glioma progression is shaped by genetic evolution and interactions in the microenvironmentby Ryan Ormond et al. Cell
Abstract
Also see
Glioma progression is shaped by genetic evolution and interactions in the microenvironment
Highlights
- Longitudinal glioma evolution follows an IDH mutation-dependent pathway
- hypermutation and CDKN2A deletions underlie increased proliferation on recurrence
- Recurrent IDH wild-type neoplastic cells regulate neuronal signaling programs
- Associate mesenchymal junctions with different myeloid cell interactions
Overview
The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-related cellular and genetic changes, we analyzed RNA and/or DNA sequence data from the transiently separated tumor pairs from 304 adult patients with isocitrate dehydrogenase (IDH) wild-type and IDH mutant glioma.
Tumors recurred in a variety of ways that were dependent on IDH mutation status and attributable to changes in the composition of histological features, somatic changes, and microenvironmental interactions.
Hypermutation and Acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells upon recurrence in both glioma subtypes, indicating active tumor growth.
IDH wild-type tumors were more invasive upon recurrence, and their neoplastic cells showed increased expression of neuronal signaling programs reflecting a possible role for neuronal interactions in promoting glioma progression.
Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells.
Collectively, these relapse-associated phenotypes represent potential targets to alter disease progression.
#Recurrent #Brain #Tumors #Shaped #Genetic #Evolution #Microenvironment #Neuroscience #News