Abstract
A new mouse model of ATRX-deficient pediatric glioblastoma reveals a DNA repair defect that renders the tumors more sensitive to DNA-damaging agents.
Mutations in the ATRX gene increase the aggressiveness and genetic instability of high-grade pediatric gliomas, but also leave tumors more susceptible to DNA-damaging drugs and radiation, according to a recently published study (Sci Transl Med 2016;8:328ra28).
ATRX, a histone chaperone protein, is inactivated by mutation in 30% of pediatric glioblastoma multiforme, tumors that progress rapidly, have no effective treatment, and are universally fatal. The study links ATRX to defects in DNA repair, and suggests that some children may benefit from treatments that induce double-stranded DNA breaks, including topoisomerase inhibitors—topotecan and irinotecan—and radiation.
“This paper helps not only to elucidate the biology of this histone protein, but also to lay the platform for deciding how to potentially treat patients who have ATRX mutations,” says Maciej Lesniak, MD, a neurosurgical oncologist and chairman of neurosurgery at Northwestern University Feinberg School of Medicine in Chicago, IL, who was not involved with the study.
In the new work, Maria Castro, PhD, of the University of Michigan School of Medicine in Ann Arbor, and colleagues created a mouse model of ATRX-deficient glioblastoma by knocking down the gene in neuronal stem cells in the lateral ventricles of newborn pups. The mice developed aggressive tumors that displayed microsatellite instability, an indicator of genomic instability.
ATRX mutations cause genetic instability in human tumors, too, the researchers showed. An analysis of publicly available genome sequencing data from 293 pediatric high-grade gliomas revealed a higher incidence of single nucleotide variation in ATRX-mutated tumors, compared to ATRX–wild-type tumors. ATRX status did not correlate with copy-number alterations or karyotypic changes. The effect of ATRX on mutation rate was unique to childhood tumors—an analysis of 290 adult glioblastomas revealed no effect of ATRX status on mutation rate.
In the mice, ATRX loss resulted in specific defects in DNA repair, mainly affecting nonhomologous end joining pathways responsible for mending double-stranded DNA breaks. Because of the repair deficit, the mouse tumors were more sensitive to agents that induce double-stranded DNA damage, including doxorubicin, topoisomerase inhibitors, and radiation.
The results suggest that ATRX loss results in tumors that are both more aggressive and more responsive to treatment. Recent studies have shown that in adults, lower-grade gliomas with ATRX mutations respond better to treatment. In the new study, the researchers showed that ATRX mutations give a survival advantage in treated high-grade pediatric gliomas as well.
“We found exactly the same as in the mouse tumor—the genome of the pediatric cancers with ATRX mutations was unstable, and the children responded better to therapeutics,” Castro says.
The model will be useful for testing novel chemotherapeutic agents, either as single agents or in combination with radiation therapy. The model has another benefit too: Because it uses immunocompetent mice, researchers can assess immunotherapies as well, Castro says. –Pat McCaffrey
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