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Brain Tumors in Childhood Cancer Survivors Reveal Radiation-Induced Mutations

NEW YORK (GenomeWeb) – Investigators have identified distinct sets of mutations in secondary brain tumors that develop in individuals who received cranial radiotherapy treatment for pediatric cancers in the past.

As they reported in Nature Communications today, researchers from the Princess Margaret Cancer Centre, the University of Toronto, and elsewhere used a combination of exome sequencing, targeted gene sequencing, RNA sequencing, and methylation testing to profile so-called radiation-induced meningiomas in dozens of long-term childhood cancer survivors.

The team found that tumors from individuals who developed meningioma after cranial radiotherapy had alterations that were missing from meningioma tumors from individuals with sporadic forms of the disease. Among them: recurrent rearrangements involving the NF2 gene that turned up in almost 40 percent of the radiation-induced meningioma cases considered. On the other hand, recurrent rearrangements affecting genes such as AKT1 were relatively common in the sporadic cases but absent in the secondary meningiomas.

"By understanding the biology, the goal is to identify a therapeutic strategy that could be implemented early on after childhood radiation to prevent the formation of these tumors in the first place," co-corresponding author Gelareh Zadeh, a neurosurgeon and neurosurgery researcher affiliated with the University of Toronto and the Princess Margaret Cancer Centre, said in a statement.

Although cranial radiotherapy has stretched out average survival times for childhood brain tumor cases, pediatric leukemia, and other cancer types, the team explained, this ionizing radiation can introduce DNA damage that prompts secondary tumors roughly one to three decades later. These include forms of meningioma that are typically more aggressive and difficult to treat than the sporadic version of these brain tumors.

"Radiation-induced meningiomas appear the same on [magnetic resonance imaging] and pathology, feel the same during surgery, and look the same under the operating microscope," Zadeh explained. "What's different is they are more aggressive, tend to recur in multiples, and invade the brain, causing significant morbidity and limitations (or impairments) for individuals who survive following childhood radiation."

For their analyses, Zadeh and colleagues began by doing exome sequencing and RNA sequencing on 18 radiation-induced meningioma tumors from 16 childhood cancer survivors, comparing mutation patterns in these protein-coding sequences with those present in 30 sporadic meningiomas.

As reported previously, mutations in the NF2 gene that tend to mark sporadic meningiomas were relatively rare in the radiation-induced cases, though their subsequent targeted sequencing search for NF2 rearrangements in an expanded set of 31 radiation-induced meningiomas revealed a dozen cases involving NF2 fusion rearrangements.

The team noted that sporadic meningiomas were also prone to recurrent mutations in the AKT1, KLF4, TRAF7, and SMO genes — focal mutations that were missing from the radiation-induced meningiomas.

The researchers also saw differences at the chromosomal level, where radiation-induced meningiomas tended to have more complex rearrangement patterns and more frequent losses involving portions of chromosome 1 and chromosome 22.

On the other hand, the researchers' array-based methylation analyses indicated that radiation-induced meningiomas and sporadic meningiomas likely arise from similar cell types. There, the tumor samples tended to cluster into methylation subgroups that divided tumors with or without fusions or focal mutations affecting the NF2 gene.

Co-corresponding author Kenneth Aldape, a laboratory medicine and pathobiology researcher at the University of Toronto and director of a neuro-oncology program at the Princess Margaret Cancer Centre, noted that still other genetic rearrangements likely remain undetected as yet in individuals with radiation-induced DNA damage.

"[O]ne of the next steps is to identify what the radiation is doing to the DNA of the meninges," Aldape said in a statement. "[I]dentifying the subset of childhood cancer patients who are at highest risk to develop meningioma is critical so that they could be followed closely for early detection and management."

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