Summary: Researchers have identified a specific rearrangement involving the NF2 gene that appears to cause radiation induced meningiomas. The Nature Communication study reports this mutation could be a basis for why many long term pediatric cancer survivors go on to develop brain tumors later in life.
Source: University Health Network.
Neuroscientists have uncovered the genetic basis for why many long-term survivors of childhood cancer develop meningiomas, the most common adult brain tumour, decades after their treatment with cranial radiation.
The findings, published online today in Nature Communications, show that radiation causes genetic rearrangements in DNA that result in meningiomas, say co-principal investigators Gelareh Zadeh, neurosurgeon-scientist, Head of Surgical Oncology, and Ken Aldape, neuropathologist-scientist, Director, MacFeeters-Hamilton Neuro-Oncology Research Program, Princess Margaret Cancer Centre, University Health Network.
Dr. Zadeh is an Associate Professor, Division of Neurosurgery, and holds the Wilkins Family Chair in Brain Tumor Research; and Dr. Aldape, Professor, Laboratory Medicine and Pathobiology, both at University of Toronto.
The study compared and contrasted the biology of radiation-induced meningiomas (RIMs) to those that appear sporadically in the general population. “Radiation-induced meningiomas appear the same on MRI and pathology, feel the same during surgery and look the same under the operating microscope. 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,” says Dr. Zadeh.
The research team analyzed RIMs from patients who had received cranial-spinal radiation as children; the majority of whom (74%) had survived either leukemia or pediatric brain cancer. The study also showed that RIMs developed regardless of the radiation dose by collaborating with scientists in Germany where low-dose radiation was a common treatment many years ago for scalp ringworm.
“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 tumours in the first place,” says Dr. Zadeh.
Dr. Aldape says: “It is an important clinical problem because it presents a paradoxical dilemma that while cranial-spinal radiation is needed to cure many childhood cancers, an unfortunate consequence is that 10-to-15-years following radiation treatment some survivors develop meningiomas.
“Our research identified a specific rearrangement involving the NF2 gene that causes radiation-induced meningiomas. But there are likely other genetic rearrangements that are occurring as a result of that radiation-induced DNA damage. So one of the next steps is to identify what the radiation is doing to the DNA of the meninges.”
He adds: “In addition, identifying 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.”
Funding: The research was funded by Canadian Institutes of Health Research, the MacFeeters-Hamilton Neuro-Oncology Research Program, the Wilkins Family Chair in Brain Tumor Research, and The Princess Margaret Cancer Foundation.
Source: Jane Finlayson – University Health Network
Image Source: NeuroscienceNews.com image is in the public domain.
Video Source: Video credited to UHNToronto.
Original Source: Full open access research for “Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas” by Sameer Agnihotri, Suganth Suppiah, Peter D. Tonge, Shahrzad Jalali, Arnavaz Danesh, Jeffery P. Bruce, Yasin Mamatjan, George Klironomos, Lior Gonen, Karolyn Au, Sheila Mansouri, Sharin Karimi, Felix Sahm, Andreas Deimling, Michael D. Taylor, Normand J. Laperriere, Trevor J. Pugh, Kenneth D. Aldape & Gelareh Zadeh in Nature Communications. Published online August 4 2017 doi:10.1038/s41467-017-00174-7
Additional information about the study can be found here.
Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas
Cranial radiotherapy improves survival of the most common childhood cancers, including brain tumors and leukemia. Unfortunately, long-term survivors are faced with consequences of secondary neoplasia, including radiation-induced meningiomas (RIMs). We characterized 31 RIMs with exome/NF2 intronic sequencing, RNA sequencing and methylation profiling, and found NF2 gene rearrangements in 12/31 of RIMs, an observation previously unreported in sporadic meningioma (SM). Additionally, known recurrent mutations characteristic of SM, including AKT1, KLF4, TRAF7 and SMO, were not observed in RIMs. Combined losses of chromosomes 1p and 22q were common in RIMs (16/18 cases) and overall, chromosomal aberrations were more complex than that observed in SM. Patterns of DNA methylation profiling supported similar cell of origin between RIMs and SMs. The findings indicate that the mutational landscape of RIMs is distinct from SMs, and have significant therapeutic implications for survivors of childhood cranial radiation and the elucidation of the molecular pathogenesis of meningiomas.
“Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas” by Sameer Agnihotri, Suganth Suppiah, Peter D. Tonge, Shahrzad Jalali, Arnavaz Danesh, Jeffery P. Bruce, Yasin Mamatjan, George Klironomos, Lior Gonen, Karolyn Au, Sheila Mansouri, Sharin Karimi, Felix Sahm, Andreas Deimling, Michael D. Taylor, Normand J. Laperriere, Trevor J. Pugh, Kenneth D. Aldape & Gelareh Zadeh in Nature Communications. Published online August 4 2017 doi:10.1038/s41467-017-00174-7