Hot Off the Press
BRAF Mutations Open Doors for N-Ethyl-N-Nitrosourea-Induced Gliomagenesis [Commentary]
Robert S. McNeill, David M. Irvin, and C. Ryan Miller
Am J Pathol 2016,
Commentary, published October 2016 in the American Journal of Pathology, written on Short Communication: Wang Q, Satomi K, Oh JE, Hutter B, Brors B, Diessl N, Liu H-K, Wolf S, Otmar S, Wiestler O, Kleihues P, Koelsch B, Kindler-Rohrborn A, Ohgaki H: Braf mutations initiate the development of rat gliomas induced by postnatal exposure to N-ethyl-N-nitrosourea. Am J Pathol 2016, 186:2569-2576; http://dx.doi.org/10.1016/j.ajpath.2016.05.024.
Genomic analyses have revealed the genetic diversity of human gliomas, resulting in increased precision in defining relevant subtypes. Moreover, these analyses alongside genetically faithful preclinical models, promise to aid in revolutionizing glioma therapy by assisting in the clinical implementation of personalized medicine. N-ethyl-N-nitrosurea (ENU)-induced rodent gliomas have been a mainstay of preclinical glioma research since the 1960s. However, whether ENU-induced mutagenesis results in highly penetrant glioma-associated mutations that converge on particular gene(s) or on common biologic pathway(s) remained unclear.
The manuscript by Wang et al sought to answer this question. Whole genome sequencing on 3 BDIV and 2 BDIX rat gliomas, induced by ENU at post-natal day one, showed 6,354-13,807 somatic mutations per tumor. Consistent with ENU-induced mutagenesis, T:A to A:T transversions and T:A to C:G transitions were the most common single nucleotide mutations.
Interestingly, Wang et al. found that all 5 tumors harbored an A to T missense mutations that corresponded to BrafV545E, a mutation analogous to the BRAFV600E mutation found in humans. The authors confirmed 100% penetrance of the BrafV545E mutations using Sanger sequencing in a panel of an additional 33 BDIV and 12 BDIX ENU-induced rat gliomas. This was an important finding because BRAFV600E is an established oncogene in many solid cancers. BRAF-mutations frequently occur in non-diffuse human gliomas, particularly pilocytic astrocytomas, gangliogliomas, and pleomorphic xanthoastrocytomas.
The ENU-induced rat gliomas from Wang et al. also had similar developmental timing and histopathology to these non-diffuse pediatric gliomas. Thus, the finding of BrafV545E mutations in ENU-induced rat gliomas is an important step in determining the underlying biology of gliomas harboring BRAF mutations and will provide a platform for improved preclinical modeling and drug development.