Physicians classify brain tumors and determine treatment options, in part, by the genes they express. According to World Health Organization standards, the abnormal activation of oncogene FOXR2 only occurs in central nervous system (CNS) neuroblastoma, but that may not be true. Findings from St. Jude Children's Research Hospital show FOXR2 activation in multiple pediatric CNS tumor types, mostly brain tumors, with significantly different clinical outcomes. The potentially practice-changing findings were published today in Neuro-Oncology , a journal of the Society for Neuro-Oncology.
"People have been using FOXR2 activation as a clinical diagnostic for CNS neuroblastoma," said corresponding author Jason Cheng-Hsuan Chiang , MD, PhD, St. Jude Department of Pathology . "But we unexpectedly saw it in a patient's recurrent non-neuroblastoma tumor, which motivated us to look into other brain tumors."
The researchers searched for and found FOXR2 activation using data from the St. Jude Cloud , which houses whole genome, whole exome and RNA sequencing data from St. Jude patients. In total, they identified 42 tumors with activated FOXR2 in 41 patients. Only 11 of the tumors were the expected CNS neuroblastoma. The other 31 were a mix of high-grade gliomas and other embryonal and rare tumors, indicating a large, previously undiscovered category of disease with implications for diagnosis, prognosis and treatment.
"When we looked at the clinical outcomes of the different types of tumors with FOXR2 activation, there was a pretty stark difference," said co-first author Emily Hanzlik , MD, St. Jude Department of Pediatric Medicine . "The CNS neuroblastomas had an exceptionally good outcome when they were treated with multimodal therapy, whereas the other types of tumors in the cohort, the high-grade gliomas and the pineoblastomas, had pretty dismal outcomes."
Those differences indicate that physicians should not use FOXR2 activation as an exclusive marker of CNS neuroblastoma since it can occur in other tumor types. "Hopefully, our findings can help guide patients to the most appropriate clinical care," Chiang said.
Finding undetected mechanisms of FOXR2 activation in multiple brain tumor types
The underlying mechanisms of FOXR2 activation has gone unnoticed in brain tumors due to the difficulty in identifying them using standard molecular diagnostics. Still, the St. Jude scientists closely examined the clinical genomic data from the St. Jude Cloud to discover and better describe these hard-to-detect alterations.
"Now that we described these genomic events, hopefully, others will be able to detect them in their patients as well," said co-first author Alexa Siskar, PhD, St. Jude Department of Pathology, who analyzed the genomic data.
"Our study highlights the importance of combining every piece of information we have for classifying a patient's tumors, including molecular findings like DNA and RNA sequencing, histology and imaging," Chiang added. "Only with a holistic view can we correctly understand a specific brain tumor and choose the best treatment approach for that patient."
Authors and funding
The study's other authors are Maria Cardenas, Mohammad Eldomery, Soniya Pinto, Christopher Tinkle, Qunyu Zhang, Xiaoyu Li, Tong Lin, Sandeep Dhanda, Giles Robinson, Arzu Onar-Thomas, Patrick Blackburn and David Wheeler, St. Jude; Gerald Reis, Memorial Healthcare System; Daphne Li, Advocate Children's Hospital; Ravi Raghavan, Loma Linda University Medical Center; Alexander Vortmeyer, University of Mississippi Medical Center and Matthias Karajannis, Memorial Sloan Kettering Cancer Center.
The study was supported by grants from the National Cancer Institute (P30CA021765, P01CA096832 and P30CA008748), the V Foundation and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org , read St. Jude Progress, a digital magazine , and follow St. Jude on social media at @stjuderesearch .
