04 Feb Single Gene Rearrangement Uses Three Paths To Cause Rare Brain Tumor
MedicalResearch.com Interview with:
Dr. Adam C. Resnick, Ph.D
Assistant Professor of Neurosurgery
Faculty, Abramson Cancer Center
Director of Children’s Brain Tumor Tissue Consortium
Division of Neurosurgery
Director, CHOP/PENN Department of Neurosurgery Brain Tumor Tissue BiorepositoryDirector for Neurosurgical Translational Research, Division of Neurosurgery
Children’s Hospital of Philadelphia
Payal Jain, PhD Candidate
Division of Neurosurgery, Children’s Hospital of Philadelphia
Department of Neurosurgery
Cell and Molecular Biology Graduate Group
Gene Therapy and Vaccines Program
Perelman School of Medicine
University of Pennsylvania Philadelphia, Pennsylvania
Medical Research: What is the background for this study? What are the main findings?
Response: This study originates from our long-standing interest in studying pediatric low-grade gliomas (PLGGs), which are the most commonly diagnosed brain tumor in children. While several PLGGs have been found to harbor mutations/gene fusions driving the mitogen-associated protein kinase (MAPK) pathway leading to clinical trials testing MAPK inhibitors, these tumors remain poorly categorized and not enough is known about specific genetic mutations driving different tumor sub-types and the potential for specific targeted therapeutics.
Our current study encompasses analysis of the largest combined genomic dataset of pediatric low-grade gliomas samples. In doing this we, identified the MYB-QKI gene fusion, a non-MAPK related event, as the common genetic event driving a rare PLGG sub-type, called angiocentric gliomas. We have reported a novel tri-partite mechanism by which MYB-QKI mediates its oncogenic effect, this being the first report of a single gene rearrangement utilizing three different paths to cause cancer.
- First, this gene rearrangement activates MYB, which is a proto-oncogene that is normally not expressed in the developed brain.
- Second, we found that the rearrangement leads to translocation of QKI-related enhancers close to MYB’s promoters, thereby driving MYB-QKI expression in these tumors. Furthermore, MYB-QKI can also regulate its expression in a positive feedback loop.
- Third, the tumor suppressor activities of QKI are disrupted in MYB-QKI. Such collaboration of genetic and epigenetic dysregulation in a single genetic rearrangement has previously not been reported.
Medical Research: What should clinicians and patients take away from your report?
Response: First, our finding that all 19 angiocentric gliomas in our cohort of 249 PLGG samples contains the MYB-QKI gene fusion holds great prognostic, diagnostic and possible therapeutic implications for this tumor sub-type.
Second, there are a number of clinical trials and efforts assessing MAPK-targeted therapies for PLGG. Our study suggests that molecular subtyping of low grade gliomas should inform these efforts further to ensure correct pairing of patients with targeted therapies.
Lastly, the underlying tripartite mechanism driving angiocentric biology is likely not unique to this fusion setting and should be considered in other fusion-drive cancers, especially as new drugs targeting epigenetic dysregulation emerge as therapeutic options.
Medical Research: What recommendations do you have for future research as a result of this study?
Response: This study is the first one to show how different mechanisms can be employed by a single mutation, one that could broadly apply to other pediatric and adult cancers with gene fusion events. This also highlights the importance for studying both fusion partners in a gene fusion as possible contributors to cancer, as opposed to previous studies solely focusing on the kinase protein partner as the key perpetrator.
Medical Research: Is there anything else you would like to add?
Response: In addition to the scientific contributions of this study to our understanding of PLGG biology, the study also highlights the importance of collaborative networks and authentic open partnerships across research hospitals and academic institutions. Only through such efforts are such studies possible in the context of pediatric cancers and rare diseases where limited access to patient samples and limited research funding is available. Complementing the academic collaboration space is the necessity for the longstanding partnerships between researchers and foundations and patient/families who make the research possible, including the foundations dedicated to supporting pediatric low-grade gliomas research that partnered to fund the collaborative science underpinning this publication: A Kids’ Brain Tumor Cure Foundation/Pediatric Low-Grade Astrocytoma Foundation, Voices Against Brain Cancer, Thea’s Star of Hope, and Why Not Me Inc.
Adam C Resnick et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nature Genetics, 2016; DOI: 10.1038/ng.3500
Dr. Adam C. Resnick, Ph.D, & Payal Jain, PhD Candidate (2016). Single Gene Rearrangement Uses Three Paths To Cause Rare Brain Tumor