Institution: Dana Farber Cancer Institute
Study Name: Evaluation of MYBL1 fusion oncogene in pediatric diffuse astrocytoma
Principal Investigator: Dr. Keith Ligon
Study date: January 2013
Pediatric diffuse astrocytomas are rare but represent a major clinical problem in pediatric neuro-oncology due to their heterogeneous pathology and unpredictable clinical behavior. Unlike adult gliomas our understanding of the molecular mechanisms which drive tumorigenesis within pediatric low grade gliomas are largely unknown. Recent genomic studies by our lab has identified several new copy number aberrations which appear to represent the first definitions of new subclasses within this disease which may be useful for targeting therapy or predicting tumor behavior.
We propose to further accelerate understanding the biology of normal MYBL1 andMYBL1tr in brain development and pediatric disuse astrocytomas while also establishing MYBL1tr as a biomarker. We will seek to do this through 2 specific aims.
1. Construction of a transgenic mouse model expressing MYBL1tr in the brain. This work would involve genetic design and engineering of a conditional MYBL1tr fl/fl allele and knock-in to the collagen locus to create a reliable transgenic model of diffuse astrocytoma grade II. Constructs for engineering mice would be created by a postdoctoral fellow in Dr. Ligon’s lab and then constructs would be sent to company or academic Core for transgenic mouse production. This portion of the project would require approximately 6-8 months. Once mice have been made they will be expanded and mated at the DFCI to generate sufficient numbers for evaluation of the brain and testing of whether mice may get brain tumors at a later time. Additional studies would involve mating with transgenic mice of other interesting tumor suppressor or onvogenes. Once generated mice would be shared with the larger pediatric glioma community as a critical tool for biological as well as preclinical studies (should tumors be generated).
2. Evaluation of the outcomes of patients found to have MYBL1 using IHC and bioinformatics approaches. Currently we believe 30% of DA2s express the oncogenic form of MYBL1. However, the clinical outcomes and behavior of this subset of patients cannot be determined in the single institution setting and instead requires evaluation across hospitals to generate significant numerical power. Therefore we propose to expand the testing of MYBL1 across tissue obtained from the known PLGA consortium sites while reaching out to additional sites for samples. Such studies would involve FISH or array CGH as indicated clinically. The project also involves the study of tissue microarrays obtained from COG (100 diffuse low grade gliomas) and performance of MYBL1 FISH assays. This work will also help to validate the assays as required clinical testing for pediatric low grade gliomas and set the stage for future clinical trials should the need arise.