Genomics

Mutations within our DNA are largely responsible for tumorigenesis, whether inherited or acquired by cells.  Pratiti Bandopadhayay, PhD, MBBS and Rameen Beroukhim, MD, PhD, are focused on the genomic characterization of different cancer types, and the development of novel methods to analyze the large datasets generated from these studies. Drs. Bandopadhayay and Beroukhim identified the MYB-QKI genetic rearrangement as a major driver of angiocentric gliomas. Most recently, they have begun an epigenetics project that is examining the programming changes associated with cancer transformation.

In addition, they have profiled the genomic alterations of grade II astrocytomas and found a small number of genetic lesions that may be acting as drivers in these tumors, suggesting that other factors may also trigger the tumors to grow. Their laboratories are currently examining how these epigenetic changes may influence the growth of low-grade astrocytomas. By understanding these processes it may be possible to identify new processes that can present potential novel therapeutic strategies for these difficult to treat tumors.

Keith Ligon, MD, PhD is a board certified pathologist and is currently developing novel human pathology methods for cancer research. Recent work by Dr. Ligon’s laboratory examined the genetic profile of diffuse tumors. Dr. Ligon developed a method to analyze genomic data from formalin-fixed, paraffin embedded tissue, a difficult material to extract DNA from.  Using this method, the genomic profiles of 44 different pediatric tumors were analyzed. They showed there is a recurrent mutation of the transcription factor MYBL1 in diffuse astrocytomas. When this mutation in MYBL1 was introduced into fibroblasts, it transformed the cells, and when these cells were explanted into mice, the mutation induced tumor growth.

Both of these observations showed mutated MYBL1 is a driver oncogene, and has the potential to become a therapeutic target in DA2 treatment.  Dr. Ligon’s laboratory is in the process of constructing a mouse model deficient in MYBL1, and a mouse model expressing the mutated form of MYBL1.  Both of these models will be tested for brain tumor development, and then mated with other transgenic mice expressing other interesting oncogenes for further study.

 


Selected Publications


Brainstem angiocentric gliomas with MYB-QKI rearrangements.
Acta Neuropathology. 2017; 134(4):667-669.

PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma
Brain Pathol. 2013 Sep;23(5):565-73. doi: 10.1111/bpa.12043. Epub 2013 Mar 18. PMID:23438035.

Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma
International Cancer Genome Consortium PedBrain Tumor Project. Nat Genet. 2013 Aug;45(8):927-32. doi: 10.1038/ng.2682. Epub 2013 Jun 30. PMID:23817572.

Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors
Blood Cancer. 2012 Dec 15;59(7):1155-7. doi: 10.1002/pbc.24315. Epub 2012 Sep 19. PMID:2997201.
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