Genomics

Mutations within our DNA are largely responsible for tumorgenesis, whether inherited or acquired by cells.  Rameen Beroukhim, MD, PhD, is focused on the genomic characterization of different cancer types, and the development of novel methods to analyze the large datasets generated from these studies. Most recently, he has begun an epigenetics project that is examining the programming changes associated with cancer transformation.

His group 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. His laboratory is 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.

In the laboratory of Sandro Santagata, MD. PhD., the focus is on understanding a fundamental challenge in tumor biology.  How do tumor cells develop their most aggressive behaviors and what are the mechanisms that they use to resist therapies?  One biological program that he focuses on in this area is a potent adaptive mechanism: called classically, the heat shock response. His group revealed that highly aggressive tumors across a broad range of tumor types co-opt the activity of heat shock factor 1 (HSF1), the dominant transcriptional regulator of this ancient survival program. He uses chemical and genetic approaches to study the unique regulation of the heat shock program in cancer and determines how other adaptive responses are conscripted by tumors. With this understanding, his research seeks to develop and implement practical and innovative diagnostic tools, and prevent drug resistance in cancer.


Selected Publications


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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