The Role of Recurrent Mutations of H3F3A and ATRIX in Pediatric High Grade Glioma

A. Thomas Look, M.D. Dana Farber Cancer Institute

New Grant Application:

High-throughput sequencing of cancer patient’s genomes has enabled the identification of genomic alterations underlying the human disease. By this technology driver mutations of high grade gliomas, an aggressive kind of brain tumor in children, have been recently described. The most prominent recurrent mutations where found in four genes, namely NF1, TP53, ATRX, and H3F3A. NF1 and TP53 are tumor suppressor genes and their loss of function is characteristic for various human malignancies. However, the mechanism through which genetic hits in H3F3A and ATRX influence tumor biology remains largely unknown. Our project employs the emerging genome engineering technology CRISPR-Cas9 to create zebra-fish models of pediatric glioma, in order to analyze the impact of such mutations on tumor onset and progression. Zebrafish have already been developed that are deficient for NF1 and TP53 tumor suppressors and they develop brain tumors reminiscent of the human malignancy, but with delayed onset and at low penetrance. By CRISPR-Cas9 we will incorporate additional defined oncogenic mutations into this preexisting animal model and search of differences in tumor time of onset, tumor penetrance, and differentiation status. Besides analyzing the impact of single mutations, this project aims at unraveling their synergistic effect when occurring simultaneously.

Understanding the function of cancer mutations and their synergy in tumor biology will be crucial to develop future therapy approaches against pediatric gliomas.

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