Identification of genetic collaborators in cancer with a brca2-mutant zebrafish model

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Project Summary/Abstract The genetic complexity of cancers impedes identification of key genetic collaborators in carcinogenesis. Heritable mutations in known cancer-associated genes, such as BRCA2, are strongly linked to cancer risk. However, somatically acquired mutations contribute significantly to cancer progression. These additional mutations are often generated through amplification and deletion events (copy number alterations; CNA). CNA can span large genomic regions and disrupt numerous genes, which impedes identification of cancer drivers. By defining recurrent cancer-associated CNA in an animal model such as the zebrafish, and comparing these data to known CNA in human cancers, we can use differences in genomic architecture between species to identify recurrently disrupted genes in cancers from both species. This approach thus identifies novel, conserved, candidate driver genes that can be easily assessed in the zebrafish model for their potential to impact carcinogenesis. The goal for this proposal is to identify and functionally characterize conserved genes that are recurrently disrupted by CNA in BRCA2-associated human and zebrafish cancers. We have previously shown genetic similarities between human and zebrafish BRCA2-associated cancers, which include the collaborative role for tp53 in brca2-associated carcinogenesis and the loss of the wild type alleles for brca2 and/or tp53 in cancers. Our central hypothesis is that novel, conserved, candidate driver genes that collaborate in BRCA2- associated carcinogenesis will be revealed through comparative genomics analyses of human and zebrafish BRCA2-associated cancers. In vivo characterization of these candidate genes in zebrafish will provide insight into how they modulate cellular events of direct relevance to cancer development, and will guide initiation of stable transgenic and mutant zebrafish lines for use in future carcinogenesis studies. Our long-term goal is to define key conserved combinatorial gene disruptions and novel molecular pathways that drive cancer progression. This K01 Research Career Award recipient is a DVM/PhD. scientist with board certification in Veterinary Anatomic Pathology. The K01 research project was performed at North Carolina State University, College of Veterinary Medicine (years 1-3), under the mentorship of Dr. Robert Smart, Dr. Matthew Breen, and Dr. Jeffrey Yoder, and is currently being performed at the Ohio State University, College of Veterinary Medicine under the mentorship of Dr. Ramesh Ganju (OSU Comprehensive Cancer Center) and continued mentorship of Drs. Smart, Breen, and Yoder. The candidate is committed to a career in biomedical research, and seeks the additional training, mentorship, and protected research time provided by this research and career development plan to facilitate her transition to an independent academic career.