The genetic complexity of cancers impedes identification of key genetic collaborators in carcinogenesis, presenting a critical barrier to the discovery of new diagnostic or therapeutic targets. Heritable mutations in known cancer-associated genes, such as BRCA2, are strongly linked to cancer risk. However, numerous additional collaborating mutations that are somatically acquired contribute significantly to cancer development. Additional mutations in cancers are often generated through amplification and deletion events (copy number alterations; CNA). CNA can span large genomic regions and impact multiple genes, which obscures the identity of driver mutations in carcinogenesis. 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 genes that are frequently disrupted 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 wildtype 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. The candidate for this K01 Research Career Award is a D.V.M./Ph.D. scientist with board certification in Veterinary Anatomic Pathology. The research proposed in this grant application will be performed at North Carolina State University, College of Veterinary Medicine, under the mentorship of Dr. Robert Smart, Dr. Matthew Breen, and Dr. Jeffrey Yoder. The candidate is committed to a career in biomedical research, and seeks the additional training, mentorship, and protected research time provided by the proposed research and career development plan to facilitate her transition to an independent academic career.
The accumulation of genetic mutations during cancer development is critical in driving cancer progression. The proposed research is designed to identify and functionally characterize conserved cancer-associated candidate genes with the zebrafish model, which are directly testable in this model for their potential contributions to cancer development. This research will ultimately increase understanding of the complex genetic interactions that underlie cancer progression, and will potentially identify novel genetic targets for cancer diagnosis or therapeutic intervention.
