T(15;19) in Aggressive Pediatric Carcinoma

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DESCRIPTION (provided by applicant): The candidate is a pathologist who has performed research full-time over the past year and has acquired substantial experience in molecular cytogenetic and gene mapping methods. Through this work, he has identified a fusion oncogene targeted by a chromosomal translocation, t(15;19), in an extraordinarily aggressive form of carcinoma. This application outlines a plan to provide a broad exposure to cancer biology research methods and to elucidate the oncogenic mechanisms associated with t(15;19). The aims are to: (1) learn skills, conceptual and theoretical approaches to molecular genetics and functional analysis of oncoproteins; and (2) identify the (15;19)-associated fusion oncoprotein and reveal functional properties of this protein. The overriding aim is to establish the candidate as an independently funded physician-scientist who can contribute original findings and concepts to cancer biology and clinical medicine. The environment is well suited to this goal. The mentor?s laboratory has substantial expertise in molecular genetics and the functional analysis of oncogenes. In addition, the candidate?s advisory committee has broad experience in cancer biology using in vitro and murine models. The mentor and t h e a dvisory committee will facilitate scientific interactions and collaborations, and will ensure an intensive curriculum, including laboratory work and didactic courses, both within and outside of the Harvard Medical Area, in order to meet the aim of a broad experience in cancer biology. The research component focuses on a devastating form of carcinoma with translocation t(15;19)(q13;p13.1). This unique carcinoma has been completely unresponsive to multi-agent chemotherapy and radiation therapy, and all patients (children and young adults) have succumbed within 9 months of diagnosis. The candidate has localized the translocation breakpoints by cytogenetic, fluorescence in situ hybridization (FISH), Southern blotting, and RT-PCR methods. His preliminary studies have recently identified the fusion oncogene, comprised of a chromosome 19 partner oncogene encoding a cell proliferation-related bromodomain protein, fused with the chromosome 15 partner oncogene encoding a novel proline-rich protein. Future studies will focus on three aims. First, the full length t(15;19) fusion oncogene will be characterized by rapid amplification of cDNA ends and, if necessary, by screening cDNA libraries from a t(15;19) cancer cell line. Second, he will establish in vitro models with which to evaluate the t(15;19) oncoprotein transforming activity and transforming mechanisms. These studies will address the hypothesis that the t(15;19) oncoprotein acts by deregulating function of one or both of its component native proteins. Third, he will determine the frequency of t(15;19), using FISH and RT-PCR assays, in clinically aggressive carcinomas from pediatric patients. These studies will also reveal the range of primary sites from which t(15;19)+ carcinomas arise.