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Kim, Eejung

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Kim

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Eejung

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Kim, Eejung
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    TRAF2 is an NF-κB activating oncogene in epithelial cancers
    (2014) Shen, Rhine R.; Zhou, Alicia Y.; Kim, Eejung; O’Connell, Joyce T.; Hagerstrand, Daniel; Beroukhim, Rameen; Hahn, William
    Aberrant NF-κB activation is frequently observed in human cancers. Genome characterization efforts have identified genetic alterations in multiple components of the NF-κB pathway, some of which have been shown to be essential for cancer initiation and tumor maintenance. Here using patient tumors and cancer cell lines, we identify the NF-κB regulator, TRAF2 as an oncogene that is recurrently amplified and rearranged in 15% of human epithelial cancers. Suppression of TRAF2 in cancer cells harboring TRAF2 copy number gain inhibits proliferation, NF-κB activation, anchorage-independent growth and tumorigenesis. Cancer cells that are dependent on TRAF2 also require NF-κB for survival. The phosphorylation of TRAF2 at serine 11 is essential for the survival of cancer cells harboring TRAF2 amplification. Together these observations identify TRAF2 as a frequently amplified oncogene.
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    Functional characterization of genetic alterations in cancer
    (2016-05-18) Kim, Eejung; Meyerson, Matthew L.; Beroukhim, Rameen; Ebert, Benjamin L.
    The comprehensive identification of genetic alterations is critical to understanding the pathophysiology of cancer. Recent advances in sequencing technology have enabled the detailed description of cancer genomes. However, to translate these findings into a deeper understanding of cancer biology, analyzing the functional impact of cancer-associated genetic aberration is essential. Here I investigate how to accelerate the functional characterization of two classes of genetic alterations, point mutations and amplifications. The wide spectrum of point mutations that arise in cancer makes them challenging to study comprehensively. I have developed a scalable systematic method to experimentally infer the functional impact of cancer-associated gene variants. I performed pooled in vivo tumor formation assays and gene expression profiling using 474 mutant alleles curated from 5,338 human tumors. I identified 12 transforming alleles including two in genes (PIK3CB, POT1) that have not been previously shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of RAS effector pathways. By correlating gene expression changes induced upon expression of wild type and mutant alleles, I could infer the activity of specific alleles. These approaches enable the interrogation of cancer-associated alleles at scale and demonstrate that rare alleles may be functionally important. Frequently amplified regions in cancer often harbor oncogenic drivers. However, identifying the driver gene among many other amplified genes is challenging. In high-grade serous ovarian cancer (HGSOC), 1,825 genes are amplified across 63 amplicons. We employed systematic loss-of-function RNAi data to identify amplified genes that were essential in the ovarian lineage. We identified 50 amplified and essential genes and validated FRS2, an adaptor protein in FGFR pathway. FRS2-amplified cancer cell lines were dependent on FRS2 expression and FRS2 overexpression in immortalized cell lines was sufficient to promote anchorage independent growth and tumorigenesis in nude mice. This approach demonstrates that intersecting structural genomics with functional genomics can facilitate the discovery of driver genes in recurrently amplified regions. Collectively, the methods I present here provide a framework to study point mutations and amplifications to accelerate the interpretation of the cancer genome.