Dana-Farber Cancer Institute (DFCI): Discovery of Novel Oncogenes: Ovarian Cancer
Widespread recurrent copy number alterations are observed across the majority of human cancers, yet the specific targets of such amplified or deleted regions remain undefined. Here, the CTD2 Center at the Dana Farber Cancer Institute took a systematic approach using cDNA overexpression screening to identify and validate oncogenes residing in such amplified regions. In representative examples, these experiments have identified the adaptor proteins CRKL, GAB2, FRS2 and the TLOC and SKIL proteins as novel amplified oncogenes.
Amplicon-Based Pooled in Vivo Transformation Screen
Amplified genes were systematically tested for their ability to promote tumor formation using an in vivo multiplexed transformation assay. One candidate, GAB2, was identified as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells.
Copy number data generated by TCGA was queried to identify 1,017 recurrently amplified genes resident in the 63 recurrently amplified regions in high-grade serous ovarian cancer (HGSOC). From this data an arrayed collection of 587 ORFs representing 455 amplified ovarian genes was created. 26 pools composed of ORF-expressing cell lines representing 16–24 ORFs was created and each group was implanted subcutaneously in six separate replicates in immunodeficient mice.
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- Cheung et al. (2011). Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer. PNAS: 108(30):12372-7.(PMID: 21746896)