title: Identification of novel driver tumor suppressors through functional interrogation of putative passenger mutations in colorectal cancer.
abstract: Cancer genome sequencing efforts are leading to the identification of genetic mutations in many types of malignancy. However, the majority of these genetic alterations have been considered random passengers that do not directly contribute to tumorigenesis. We have previously conducted a soft agar-based short hairpin RNA (shRNA) screen within colorectal cancer (CRC) candidate driver genes (CAN-genes) using a karyotypically diploid hTERT- and CDK4-immortalized human colonic epithelial cell (HCEC) model and discovered that depletion of 65 of the 151 CAN-genes enhanced anchorage-independent growth in HCECs with ectopic expression of K-Ras(V12)  and/or TP53 knockdown. We now constructed an interaction map of the confirmed CAN-genes with CRC non-CAN-genes and screened for functional tumor suppressors. Remarkably, depletion of 15 out of 25 presumed passenger genes that interact with confirmed CAN-genes (60%) promoted soft agar growth in HCECs with TP53 knockdown compared to only 7 out of 55 (12.5%) of presumed passenger genes that do not interact. We have thus demonstrated a pool of driver mutations among the putative CRC passenger/incidental mutations, establishing the importance of employing biological filters, in addition to bioinformatics, to identify driver mutations.
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039, USA.
authors: Lu
authors: L
authors: Zhang
authors: Kakajan
authors: K
authors: Komurov
authors: Woodring E
authors: WE
authors: Wright
authors: Jerry W
authors: JW
authors: Shay
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)