Discovery and functional characterization of an oncogenic PTEN mutation: Implications for personalized cancer genome therapy. H. A. Costa1, M. G. Leitner2, M. L. Sos3, A. Mavrantoni2, A. Rychkova1, M. C. Yee1, F. M. De La Vega1, J. M. Ford1, K. M. Shokat3, D. Oliver2, C. R. Halaszovich2, C. D. Bustamante1 1) Stanford University School of Medicine, Department of Genetics, Stanford, CA, 94305, USA; 2) Philipps-Universitšt Marburg, Department of Neurophysiology, 35037, Marburg, Germany; 3) Univeristy of California, San Francisco, Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, San Francisco, CA, 94158, USA.

   While a variety of genetic alterations have been found across cancer types, the functional characterization of genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor (and matched germline genome), computational analysis, and experimental validation to identify a novel (A126G) oncogenic mutation in the PTEN tumor suppressor protein. We demonstrate that this mutation produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphosinositide (PI) 3-phosphatase to a phosphosinositide (PI) 5-phosphatase and resulting in an increase in PI(3,4)P2 levels. Using cellular assays we show that PTEN A126G hyperactivates the PI3K/Akt cell proliferation pathway and exhibits increased cell invasion and we conclude that these effects can be substantially mitigated through chemical PI3K- inhibitors. These results suggest a new dysfunction paradigm for PTEN cancer biology, highlight the difficulty of inferring the impact of mutations solely through variant annotation and bioinformatic analysis, and display the power of experimental validation to uncover new biology and guide individualized therapy and diagnostics.

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