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Personalized Medicine Analysis Identifies Novel Mutation That Gives PTEN Protein New Tumor-Promoting Ability, While Preserving Its Normal Tumor Suppressor Activity

In a “personalized medicine” study that presents a framework for interpreting a single patient’s genome, collaborating scientists at the Stanford University School of Medicine, UCSF, Gladstone Institutes, and Phillipps-Universitat Marburg, have identified a novel point mutation in the PTEN tumor suppressor gene that allows the altered PTEN protein product (image shows structure of normal PTEN protein) to retain its known suppressor function, while gaining new tumor-promoting activities. In addition, the scientists have demonstrated that the tumor-promoting activities of the mutated PTEN protein can be substantially mitigated by chemical inhibitors of PI3K (phosphoinositide 3-kinase). The researchers believe that their work suggests a new role for PTEN, as well as other tumor suppressors, in cancer formation, and also reveals the potential wealth of biological information currently underexploited by the lack of systematic approaches for cancer genome interpretation services. The authors believe that their results “demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.” The new PTEN mutation and the systematic analyses that led to its discovery and characterization are described in an online open-access article published on October 26, 2015 in PNAS. The article is titled “Discovery and Functional Characterization of a Neomorphic PTEN Mutation.” In the PNAS article abstract, the authors note that “although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles.” In thisthithis study, the sc this study, the scientific team employed whole genome sequencing (WGS) of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein. The team then demonstrated that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from that of a phosphoinositide (PI) 3-phosphatase to a that of a phosphoinositide (PI) 5-phosphatase. The scientists then used cellular assays to demonstrate that this PTEN gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. They concluded that these findings suggest that this novel, gain-of-funtion mutatin in PTEN can actively contribute to well-defined hallmarks of cancer. The results “demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy,” the scientists write.

The authors of this article are Helio A. Costa (Stanford), Michael G. Leitner (Marburg), Martin L. Sosc (UCSF, HHMI), Angeliki Mavrantoni (Marburg), Anna Rychkova (Stanford), Jeffrey R. Johnson (UCSF, Gladstone), Billy W. Newton (UCSF, Gladstone), Muh-Ching Yee (Stanford), Francisco M. De La Vega (Stanford), James M. Forda (Stanford), Nevan J. Krogan (UCSF, Stanford), Kevan M. Shokat (UCSF, HHMI), Dominik Oliver (Marburg), Christian R. Halaszovichb (Marburg), and Carlos D. Bustamante (Stanford).

[PNAS article] [Related PTEN article in BioQuick News & Nature]