Discovery and functional characterization of a neomorphic PTEN mutation.

Abstract

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. Here, we use whole genome sequencing 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. We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this 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. These findings suggest that mutationally modified PTEN can actively contribute to well-defined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These 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.

• Authors: Helio A Costa, Michael G Leitner, Martin L Sos, Angeliki Mavrantoni, Anna Rychkova, Jeffrey R Johnson, Billy W Newton, Muh-Ching Yee, Francisco M De La Vega, James M Ford, Nevan J Krogan, Kevan M Shokat, Dominik Oliver, Christian R Halaszovich, Carlos D Bustamante
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 45 Pg. 13976-81 (Nov 10 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26504226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Neoplasm Proteins
• Phosphatidylinositols
• Phosphoric Monoester Hydrolases
• phosphoinositide 5-phosphatase
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Analysis of Variance
• Animals
• Base Sequence
• CHO Cells
• Cell Movement (physiology)
• Cell Proliferation (physiology)
• Computational Biology (methods)
• Cricetinae
• Cricetulus
• Genes, Tumor Suppressor
• Humans
• Immunoblotting
• Male
• Microscopy, Fluorescence
• Molecular Sequence Annotation
• Molecular Sequence Data
• Mutagenesis, Site-Directed
• Neoplasm Proteins (genetics)
• PTEN Phosphohydrolase (genetics)
• Patch-Clamp Techniques
• Phosphatidylinositols (metabolism)
• Phosphoric Monoester Hydrolases (genetics, metabolism)
• Prostatic Neoplasms (genetics)
• Sequence Analysis, DNA