Discovery and functional characterization of a neomorphic PTEN mutation.
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.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
Helio A
HA
Costa
Department of Neurophysiology, Philipps-Universität Marburg, 35037 Marburg, Germany;
Michael G
MG
Leitner
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; Howard Hughes Medical Institute, San Francisco, CA 94158;
Martin L
ML
Sos
Department of Neurophysiology, Philipps-Universität Marburg, 35037 Marburg, Germany;
Angeliki
A
Mavrantoni
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
Anna
A
Rychkova
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; J. David Gladstone Institutes, San Francisco, CA 94158.
Jeffrey R
JR
Johnson
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; J. David Gladstone Institutes, San Francisco, CA 94158.
Billy W
BW
Newton
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
Muh-Ching
MC
Yee
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
Francisco M
FM
De La Vega
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305;
James M
JM
Ford
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; J. David Gladstone Institutes, San Francisco, CA 94158.
Nevan J
NJ
Krogan
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158; Howard Hughes Medical Institute, San Francisco, CA 94158;
Kevan M
KM
Shokat
Department of Neurophysiology, Philipps-Universität Marburg, 35037 Marburg, Germany;
Dominik
D
Oliver
Department of Neurophysiology, Philipps-Universität Marburg, 35037 Marburg, Germany; cdbustam@stanford.edu christian.halaszovich@staff.uni-marburg.de.
Christian R
CR
Halaszovich
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305; cdbustam@stanford.edu christian.halaszovich@staff.uni-marburg.de.
Carlos D
CD
Bustamante
D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D019295:Computational Biology / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D016147:Genes, Tumor Suppressor; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008856:Microscopy, Fluorescence; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D018408:Patch-Clamp Techniques; D010716:Phosphatidylinositols / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000099182:Phosphoinositide 5-Phosphatases
D009363:Neoplasm Proteins; D051059:PTEN Phosphohydrolase; D010716:Phosphatidylinositols; D010744:Phosphoric Monoester Hydrolases; D000099182:Phosphoinositide 5-Phosphatases; C494929:PTEN protein, human
PTEN; functional genomics; tumor suppressor