Discovery and functional characterization of a neomorphic PTEN mutation

Identification of putative functional genetic mutations involved in cancer has been dramatically accelerated by developments in next generation sequencing technologies. However, analyzing an individual patient genome and interpreting mutation spectra to inform cancer origin and targeted treatment have been challenging. This study presents a framework interpreting a single patient’s genome and identifies a novel causal mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor. Through computational and experimental approaches, we demonstrate that this mutation causes PTEN to retain known tumor suppressor function while gaining protumor activity. This finding suggests a new role for PTEN and other tumor suppressor involvement in cancer formation and reveals the potential wealth of biological information currently underexploited by the lack of systematic approaches for cancer genome interpretation services.

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.