Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

Ilya G. Serebriiskii (), Valery Pavlov, Rossella Tricarico, Grigorii Andrianov, Emmanuelle Nicolas, Mitchell I. Parker, Justin Newberg, Garrett Frampton, Joshua E. Meyer and Erica A. Golemis ()
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Ilya G. Serebriiskii: Program in Molecular Therapeutics, Fox Chase Cancer Center
Valery Pavlov: Kazan Federal University, Russian Federation
Rossella Tricarico: Program in Molecular Therapeutics, Fox Chase Cancer Center
Grigorii Andrianov: Program in Molecular Therapeutics, Fox Chase Cancer Center
Emmanuelle Nicolas: Program in Molecular Therapeutics, Fox Chase Cancer Center
Mitchell I. Parker: Program in Molecular Therapeutics, Fox Chase Cancer Center
Justin Newberg: Foundation Medicine Inc
Garrett Frampton: Foundation Medicine Inc
Joshua E. Meyer: Program in Molecular Therapeutics, Fox Chase Cancer Center
Erica A. Golemis: Program in Molecular Therapeutics, Fox Chase Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.

Date: 2022
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DOI: 10.1038/s41467-022-29227-2

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