Oncotarget

Research Papers:

Tumor-biopsy stratification based on mTOR-pathway activity and functional mutations in the upstream genes PIK3CA and PTEN

Jean-François Laes _, Sebastien Sauvage, Gregori Ghitti

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Oncotarget. 2017; 8:84426-84433. https://doi.org/10.18632/oncotarget.21348

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Abstract

Jean-François Laes1, Sebastien Sauvage1 and Gregori Ghitti1

1OncoDNA SA, 6041 Gosselies, Belgium

Correspondence to:

Jean-François Laes, email: jf.laes@oncodna.com

Keywords: cancer, biomarker, tumor stratification, mTor activation, PIK3CA activation and PTEN loss

Received: August 16, 2016    Accepted: September 01, 2017    Published: September 28, 2017

ABSTRACT

The mechanistic target of the rapamycin (mTOR) pathway is frequently activated in human cancers. Our objective was to evaluate relationships between mTOR-pathway activity and functional mutations in the upstream genes PIK3CA and PTEN in solid-tumor biopsies from a broad selection of cancer types.

Formalin-fixed paraffin-embedded (FFPE) tumor samples were analyzed by immunohistochemistry (IHC) and next-generation sequencing (NGS). TOR-pathway activation was identified by expression (by IHC) of the downstream effector p-4E-BP1. Activating PIK3CA mutations and null PTEN mutations were identified by NGS, and for PTEN, confirmed by IHC.

Overall, mTOR-pathway activation was identified in 444/538 (83%) samples representing 40 different cancer types. Functional mutations in either or both PIK3CA and PTEN genes were identified in 173/538 (32%) samples. PIK3CA mutations were identified in 60/538 (11%) samples, PTEN mutations were identified in 155/538 (29%) samples and mutations in both PIK3CA and PTEN were identified in 18/538 (3%) samples. Overall, mTOR-pathway activation was not significantly associated with the PIK3CA and PTEN genotypes. However, all 18 samples with both PIK3CA and PTEN mutations also displayed mTOR-pathway activation (χ2 p=0.0471). Also, out of a total of 95 breast cancer samples, there were 5 breast-cancer samples which did not have mTOR-pathway activation, and all 5 (100%) of these had PIK3CA and PTEN mutations compared to 51/90 (57%) in the breast-cancer samples with mTOR-pathway activation (χ2 p=0.0134). Finally, the percentages of PIK3CA mutations were higher in colorectal-cancer samples which had mTOR-pathway activation (9/27, 33%) than in colorectal-cancer samples without mTOR-pathway activation (6/44; 14%; χ2 p=0.0484).

Therefore, tumor-biopsy analyses based on combined mTOR-pathway biomarkers (and combined NGS and IHC assessments) could potentially provide treatment-informative stratification for particular cancer types.


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