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

Jean-François Laes1, Sebastien Sauvage1, Gregori Ghitti1

  • 1OncoDNA SA, 6041 Gosselies, Belgium.

Oncotarget
|November 16, 2017
PubMed

Insights

The mechanistic target of rapamycin (mTOR) pathway is activated in most cancers. Mutations in PIK3CA and PTEN genes were analyzed, revealing potential biomarkers for cancer stratification.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The mechanistic target of rapamycin (mTOR) pathway is frequently hyperactivated in various human cancers.
  • Understanding the interplay between mTOR pathway activation and genetic mutations in upstream regulators like PIK3CA and PTEN is crucial for cancer research.

Purpose of the Study:

  • To investigate the association between mTOR pathway activation and functional mutations in PIK3CA and PTEN genes.
  • To evaluate the utility of combined biomarkers for cancer stratification.

Main Methods:

  • Analysis of formalin-fixed paraffin-embedded (FFPE) solid-tumor biopsies from diverse cancer types.
  • Utilized immunohistochemistry (IHC) to assess mTOR pathway activation via p-4E-BP1 expression.
  • Employed next-generation sequencing (NGS) to identify PIK3CA and PTEN mutations, with PTEN mutations confirmed by IHC.

Main Results:

  • mTOR pathway activation was observed in 83% of 538 tumor samples across 40 cancer types.
  • Functional mutations in PIK3CA and/or PTEN were found in 32% of samples.
  • While overall mTOR activation was not significantly linked to PIK3CA/PTEN genotypes, all samples with mutations in both genes showed mTOR activation (p=0.0471).
  • Specific associations were noted in breast cancer (lack of mTOR activation linked to PIK3CA/PTEN mutations) and colorectal cancer (higher PIK3CA mutation rates with mTOR activation).

Conclusions:

  • Combined assessment of mTOR pathway biomarkers using NGS and IHC may offer treatment-informative stratification for specific cancer types.
  • The study highlights the complex relationship between PIK3CA/PTEN mutations and mTOR pathway activity in solid tumors.
Keywords:
PIK3CA activation and PTEN lossbiomarkercancermTor activationtumor stratification

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