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Insulin Pathway Changes in Localized Prostate Cancer: A Multi-Institutional Analysis.

Evan R Adler1, Anwaruddin Mohammad2, Pankaj Kumar2

  • 1Department of Internal Medicine, University of Virginia, Charlottesville, VA 22904, USA.

Cancers
|May 27, 2026
PubMed
Summary
This summary is machine-generated.

Two prostate cancer patient groups showed distinct insulin pathway gene expression. While one group initially had worse survival, this difference vanished after accounting for other factors like tumor stage.

Keywords:
AKT-mTOR-PI3K signalingPTENRNA expressioninsulin resistanceinsulin signalinglocalizedprostate cancertranscriptome

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Prostate cancer progression to metastatic castrate-resistant disease remains a challenge.
  • Epidemiological studies link elevated IGF-1, hyperinsulinemia, and metabolic syndrome to increased prostate cancer risk.
  • Key insulin pathway genes (PTEN, FOXO, PIK3CA) are frequently altered in localized prostate tumors.

Purpose of the Study:

  • Characterize insulin pathway gene expression in localized prostate cancer.
  • Identify molecular mechanisms driving progression to metastatic disease.
  • Enrich for prostate tumors with worse survival outcomes.

Main Methods:

  • Utilized the Oncology Research Information Exchange Network (ORIEN) database for gene expression data.
  • Performed non-negative matrix factorization (NMF) clustering on 176 insulin pathway genes.
  • Conducted Gene Set Enrichment Analysis (GSEA) and Kaplan-Meier survival analysis.

Main Results:

  • Identified two distinct insulin gene expression clusters (Cluster 1: n=96, Cluster 2: n=337).
  • Cluster 1 showed decreased PTEN/PIK3R1 and increased AKT1/IRS1/2/FASN/IGFBP2/MTOR expression, with altered lipid metabolism and WNT pathways.
  • Cluster 1 patients had higher T and N stages, increased metastasis, and chemotherapy needs, but survival differences disappeared after adjusting for confounders.

Conclusions:

  • A subset of localized prostate cancers exhibits insulin pathway dysregulation.
  • Initial survival disadvantages in the dysregulated group were explained by confounders like tumor stage, grade, and age.
  • Mediation analysis indicated cluster status's effect on survival was independent of T or N stage, suggesting other factors influence outcomes.