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  1. Home
  3. A Comparative Analysis Indicates Slc7a11 Expression Regulate The Prognostic Value Of Keap1-nfe2l2-cul3 Mutations In Human Uterine Corpus Endometrial Carcinoma.
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A Comparative Analysis Indicates Slc7a11 Expression Regulate The Prognostic Value Of Keap1-nfe2l2-cul3 Mutations In Human Uterine Corpus Endometrial Carcinoma.

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A comparative analysis indicates SLC7A11 expression regulate the prognostic value of KEAP1-NFE2L2-CUL3 mutations in

Akhileshwar Namani1, Durgadevi Veeraiyan1, Tapas Patra1

  • 1Department of Molecular Research, Sri Shankara Cancer Hospital and Research Centre, Bangalore, India.

Free Radical Biology & Medicine
|June 14, 2024

View abstract on PubMed

Summary
This summary is machine-generated.

KEAP1-NFE2L2-CUL3 gene mutations in uterine corpus endometrial cancer (UCEC) are linked to better progression-free survival, unlike in lung adenocarcinoma (LUAD). This suggests a novel therapeutic vulnerability in UCEC related to oxidative stress and glutathione metabolism.

Keywords:
Glutathione synthesisKEAP1-NFE2L2-CUL3 mutationProgression free survivalThe cancer genome atlasUterine corpus endometrial carcinoma

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Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Uterine corpus endometrial cancer (UCEC) is a prevalent malignancy with poor outcomes in advanced stages.
  • Understanding the molecular drivers of UCEC is crucial for developing effective therapeutic strategies.
  • Comparative multi-omics analysis across different cancer types can reveal cancer-specific vulnerabilities.

Purpose of the Study:

  • To conduct an integrated comparative analysis of exome and transcriptome data from UCEC and Lung Adenocarcinoma (LUAD) patients.
  • To investigate the differential impact of KEAP1-NFE2L2-CUL3 gene mutations on patient outcomes and molecular mechanisms in UCEC versus LUAD.
  • To elucidate the role of glutathione metabolism and cystine import in UCEC pathogenesis associated with specific genetic mutations.

Main Methods:

  • Comparative analysis of The Cancer Genome Atlas (TCGA) exome and transcriptome data from UCEC and LUAD cohorts.
  • Investigated the association between KEAP1-NFE2L2-CUL3 gene mutations and progression-free survival (PFS).
  • Performed functional annotations and correlative expression studies focusing on genes involved in glutathione synthesis, recycling, and cystine import (e.g., SLC7A11, GCLC, GCLM).

Main Results:

  • KEAP1-NFE2L2-CUL3 mutations were associated with better PFS in UCEC but poorer outcomes in LUAD.
  • UCEC patients with these mutations exhibited lower expression of glutathione synthesis genes (GCLC, GCLM), leading to glutathione deficiency and potential ROS imbalance.
  • Increased SLC7A11 expression in UCEC facilitated high cystine import, causing di-sulfite stress due to impaired glutathione synthesis; co-occurring ARID1A mutations further worsened PFS.

Conclusions:

  • KEAP1-NFE2L2-CUL3 mutations in UCEC create a unique cellular environment characterized by glutathione deficiency and di-sulfite stress, paradoxically leading to favorable clinical outcomes.
  • The interplay between KEAP1-NFE2L2-CUL3 mutations, altered glutathione metabolism, and increased cystine import represents a potential therapeutic vulnerability in UCEC.
  • Targeting pathways involved in oxidative stress and amino acid import may offer novel treatment strategies for UCEC patients with specific genetic profiles.