Integrated Omics and Multicohort Analyses Identify an Enhancer Variant Linking Ferroptosis to Precision Therapy in...

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Prostate cancer is a leading global cancer in men with high heritability.
• Understanding genetic risk factors is crucial for developing targeted therapies.

Purpose of the Study:

• To identify genetic variants influencing prostate cancer susceptibility.
• To elucidate the molecular mechanisms underlying the identified genetic risk.

Main Methods:

• Integrative analysis of chromatin accessibility, transcriptomics, and case-control studies.
• Phenome-wide exploration in the FinnGen cohort.
• CRISPR/Cas9 gene editing and functional assays.

Main Results:

• Identified rs7077830 (10q11) as a key prostate cancer susceptibility SNP.
• rs7077830 drives NCOA4 expression via enhancer activity, impacting tumor progression.
• NCOA4 promotes ferroptosis, acting as a tumor suppressor and influencing treatment sensitivity.

Conclusions:

• Noncoding variants like rs7077830 play a significant role in prostate cancer.
• Enhancer-driven ferroptosis regulation offers new therapeutic strategies.
• rs7077830 genotypes correlate with ferroptosis status, suggesting personalized treatment approaches.