High-resolution functional mapping of androgen receptor variants.

Area of Science:

• Molecular biology
• Genetics
• Oncology

Background:

• The androgen receptor (AR) is crucial in prostate cancer progression and treatment resistance.
• Current therapies like enzalutamide face challenges from drug-resistant AR variants.
• Germline AR loss-of-function mutations cause androgen insensitivity syndrome, but many AR variants have unknown significance.

Purpose of the Study:

• To comprehensively map single amino acid variants in the AR ligand-binding domain.
• To identify novel non-functional and drug-resistant AR variants.
• To improve diagnosis of androgen insensitivity syndrome and prognosis prediction for prostate cancer patients.

Main Methods:

• Utilized advanced prime editing technology.
• Generated and assessed 2,765 distinct AR variants.
• Covered 99.95% of single nucleotide variants in the AR ligand-binding domain.

Main Results:

• Identified 755 previously unknown non-functional AR variants.
• Discovered 225 new enzalutamide-resistant AR variants.
• Found 40 new bavdegalutamide-resistant AR variants.

Conclusions:

• Established a comprehensive variant map for the AR ligand-binding domain.
• Enabled better prediction of prostate cancer patient prognosis based on AR mutation profiles.
• Offers potential for improved androgen insensitivity syndrome diagnosis and precision prostate cancer treatments.