Genomic Determinants of Lethality and Therapeutic Vulnerability in Castration-Resistant Prostate Cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) progression and treatment outcomes are influenced by complex molecular factors.
• Understanding the distinct genomic landscape of primary versus castration-resistant prostate cancer is crucial for targeted therapies.

Purpose of the Study:

• To identify key genomic drivers of progression and survival in mCRPC.
• To develop a multi-omic prognostic classifier for stratifying mCRPC patients.

Main Methods:

• Analysis of a large, multi-institutional cohort of mCRPC samples.
• Genomic profiling including detection of gene fusions, copy number alterations, and mutations.
• Integration of genomic data with transcriptomic phenotypes to develop a prognostic model.

Main Results:

• Androgen-regulated MYC fusions identified as early drivers of progression.
• TP53, RB1, and CDKN1B alterations are validated as strong predictors of poor survival in mCRPC.
• Distinct AR alterations (amplifications, mutations) show differential prognostic value in TP53-altered tumors.
• The CAPrisk classifier effectively stratifies patients into distinct risk groups with significant survival differences.
• CAPrisk demonstrates predictive value across multiple standard-of-care therapies.

Conclusions:

• Genomic determinants of mCRPC are distinct from primary prostate cancer.
• Specific genetic alterations (MYC, TP53, RB1, CDKN1B, AR) significantly impact mCRPC progression and survival.
• The multi-omic CAPrisk classifier provides a robust framework for risk stratification and personalized treatment selection in advanced prostate cancer.