Subclonal p27 Loss and Altered Tumor Immune Microenvironment as a Driver of Fatal Prostate Cancer

Black or African American (AA) males are more likely to be diagnosed with advanced prostate cancer and are nearly 2.5 times more likely to die from the disease than European American (EA) males. This increased mortality may be due in part to a more aggressive molecular phenotype of the tumors of AA individuals. Key somatic genomic driver alterations in prostate cancer occur at differing frequency in AA and EA males, potentially contributing to differences in clinical outcomes. Likewise, many known somatic genomic driver alterations that are currently used in prognostic tests are more common in EA than AA males. Our preliminary studies indicate that p27 genomic alterations by somatic mutation and/or deletion are an unexpectedly common occurrence in primary prostate cancer, with subclonal complete loss observed in close to one out of every five cancers that we assessed. This finding would place p27 as one of the most frequently mutated/deleted genes in primary prostate cancer. Furthermore, subclonal p27 loss in primary prostate cancer was associated with worse outcomes including the development of biochemical recurrence and metastasis after radical prostatectomy, specifically in AA individuals. We hypothesize that the prevalence of p27 hemizygosity (p27+/-) and homozygous loss (p27-/-) has been underestimated in both primary prostate cancer and metastatic disease, and may contribute to worse prostate cancer outcomes in AA males. Our objective is to perform a systematic analysis of p27 alterations in both primary and metastatic prostate cancer in large, comprehensive cohorts. We ultimately aim to understand how subclonal p27 loss mediates worse prostate cancer outcomes. Furthermore, our study will lay the foundation for future clinical studies and/or clinical trials that will associate p27 loss in metastatic disease with treatment response to therapies for advanced prostate cancer including AR axis-targeted therapies, bipolar androgen therapy, and chemotherapy. Finally, we aim to assess a potentially modifiable risk factor (e.g., chronic inflammation) in driving subclonal p27 loss and prostate cancer aggressiveness.