Landscape of Cyclin Pathway Genomic Alterations Across 5,356 Prostate Cancers: Implications for Targeted Therapeutics

The cyclin pathway may confer resistance to standard treatments but also offer novel therapeutic opportunities in prostate cancer. Herein, we analyzed prostate cancer samples (majority metastatic) using comprehensive genomic profiling performed by next-generation sequencing (315 genes, >500x coverage) for alterations in activating and sensitizing cyclin genes (CDK4 amplification, CDK6 amplification, CCND1, CCND2, CCND3, CDKN2B [loss], CDKN2A [loss], SMARCB1), androgen receptor (AR) gene, and coalterations in genes leading to cyclin inhibitor therapeutic resistance (RB1 and CCNE1). Overall, cyclin sensitizing pathway genomic abnormalities were found in 9.7% of the 5,356 tumors. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Alterations in possible resistance genes, RB1 and CCNE1, were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, whereas AR alterations were seen in 20.9% of tumors (similar to 27.3% in anaplastic). Cyclin sensitizing alterations were also more frequently associated with concomitant AR alterations.

Automated summary

This study found that 9.7% of prostate cancer samples exhibited genomic abnormalities in the cyclin sensitizing pathway, with frequent alterations including CCND1 amplification and CDKN2A and B loss. Additionally, alterations in possible resistance genes RB1 and CCNE1 were detected in a smaller percentage of cases. Furthermore, cyclin sensitizing alterations were often associated with concomitant AR alterations.