Copy Number Loss of 17q22 Is Associated with Enzalutamide Resistance and Poor Prognosis in Metastatic Castration-Resistant Prostate Cancer.

Abstract

The purpose of this study was to measure genomic changes that emerge with enzalutamide treatment using analyses of whole-genome sequencing and RNA sequencing. One hundred and one tumors from men with metastatic castration-resistant prostate cancer (mCRPC) who had not been treated with enzalutamide (<i>n</i> = 64) or who had enzalutamide-resistant mCRPC (<i>n</i> = 37) underwent whole genome sequencing. Ninety-nine of these tumors also underwent RNA sequencing. We analyzed the genomes and transcriptomes of these mCRPC tumors. Copy number loss was more common than gain in enzalutamide-resistant tumors. Specially, we identified 124 protein-coding genes that were more commonly lost in enzalutamide-resistant samples. These 124 genes included eight putative tumor suppressors located at nine distinct genomic regions. We demonstrated that focal deletion of the 17q22 locus that includes <i>RNF43</i> and <i>SRSF1</i> was not present in any patient with enzalutamide-naïve mCRPC but was present in 16% (6/37) of patients with enzalutamide-resistant mCRPC. 17q22 loss was associated with lower <i>RNF43</i> and <i>SRSF1</i> expression and poor overall survival from time of biopsy [median overall survival of 19.3 months in 17q22 intact vs. 8.9 months in 17q22 loss, HR, 3.44 95% confidence interval (CI), 1.338-8.867, log-rank <i>P</i> = 0.006]. Finally, 17q22 loss was linked with activation of several targetable factors, including CDK1/2, Akt, and PLK1, demonstrating the potential therapeutic relevance of 17q22 loss in mCRPC. Copy number loss is common in enzalutamide-resistant tumors. Focal deletion of chromosome 17q22 defines a previously unappreciated molecular subset of enzalutamide-resistant mCRPC associated with poor clinical outcome.