RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer.

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a lethal but clinically heterogeneous disease, with patients having variable benefit from endocrine and cytotoxic treatments. Intrapatient genomic heterogeneity could be a contributing factor to this clinical heterogeneity. Here, we used whole-genome sequencing (WGS) to investigate genomic heterogeneity in 21 previously treated CRPC metastases from 10 patients to investigate intrapatient molecular heterogeneity (IPMH).<b>Experimental Design:</b> WGS was performed on topographically separate metastases from patients with advanced metastatic prostate cancer. IPMH of the <i>RB1</i> gene was identified and further evaluated by FISH and IHC assays. WGS identified limited IPMH for putative driver events. However, heterogeneous genomic aberrations of <i>RB1</i> were detected. We confirmed the presence of these <i>RB1</i> somatic copy-number aberrations, initially identified by WGS, with FISH, and identified novel structural variants involving <i>RB1</i> in 6 samples from 3 of these 10 patients (30%; 3/10). WGS uncovered a novel deleterious <i>RB1</i> structural lesion constituted of an intragenic tandem duplication involving multiple exons and associating with protein loss. Using RB1 IHC in a large series of mCRPC biopsies, we identified heterogeneous expression in approximately 28% of mCRPCs. mCRPCs have a high prevalence of <i>RB1</i> genomic aberrations, with structural variants, including rearrangements, being common. Intrapatient genomic and expression heterogeneity favors <i>RB1</i> aberrations as late, subclonal events that increase in prevalence due to treatment-selective pressures.