RB1 Heterogeneity in Advanced Metastatic Castration Resistant Prostate Cancer

Purpose: Metastatic castration resistant prostate cancer (mCRPC) is a lethal but clinically heterogeneous disease, with patients having variable benefit from endocrine and cytotoxic treatments. Intra-patient 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 intra-patient molecular heterogeneity (IPMH). Experimental Design: WGS was performed on topographically separate metastases from patients with advanced metastatic prostate cancer (PCa). IPMH of the RB1 gene was identified and further evaluated by fluorescent in situ (FISH) and immunohistochemistry (IHC) assays. Results: WGS identified limited IPMH for putative driver events. However, heterogeneous genomic aberrations of RB1 were detected. We confirmed the presence of these RB1 somatic copy number aberrations (SCNA), initially identified by WG, with FISH, and identified novel structural variants (SV) involving RB1 in 6 samples from three of these ten patients (30%; 3/10). WGS uncovered a novel deleterious RB1 structural lesion constituted of an intra-genic 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 ~28% of mCRPCs. Conclusion: mCRPCs have a high prevalence of RB1 genomic aberrations, with structural variants, including rearrangements, being common. Intra-patient genomic and expression heterogeneity favor RB1 aberrations as late, sub-clonal events that increase in prevalence due to treatment selective pressures.

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