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Clin Cancer Res. 2019 Jan 15;25(2):687-697. doi: 10.1158/1078-0432.CCR-18-2068. Epub 2018 Sep 26.

RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer.

Author information

1
The Royal Marsden NHS Foundation Trust, London, United Kingdom.
2
The Institute of Cancer Research, London, United Kingdom.
3
Centre for Integrative Biology (CIBIO), University of Trento, Laboratory of Functional and Computational Oncology, Trento, Italy.
4
Centre for Integrative Biology (CIBIO), University of Trento, Laboratory of Bioinformatics and Computational Genomics, Trento, Italy.
5
Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain.
6
Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, New York.
7
Centre for Integrative Biology (CIBIO), University of Trento, Laboratory of Functional and Computational Oncology, Trento, Italy. johann.de-bono@icr.ac.uk f.demichelis@unitn.it.
8
The Royal Marsden NHS Foundation Trust, London, United Kingdom. johann.de-bono@icr.ac.uk f.demichelis@unitn.it.
#
Contributed equally

Abstract

PURPOSE:

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).Experimental Design: WGS was performed on topographically separate metastases from patients with advanced metastatic prostate cancer. IPMH of the RB1 gene was identified and further evaluated by FISH and 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, initially identified by WGS, with FISH, and identified novel structural variants involving RB1 in 6 samples from 3 of these 10 patients (30%; 3/10). WGS uncovered a novel deleterious RB1 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.

CONCLUSIONS:

mCRPCs have a high prevalence of RB1 genomic aberrations, with structural variants, including rearrangements, being common. Intrapatient genomic and expression heterogeneity favors RB1 aberrations as late, subclonal events that increase in prevalence due to treatment-selective pressures.

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