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).
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.
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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Sep 26 [Epub ahead of print]
Daniel Nava Rodrigues, Nicola Casiraghi, Alessandro Romanel, Mateus Crespo, Susana Miranda, Pasquale Rescigno, Ines Figueiredo, Ruth Riisnaes, Suzanne Carreira, Semini Sumanasuriya, Paola Gasperini, Adam Sharp, Joaquin Mateo, Alan Mackay, Christopher McNair, Matthew J Schiewer, Karen E Knudsen, Gunther Boysen, Francesca Demichelis, Johann S de Bono
The Institute of Cancer Research., University of Trento., Centre for Integrative Biology (CIBIO), University of Trento., Section of Medicine, The Institute of Cancer Research., Division of Clinical Studies, The Institute of Cancer Research., Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research., Cancer Biomarkers Team, The Institute of Cancer Research., Centre for Integrative Biology (CIBIO), Univeristy of Trento., Prostate Cancer Targeted Therapy Group, The Institute of Cancer Research., Prostate Cancer Translational Research, Vall d'Hebron Institute of Oncology (VHIO)., The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research., Cancer Biology, Thomas Jefferson University., Cancer Biology, Sidney Kimmel Cancer Center at Jefferson., Department of Cancer Biology, Thomas Jefferson University., The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust .