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RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer.

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Date
2019-01
ICR Author
Sumanasuriya, Semini
Rescigno, Pasquale
Sharp, Adam
Carreira, Suzanne
Mackay, Alan
De Bono, Johann
Miranda, Susana
Crespo, Mateus
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Author
Nava Rodrigues, D
Casiraghi, N
Romanel, A
Crespo, M
Miranda, S
Rescigno, P
Figueiredo, I
Riisnaes, R
Carreira, S
Sumanasuriya, S
Gasperini, P
Sharp, A
Mateo, J
Makay, A
McNair, C
Schiewer, M
Knudsen, K
Boysen, G
Demichelis, F
de Bono, JS
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/2930
DOI
https://doi.org/10.1158/1078-0432.ccr-18-2068
Collections
  • Cancer Therapeutics
  • Clinical Studies
  • Molecular Pathology
Subject
Cell Line, Tumor
Humans
Ubiquitin-Protein Ligases
Neoplasm Staging
Immunohistochemistry
In Situ Hybridization, Fluorescence
Genetic Heterogeneity
Aged
Middle Aged
Male
Genetic Variation
Genome-Wide Association Study
Retinoblastoma Binding Proteins
DNA Copy Number Variations
Neoplasm Grading
Prostatic Neoplasms, Castration-Resistant
Biomarkers, Tumor
Whole Genome Sequencing
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Glioma Team
Language
eng
Date accepted
2018-09-18
License start date
2019-01
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (2), pp. 687 - 697

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