RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer

RB1 Heterogeneity in Advanced Metastatic Castration-Resistant Prostate Cancer

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 who...

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Published in:Clinical cancer research Vol. 25; no. 2; pp. 687 - 697
Main Authors: Nava Rodrigues, Daniel, Casiraghi, Nicola, Romanel, Alessandro, Crespo, Mateus, Miranda, Susana, Rescigno, Pasquale, Figueiredo, Ines, Riisnaes, Ruth, Carreira, Suzanne, Sumanasuriya, Semini, Gasperini, Paola, Sharp, Adam, Mateo, Joaquin, Makay, Alan, McNair, Christopher, Schiewer, Matthew, Knudsen, Karen, Boysen, Gunther, Demichelis, Francesca, de Bono, Johann S
Format: Journal Article
Language:English
Published: United States 15-01-2019
Subjects:
Aged
Biomarkers, Tumor
Cell Line, Tumor
DNA Copy Number Variations
Genetic Heterogeneity
Genetic Variation
Genome-Wide Association Study
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Male
Middle Aged
Neoplasm Grading
Neoplasm Staging
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - pathology
Retinoblastoma Binding Proteins - genetics
Ubiquitin-Protein Ligases - genetics
Whole Genome Sequencing
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Summary: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). WGS was performed on topographically separate metastases from patients with advanced metastatic prostate cancer. IPMH of the gene was identified and further evaluated by FISH and IHC assays. WGS identified limited IPMH for putative driver events. However, heterogeneous genomic aberrations of were detected. We confirmed the presence of these somatic copy-number aberrations, initially identified by WGS, with FISH, and identified novel structural variants involving in 6 samples from 3 of these 10 patients (30%; 3/10). WGS uncovered a novel deleterious 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 genomic aberrations, with structural variants, including rearrangements, being common. Intrapatient genomic and expression heterogeneity favors aberrations as late, subclonal events that increase in prevalence due to treatment-selective pressures.
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ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-18-2068