Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer

Abstract

Next-generation sequencing is making sequence-based molecular pathology and personalized oncology viable. We selected an individual initially diagnosed with conventional but aggressive prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology-pathology and copy number profiles were remarkably homogeneous, yet it was possible to propose the quadrant of the prostate tumour that likely seeded the metastatic diaspora. Despite a homogeneous cell type, our transcriptome analysis revealed signatures of both luminal and neuroendocrine cell types. Remarkably, the repertoire of expressed but apparently private gene fusions, including C15orf21:MYC, recapitulated this biology. We hypothesize that the amplification and over-expression of the stem cell gene MSI2 may have contributed to the stable hybrid cellular identity. This hybrid luminal-neuroendocrine tumour appears to represent a novel and highly aggressive case of prostate cancer with unique biological features and, conceivably, a propensity for rapid progression to castrate-resistance. Overall, this work highlights the importance of integrated analyses of genome, exome and transcriptome sequences for basic tumour biology, sequence-based molecular pathology and personalized oncology.

High Fidelity Patient-Derived Xenografts for Accelerating Prostate Cancer Discovery and Drug Development

“…For DNA and RNA isolation, patient and xenograft tumor sections were processed as previously described (22). We performed genome copy-number profiling using the Agilent SurePrint G3 Human CGH 4 Â 180K and 8 Â 60K Microarray platforms.…”

“…We performed genome copy-number profiling using the Agilent SurePrint G3 Human CGH 4 Â 180K and 8 Â 60K Microarray platforms. Of note, 0.5 mg of genomic DNA was used for hybridization, according to the manufacturer's standard protocols as previously described (7,22). Limited sample availability of patient samples 972 and 1,005 prevented array comparative genomic hybridization (aCGH) analysis.…”

Prostate-specific membrane antigen–directed nanoparticle targeting for extreme nearfield ablation of prostate cancer cells

“…Different amounts (2,5,8,10, and 12 µg) of α-mouse HRP-IgG were conjugated onto MWCNTs as outlined in our protocol. A diluted (1:10) portion of each sample was loaded onto a microtiter plate and mixed with chemiluminescent solution.…”

“…CaP studies have shown extensive genetic alterations exemplified by single missense mutations, copy number variation, splicing variants, genetic rearrangements, and short DNA alterations in a large number of genes. 3,[7][8][9][10][11][12] However, physical agent therapies are immune to genetic alterations, as they are more likely to deliver damaging entities to a targeted "area" or "field," and as such are lethal to tumor cells irrespective of their genetic background, as long as they are present within the targeted area.…”

Generation 2.5 Antisense Oligonucleotides Targeting the Androgen Receptor and Its Splice Variants Suppress Enzalutamide-Resistant Prostate Cancer Cell Growth

“…Genome copy number profiling was performed on Agilent SurePrint G3 Human CGH Microarray Kit, 4 Â 180 K in 4 ENZ-R LNCaP and 2 CRPC LNCaP xenografts tumors as described previously (27). Array CGH copy number data are available at GEO accession number GSE55345.…”