Abstract:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2–4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three differ… Show more
“…First, we compared PC3 whole genomes with the whole genomes of patients with mCRPC [35,36]. Of 31 genes that have been found altered in mCRPC (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…10.1080/20013078.2018.1505403-F0003Figure 3. The DNA in PC3-derived L-EVs reports mCRCP-specific SCNV . (a) A subset of genes that are frequently amplified ( MYC, AKT1, PTK2, KLF10 ) or deleted ( PTEN ) in patients with mCRPC, as identified by two independent studies [35,36] and in PC3 cells and derived L-EVs (Table 1). (b) mRNA levels of MYC, AKT1, PTK2 and KLF10 are upregulated in mCRPC patients versus controls except PTEN is downregulated, in line with genomic data.…”
Cancer-derived extracellular vesicles (EVs) are membrane-enclosed structures of highly variable size. EVs contain a myriad of substances (proteins, lipid, RNA, DNA) that provide a reservoir of circulating molecules, thus offering a good source of biomarkers. We demonstrate here that large EVs (L-EV) (large oncosomes) isolated from prostate cancer (PCa) cells and patient plasma are an EV population that is enriched in chromosomal DNA, including large fragments up to 2 million base pair long. While L-EVs and small EVs (S-EV) (exosomes) isolated from the same cells contained similar amounts of protein, the DNA was more abundant in L-EV, despite S-EVs being more numerous. Consistent with in vitro observations, the abundance of DNA in L-EV obtained from PCa patient plasma was variable but frequently high. Conversely, negligible amounts of DNA were present in the S-EVs from the same patients. Controlled experimental conditions, with spike-ins of L-EVs and S-EVs from cancer cells in human plasma from healthy subjects, showed that circulating DNA is almost exclusively enclosed in L-EVs. Whole genome sequencing revealed that the DNA in L-EVs reflects genetic aberrations of the cell of origin, including copy number variations of genes frequently altered in metastatic PCa (i.e. MYC, AKT1, PTK2, KLF10 and PTEN). These results demonstrate that L-EV-derived DNA reflects the genomic make-up of the tumour of origin. They also support the conclusion that L-EVs are the fraction of plasma EVs with DNA content that should be interrogated for tumour-derived genomic alterations.
“…First, we compared PC3 whole genomes with the whole genomes of patients with mCRPC [35,36]. Of 31 genes that have been found altered in mCRPC (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…10.1080/20013078.2018.1505403-F0003Figure 3. The DNA in PC3-derived L-EVs reports mCRCP-specific SCNV . (a) A subset of genes that are frequently amplified ( MYC, AKT1, PTK2, KLF10 ) or deleted ( PTEN ) in patients with mCRPC, as identified by two independent studies [35,36] and in PC3 cells and derived L-EVs (Table 1). (b) mRNA levels of MYC, AKT1, PTK2 and KLF10 are upregulated in mCRPC patients versus controls except PTEN is downregulated, in line with genomic data.…”
Cancer-derived extracellular vesicles (EVs) are membrane-enclosed structures of highly variable size. EVs contain a myriad of substances (proteins, lipid, RNA, DNA) that provide a reservoir of circulating molecules, thus offering a good source of biomarkers. We demonstrate here that large EVs (L-EV) (large oncosomes) isolated from prostate cancer (PCa) cells and patient plasma are an EV population that is enriched in chromosomal DNA, including large fragments up to 2 million base pair long. While L-EVs and small EVs (S-EV) (exosomes) isolated from the same cells contained similar amounts of protein, the DNA was more abundant in L-EV, despite S-EVs being more numerous. Consistent with in vitro observations, the abundance of DNA in L-EV obtained from PCa patient plasma was variable but frequently high. Conversely, negligible amounts of DNA were present in the S-EVs from the same patients. Controlled experimental conditions, with spike-ins of L-EVs and S-EVs from cancer cells in human plasma from healthy subjects, showed that circulating DNA is almost exclusively enclosed in L-EVs. Whole genome sequencing revealed that the DNA in L-EVs reflects genetic aberrations of the cell of origin, including copy number variations of genes frequently altered in metastatic PCa (i.e. MYC, AKT1, PTK2, KLF10 and PTEN). These results demonstrate that L-EV-derived DNA reflects the genomic make-up of the tumour of origin. They also support the conclusion that L-EVs are the fraction of plasma EVs with DNA content that should be interrogated for tumour-derived genomic alterations.
“…Through integration of the mutation and copy number data, they implicated the WNT and PTEN pathways as being altered in a large number of tumors. Grasso et al 47 also described a frequent copy number loss on chromosome 5q21 at the location of CHD1, a gene encoding a chromatinremodeling enzyme, and documented loss or mutation in multiple chromatin-remodeling genes, as has been found for multiple tumor types. 47,[52][53][54] They documented that multiple of these chromatinmodifying genes directly interact with the androgen receptor and along with additional regulators, such as FOXA1, can partially explain the androgen-resistant nature of the tumors they sequenced.…”
Section: Somatic Alterations In Tumorsmentioning
confidence: 79%
“…Three studies [45][46][47] have been published to date with genome/exome sequence of more than 10 prostate tumors. One challenge with PCa is the high proportion of normal cells and heterogeneity in the primary tumor.…”
Section: Somatic Alterations In Tumorsmentioning
confidence: 99%
“…46 These SPOP mutations affect conserved residues in the putative substrate-binding cleft and these altered residues (Tyr87, Trp131 and Phe133) have key roles in substrate interaction, 51 and knockdown of SPOP increases invasiveness of PCa cell lines. 46 Grasso et al 47 sequenced the exomes of 50 lethal, metastatic castrate-resistant PCas and 11 treatment-naive, high-grade localized tumors. They identified mutations in the known genes TP53, AR, ZFHX3, RB1, PTEN and APC and described three additional significantly mutated genes: MLL2, OR5L1 and CDK12.…”
Prostate cancer (PCa) is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically through tumors that evolve to be hormone-refractory or castrate-resistant. Despite intensive epidemiological study, there are few known environmental risk factors, and age and family history are the major determinants. However, there is extreme heterogeneity in PCa incidence worldwide, suggesting that major determining factors have not been described. Genome-wide association studies have been performed and a considerable number of significant, but low-risk loci have been identified. In addition, several groups have analyzed PCa by determination of genomic copy number, fusion gene generation and targeted resequencing of candidate genes, as well as exome and whole genome sequencing. These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53 and other potential driver genes, and the disturbance of androgen response and cell cycle pathways. It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding, diagnosing and better treating PCa.
Key Points
Question
Is there a role for platinum-based treatment in molecularly selected patients with advanced prostate cancer?
Findings
In a case series of 508 patients, platinum-based therapy was associated with antitumor activity, especially among patients with known DNA repair gene aberrations. In patients with DNA repair gene aberrations, nearly half had a decrease in prostate-specific antigen levels of at least 50% and experienced soft tissue responses.
Meaning
In patients with prostate cancer and DNA repair gene aberrations, platinum-based therapy may be considered a treatment option.
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