Genomic Profiling of Hormone-Naïve Lymph Node Metastases in Patients with Prostate Cancer

Department of Urology, University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA 94115, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 4.25). 01/2007; 8(12):1083-9. DOI: 10.1593/neo.06421
Source: PubMed


The progression of organ-confined prostate cancer to metastatic cancer is inevitably fatal. Consequently, identification of structural changes in the genome and associated transcriptional responses that drive this progression is critical to understanding the disease process and the development of biomarkers and therapeutic targets. In this study, whole genome copy number changes in genomes of hormone-naïve lymph node metastases were profiled using array comparative genomic hybridization, and matched primaries were included for a subset. Matched primaries and lymph node metastases showed very similar copy number profiles that are distinct from primary tumors that fail to metastasize.

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Available from: Giancarlo Albo, Jan 30, 2014
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    • "These data suggest that 8/12 primary-met pairs are more genetically similar to each other than the other tumors, consistent with a clonal expansion model [2], [23] and patient specific evolutionary trajectories [32]. Notably, almost every region of the genome is represented in the cumulative spectrum of CNAs observed in the collection of tumors, consistent with the known extensive genomic instability of EOC [3], [33] (Figure S4). Many CNAs are similar between the primary and metastatic tumor, as suggested by hierarchical clustering, however, notable differences are observed in each patient suggesting the metastases are genetically distinct from the primary tumor (Figure 3B). "
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    ABSTRACT: The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development.
    PLoS ONE 04/2014; 9(4):e94476. DOI:10.1371/journal.pone.0094476 · 3.23 Impact Factor
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    • "Advanced metastatic disease remains a daunting challenge to treat, most often leading to recurrent, drug resistant tumors. Metastases can be enriched for a distinct mutational spectrum compared to primary tumors [2], [3], [4]. Comparing primary and metastatic tumors has generated important insights into disease progression in both animal models [5] and in patients [2]. "
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    ABSTRACT: Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential expression in omental lesions compared to primary tumors. miR-21, miR-150, and miR-146a have low expression in most primary tumors with significantly increased expression in omental lesions, with concomitant decreased expression of predicted mRNA targets based on mRNA expression. We find that miR-150 and miR-146a mediate spheroid size. Both miR-146a and miR-150 increase the number of residual surviving cells by 2-4 fold when challenged with lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be critical regulators of the emergence of drug resistant disease.
    PLoS ONE 03/2013; 8(3):e58226. DOI:10.1371/journal.pone.0058226 · 3.23 Impact Factor
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    • "Using aCGH, we previously found a significant concordance between the copy number changes in primary prostate tumors and unmatched metastatic tumors [31]. Also, copy number changes of matched primary prostate tumor and hormone naïve lymph node metastasis are almost identical, suggesting that this method could be used for detecting genomic biomarkers with associated metastatic phenotypes [32]. Based on these observations, we hypothesize that a subset of copy number aberrations representative of a primary tumor and its metastatic lesions can be identified in CTCs, and thereby potentially extending the clinical utility of such a biomarker. "
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    ABSTRACT: Circulating tumor cells (CTCs) hold promise for studying advanced prostate cancer. A functional collagen adhesion matrix (CAM) assay was used to enrich CTCs from prostate cancer patients' blood. CAM ingestion and epithelial immuno-staining identified CTCs, which were genotyped using oligonucleotide array comparative genomic hybridization. The highest CTC counts were observed in men with metastatic castration resistant prostate cancer (CRPC) compared to castration sensitive prostate cancer. Copy number profiles for CRPC CTCs were similar to paired solid tumor DNA, and distinct from corresponding DNA from the residual CAM-depleted blood. CAM CTC enrichment may allow cellular and genetic analyses in prostate cancer.
    Cancer letters 02/2009; 277(2):164-73. DOI:10.1016/j.canlet.2008.12.007 · 5.62 Impact Factor
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