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Integrated Analysis Reveals Critical Genomic Regions in Prostate Tumor Microenvironment Associated with Clinicopathologic Phenotypes

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Integrated Analysis Reveals Critical Genomic Regions in Prostate Tumor Microenvironment Associated with Clinicopathologic Phenotypes Published OnlineFirst January 24, 2012; DOI: 10.1158/1078-0432.CCR-11-2535 Clinical Cancer Human Cancer Biology Research Integrated Analysis Reveals Critical Genomic Regions in Prostate Tumor Microenvironment Associated with Clinicopathologic Phenotypes Shingo Ashida1, Mohammed S. Orloff1,3, Gurkan Bebek1,5,7, Li Zhang1,2, Pan Zheng8,9, Donna M. Peehl10, and Charis Eng1,3,4,6,7 Abstract Purpose: Recent studies suggest that tumor microenvironment (stroma) is important in carcinogenesis and progression. We sought to integrate global genomic structural and expressional alterations in prostate cancer epithelium and stroma and their association with clinicopathologic features. Experimental Design: We conducted a genome-wide LOH/allelic imbalance (AI) scan of DNA from epithelium and stroma of 116 prostate cancers. LOH/AI hot or cold spots were defined as the markers with significantly higher or lower LOH/AI frequencies compared with the average frequency for markers along the same chromosome. These data were then integrated with publicly available transcriptome data sets and our experimentally derived data. Immunohistochemistry on an independent series was used for validation. Results: Overall, we identified 43 LOH/AI hot/cold spots, 17 in epithelium and stroma (P < 0.001), 18 only in epithelium (P < 0.001), and eight only in stroma (P < 0.001). Hierarchical clustering of expression data supervised by genes within LOH/AI hot/cold spots in both epithelium and stroma accurately separated samples into normal epithelium, primary cancer, and metastatic cancer groups, which could not be achieved with data from only epithelium. Importantly, our experimental expression data of the genes within the LOH/AI hot/cold spots in stroma accurately clustered normal stroma from cancer stroma. We also identified 15 LOH/AI markers that were associated with Gleason score, which were validated functionally in each compartment by transcriptome data. Independent immunohistochemical validation of STIM2 within a stromal significant LOH marker (identified as associated with Gleason grade) confirmed its downregulation in the transition from moderate to high Gleason grade. Conclusions: Compartment-specific genomic and transcriptomic alterations accurately distinguish clinical and pathologic outcomes, suggesting new biomarkers for prognosis and targeted therapeutics. Clin Cancer Res; 18(6); 1578–87. Ó2012 AACR. Introduction tumor microenvironment as equally important in carcino- Previous studies have mainly focused on changes in the genesis and progression. Genetic changes in tumor stroma epithelium, but recent investigations have highlighted the have been reported by several independent groups working on a range of solid tumors (1–19), although typically, only selected markers have been used in most of these studies to Authors' Affiliations: 1Genomic Medicine Institute, 2Section of Statistical assess LOH/allelic imbalance (AI). Genetics and Bioinformatics, Department of Quantitative Health Sciences, Lerner Research Institute; 3Taussig Cancer Institute; 4Stanley Shalom In prostate cancer, it has also been suggested that tumor Zielony Institute for Nursing Excellence, Cleveland Clinic; 5Center for microenvironment plays an important role in the progres- 6 7 Proteomics and Bioinformatics, Department of Genetics, CASE Com- sion, acquisition of androgen independence, and distant prehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland; 8Department of Pathology, The Ohio State University, metastases (20–22). Tumor–microenvironment interac- Columbus, Ohio; 9Division of Immunotherapy, Department of Surgery, and tions through diffusible soluble factors such as TGF-b,as Program of Molecular Medicine, Comprehensive Cancer Center, University of Michigan Medical Center, Ann Arbor, Michigan; and 10Department of well as the extracellular matrix, likely lead to the develop- Urology, Stanford University School of Medicine, Stanford, California ment of metastasis (20). Nonetheless, little is known about Note: Supplementary data for this article are available at Clinical Cancer the genetic basis of the human prostate tumor microenvi- Research Online (http://clincancerres.aacrjournals.org/). ronment; one report described genotypic heterogeneity in Corresponding Author: Charis Eng, Cleveland Clinic Genomic Medicine mesenchymal cells with a small number of markers (9) and Institute, 9500 Euclid Avenue, Mailstop NE-50, Cleveland, OH 44195. another showed allelic losses in the stromal component Phone: 216-444-3440; Fax: 216-636-0655; E-mail: [email protected] with a small number of samples and markers (23). These doi: 10.1158/1078-0432.CCR-11-2535 findings suggest that genetic alterations in prostate cancer Ó2012 American Association for Cancer Research. stroma exist and may be biologically relevant. 1578 Clin Cancer Res; 18(6) March 15, 2012 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst January 24, 2012; DOI: 10.1158/1078-0432.CCR-11-2535 Integrated Genome-Wide Analyses for Prostate Cancer Stroma we used standard and well-established protocols to mini- Translational Relevance mize this, as reported previously (8, 18, 24, 25). Corre- Genome-wide LOH/allelic imbalance (AI) analysis of sponding normal DNA for each case was procured from DNA from epithelium and stroma of 116 prostate can- normal tissue, located a distance away from the tumor or cers revealed 43 LOH/AI hot/cold spots, 17 in both from a different tissue (formalin-fixed, paraffin-embedded) epithelium and stroma (P < 0.001), 18 only in epithe- block containing only normal tissue (latter being the first lium (P < 0.001), and eight only in stroma (P < 0.001). choice). Genomic DNA was extracted as previously Integration of experimentally derived transcriptome described, with the exception that incubation in proteinase data of genes within the significant LOH/AI hot/cold K was done at 65C for 2 days (7). Primer sets for multiplex spots in stroma revealed 15 LOH/AI markers that were PCR defined 381 microsatellite markers in 72 multiplex associated with Gleason score. Independent immuno- panels (Research Genetics, Invitrogen). Genotyping, anal- histochemical validation of one of these identified yses, and scoring of LOH/AI were done as reported STIM2 genes within a stromal significant LOH marker (24, 26, 27). The methodologic veracity of LOH/AI scan (identified as associated with Gleason grade) confirmed using multiplex PCR on archived templates was extensively its downregulation in the transition from moderate to validated as published, that is, by a series of control experi- high Gleason grade. Stromal genomic and transcrip- ments using chromogenic in situ hybridization (CISH), tomic alterations may be helpful in pinpointing aggres- quantitative PCR, to eliminate the possibility of epitheli- sive prostate cancers. al–stromal cell cross-contamination and to exclude any possibility of PCR artifact (24, 25). Data analysis The data set contains LOH/AI status at 381 microsatellite To attain a global perspective of epithelial and stromal markers for 116 different samples, each with neoplastic specific LOH/AI changes for prostate cancer and further epithelium, tumor stroma, and normal tissue. The same 10 refine our understanding of the LOH/AI regions, we con- markers were never informative in at least one compartment ducted a genome-wide LOH/AI scan using 381microsatel- and so excluded from further analyses. First, we sought to lite markers and subsequently integrated these structural define regional LOH/AI hot/cold spots as the markers with data with publicly available and experimental expressional significantly higher or lower frequency of LOH/AI com- array analyses. We also sought to determine whether com- pared with the average frequency of the markers along the partment-specific LOH/AI could be correlated with clinico- same chromosome. We analyzed hot and cold spots of pathologic features. Finally, we conducted two types of LOH/AI together with the concept that the genetic endpoint validation: functional genomic validation and immunohis- may be similar, for example, loss of a tumor suppressor gene tochemistry in an independent series of prostate cancer. and gain (cold spot) of an oncogenic event. Toward those ends, for each informative marker, the statistical signifi- Materials and Methods cance of overall (across all samples) LOH/AI frequency Patients and samples compared with the respective chromosome average was We obtained 116 prostate cancer samples at any tumor analyzed using the exact binomial test (R base package classification with or without lymph node metastasis and binom.test; http://www.r-project.org). Second, the associa- analyzed them in accordance with the respective Institu- tions of LOH/AI across all informative markers (not just hot/ tion’s Human Subjects Protection Committees. All slides cold spot markers) in epithelial and stromal samples with were rereviewed by a single genitourinary pathologist (P. presenting clinicopathologic features (i.e., Gleason score, Zheng). Clinical information such as Gleason score, tumor tumor volume, and the status of lymph node metastasis) volume, and the status of lymph node metastasis was noted were analyzed using a logistic model with LOH frequency as (Supplementary Table S1). An independent validation an outcome and each clinicopathologic feature as a predic- series of prostate cancer is described under Immunohisto- tor (28, 29). Multiple testing adjustment was applied by
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