title: Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations.
abstract: Prostate cancer-associated stroma (CAS) plays an active role in malignant transformation, tumor progression, and metastasis. Molecular analyses of CAS have demonstrated significant changes in gene expression; however, conflicting evidence exists on whether genomic alterations in benign cells comprising the tumor microenvironment (TME) underlie gene expression changes and oncogenic phenotypes. This study evaluates the nuclear and mitochondrial DNA integrity of prostate carcinoma cells, CAS, matched benign epithelium and benign epithelium-associated stroma by whole-genome copy-number analyses, targeted sequencing of TP53, and FISH. Array comparative genomic hybridization (aCGH) of CAS revealed a copy-neutral diploid genome with only rare and small somatic copy-number aberrations (SCNA). In contrast, several expected recurrent SCNAs were evident in the adjacent prostate carcinoma cells, including gains at 3q, 7p, and 8q, and losses at 8p and 10q. No somatic TP53 mutations were observed in CAS. Mitochondrial DNA (mtDNA) extracted from carcinoma cells and stroma identified 23 somatic mtDNA mutations in neoplastic epithelial cells, but only one mutation in stroma. Finally, genomic analyses identified no SCNAs, LOH, or copy-neutral LOH in cultured cancer-associated fibroblasts, which are known to promote prostate cancer progression in vivo
  
  
  CONCLUSIONS
  The gene expression changes observed in prostate cancer-adjacent stroma and the attendant contribution of the stroma to the development and progression of prostate cancer are not due to frequent or recurrent genomic alterations in the TME.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Daniella
authors.initials: D
authors.lastname: Bianchi-Frias
authors.affiliation: Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ryan
authors.initials: R
authors.lastname: Basom
authors.affiliation: Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Delrow
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ilsa M
authors.initials: IM
authors.lastname: Coleman
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Dakhova
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Qu
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.affiliation: Departments of Urologic Surgery and Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Nolan G
authors.initials: NG
authors.lastname: Ericson
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Bielas
authors.affiliation: Departments of Urologic Surgery and Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Lawrence
authors.initials: L
authors.lastname: True
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Lisha
authors.initials: L
authors.lastname: Brown
authors.affiliation: Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Bhowmick
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rowley
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Pathology, University of Washington, Seattle, Washington. Department of Urology, University of Washington, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington. pnelson@fhcrc.org.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D004272:DNA, Mitochondrial / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics*; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53