title: Chromosomal structural variations during progression of a prostate epithelial cell line to a malignant metastatic state inactivate the NF2, NIPSNAP1, UGT2B17, and LPIN2 genes.
abstract: Prostate cancer is the second highest cause of male cancer deaths in the United States. A significant number of tumors advance to a highly invasive and metastatic stage, which is typically resistant to traditional cancer therapeutics. In order to identify chromosomal structural variants that may contribute to prostate cancer progression we sequenced the genomes of a HPV-18 immortalized nonmalignant human prostate epithelial cell line, RWPE1, and compared it to its malignant, metastatic derivative, WPE1-NB26. There were a total of 34 large (> 1 Mbp) and 38 small copy number variants (<100 kbp) in WPE1-NB26 that were not present in the precursor cell line. We also identified and validated 46 structural variants present in the two cell lines, of which 23 were unique to WPE1-NB26. Structural variants unique to the malignant cell line inactivated: (1) the neurofibromin2 (NF2) gene, a known tumor suppressor; (2) its neighboring gene NIPSNAP1, another putative tumor suppressor that inhibits TRPV6, an anti-apoptotic oncogene implicated in prostate cancer progression; (3) UGT2B17, a gene that inactivates dihydrotestosterone, a known activator of prostate cancer progression; and (4) LPIN2, a phosphatidic acid phosphatase and a co-factor of PGC1a that is important for lipid metabolism and for suppressing autoinflammation. Our results illustrate the value of comparing the genomes of defined related pairs of cell lines to discover chromosomal structural variants that may contribute to cancer progression.
authors.affiliation: Department of Biochemistry and Molecular Genetics; University of Virginia School of Medicine; Charlottesville, VA USA.
authors.forename: Ankit
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Department of Biochemistry and Molecular Genetics; University of Virginia School of Medicine; Charlottesville, VA USA.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: Department of Biochemistry and Molecular Genetics; University of Virginia School of Medicine; Charlottesville, VA USA.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Hall
authors.affiliation: Department of Biochemistry and Molecular Genetics; University of Virginia School of Medicine; Charlottesville, VA USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Dutta
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000473:pathology*; D016147:Genes, Tumor Suppressor; D056914:Genomic Structural Variation; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C502575:LPIN2 protein, human; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human
keywords: AbCNV; HYDRA; NF2; NIPSNAP1; complex rearrangements; high throughput sequencing; metastasis; prostate cancer