title: Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret.
abstract: Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Transcriptome analysis and DNA methylation mapping were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated using a combination of laser capture microdissection, quantitative RT-PCR, in situ hybridization, and immunohistochemistry. Microarray expression profiling of whole adrenal mRNA from ovariectomized vs. intact mice demonstrated selective upregulation of gonadal-like genes including Spinlw1 and Insl3 in GDX-induced adrenocortical tumors of the mouse. A complementary candidate gene approach identified Foxl2 as another gonadal-like marker expressed in GDX-induced neoplasms of the mouse and ferret. That both "male-specific" (Spinlw1) and "female-specific" (Foxl2) markers were identified is noteworthy and implies that the neoplasms exhibit mixed characteristics of male and female gonadal somatic cells. Genome-wide methylation analysis showed that two genes with hypomethylated promoters, Igfbp6 and Foxs1, are upregulated in GDX-induced adrenocortical neoplasms. These new genetic and epigenetic markers may prove useful for studies of steroidogenic cell development and for diagnostic testing.
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
authors.forename: Maximiliaan
authors.initials: M
authors.lastname: Schillebeeckx
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland.
authors.forename: Marjut
authors.initials: M
authors.lastname: Pihlajoki
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Hochschule Mannheim, University of Applied Sciences, Mannheim 68163, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gretzinger
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Hochschule Mannheim, University of Applied Sciences, Mannheim 68163, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Thol
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Hochschule Mannheim, University of Applied Sciences, Mannheim 68163, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Hiller
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Hochschule Mannheim, University of Applied Sciences, Mannheim 68163, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Löbs
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Hochschule Mannheim, University of Applied Sciences, Mannheim 68163, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Röhrig
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland.
authors.forename: Anja
authors.initials: A
authors.lastname: Schrade
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cochran
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki 00290, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Heikinheimo
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA.
authors.forename: Robi D
authors.initials: RD
authors.lastname: Mitra
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA. Electronic address: wilson_d@wustl.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Wilson
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D005260:Female; D005289:Ferrets; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009919:Orchiectomy; D010052:Ovariectomy; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins
keywords: Adrenal cortex; Endocrine tumor; Gonadotropin; Ovariectomy; Steroidogenesis