title: Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.
abstract: Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Fujisawa
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Sakaguchi
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ono
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Kato
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Kagami
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: tomogata@hama-med.ac.jp.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D000311:Adrenal Glands / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism*; D053898:Biosynthetic Pathways; D045744:Cell Line, Tumor; D002675:Child, Preschool; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D015870:Gene Expression; D018095:Germ-Line Mutation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007985:Leydig Cells / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D010375:Pedigree; D011506:Proteins / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D007328:Insulin; C084797:Leydig insulin-like protein; D011506:Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme
keywords: Adrenocortical carcinoma; Androgen production; Steroidogenesis; TP53; Tumorigenesis