Molecular and Cellular Endocrinology 336 (2011) 169–173 Contents lists available at ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce Review Genetics and genomics of childhood adrenocortical tumors Abeer El Wakil a,b , Mabrouka Doghman a,b , Perle Latre De Late a,b , Gerard P. Zambetti c , Bonald C. Figueiredo d , Enzo Lalli a,b,∗ a Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 6097, France b Université de Nice - Sophia Antipolis, Valbonne, France c Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, TN, USA d Instituto de Pesquisa Pelé Pequeno Principe and Faculdades Pequeno Principe, Curitiba PR, Brazil article info Article history: Received 23 August 2010 Received in revised form 10 November 2010 Accepted 11 November 2010 Keywords: Adrenal cortex Tumors Genetics abstract Adrenocortical tumors in children are usually diagnosed because of signs of virilization and their prog- nosis is poor. They possess several distinct pathological features compared to adrenocortical tumors in adults and have an exceptional prevalence in southern Brazil, where they are nearly invariably linked to the presence of a germline specific TP53 (R337H) mutation. Other important factors in childhood adreno- cortical tumor pathogenesis are overexpression of the Steroidogenic Factor-1 transcription factor and imprinting defects in the 11p15 genomic region, causing overexpression of Insulin-like Growth Factor-2. Genomic studies have revealed the prognostic relevance of the expression of some Major Histocom- patibility Complex genes and the deregulation of the Insulin-like Growth Factor/mammalian Target Of Rapamycin pathway by microRNAs in these tumors. Our hope is that these findings will constitute the basis for the development of novel therapies that will be more active against these tumors and less toxic for the patients. © 2010 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction .......................................................................................................................................... 169 2. An exceptional prevalence of TP53 mutations in southern Brazil and its impact on ACT pathogenesis ............................................ 170 3. Other genetic alterations in childhood ACT: role of an increased SF1 dosage and of imprinting defects in the 11p15 region .................... 170 4. Transcriptome profiling of childhood ACT ........................................................................................................... 171 5. miRNA expression patterns in childhood ACT: regulation of IGF–mTOR signaling by miRNAs .................................................... 171 6. Perspectives .......................................................................................................................................... 172 Conflict of interest ................................................................................................................................... 172 Acknowledgements .................................................................................................................................. 172 References ........................................................................................................................................... 172 1. Introduction Starting just after birth, a profound remodeling process per- vades the human fetal adrenal. Cells of the outer definitive zone Abbreviations: ACT, adrenocortical tumors; IGF2, Insulin-like Growth Factor- 2; LFS, Li-Fraumeni syndrome; mTOR, mammalian Target Of Rapamycin; NOV/CCN3, Nephroblastoma OVerexpressed/CYR61-CTGF-NOV family member 3; SF1, Steroidogenic Factor-1; TP53, tumor protein 53. ∗ Corresponding author at: Institut de Pharmacologie Moléculaire et Cellulaire, 660 route des Lucioles, 06560 Valbonne, France. Tel.: +33 4 93 95 77 55; fax: +33 4 93 95 77 08. E-mail address: ninino@ipmc.cnrs.fr (E. Lalli). proliferate and differentiate to form the glomerulosa, fasciculata and reticularis zones of the adult cortex, while the inner androgenic steroid-secreting fetal zone regresses progressively by apoptosis (Mesiano and Jaffe, 1997). Childhood adrenocortical tumors (ACT) are thought to be originated by abnormal persistence and/or defec- tive apoptosis of the fetal adrenal because of their early postnatal age distribution, their pattern of hormone secretion and their molecular phenotype (Wilkin et al., 2000; Michalkiewicz et al., 2004). According to the published studies taking into analysis the highest numbers of patients (Liou and Kay, 2000; Wieneke et al., 2003; Michalkiewicz et al., 2004), the median age at diagnosis is around 3 years or earlier (considering the usual diagnosis delay reported by these and other authors), with a predominance of 0303-7207/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2010.11.008