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Cell, Tumor, and Stem Cell Biology |
1 Interdisciplinary Science Program, University of Tennessee Health Science Center; 2 Hartwell Center for Biotechnology; 3 International Outreach Program; and the Departments of 4 Biostatistics, 5 Oncology, and 6 Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee; 7 Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; 8 Center for Molecular Genetics and Cancer Research in Children and 9 Division of Pediatric Hematology and Oncology, Erasto Gaertner Hospital, and Department of Pediatrics, Universidade Federal do Parana, Curitiba, Brazil; 10 Instituto de Pesquisa e Ensino Boldrini, Campinas, Brazil; and 11 Institut de Pharmacologie Moléculaire et Cellulaire Centre National de la Recherche Scientifique Unité Mixte de Recherche 6097, Valbonne, France
Requests for reprints: Gerard P. Zambetti, Department of Biochemistry, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105. Phone: 901-495-3429; Fax: 901-525-8025; E-mail: gerard.zambetti{at}stjude.org.
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Abstract |
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Introduction |
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The adrenal cortex synthesizes essential steroids (e.g., glucocorticoids, androgens, and mineralocorticoids) that regulate diverse biological processes such as blood pressure, glucose metabolism, immune surveillance, and sexual development (4, 5). During gestation, the cortex is subdivided into the outer-definitive and inner-fetal zones, which contribute to the maintenance of normal pregnancy through the production of dihydroepiandrosterone sulfate. As this function is no longer required after birth, the adrenal gland rapidly loses 50% of its volume within the first 2 weeks due to massive apoptosis. Subsequently, the adrenal cortex undergoes significant tissue remodeling and develops into three defined regions: outer zona glomerulosa, middle zona fasciculata, and inner zona reticularis. The zona glomerulosa is primarily responsible for the production of aldosterone, whereas the zona fasciculata and zona reticularis produce corticosteroids and androgens, respectively. Various genetic abnormalities, either acquired or inherited (see below), promote ACT development during childhood or late adulthood (6).
Pediatric ACT is frequently reported in families with Li-Fraumeni syndrome and Li-Fraumeni–like syndrome, which are usually associated with TP53 tumor-suppressor germ line mutations (7, 8). The most frequently observed tumors in Li-Fraumeni syndrome include soft tissue sarcomas, osteosarcomas, breast carcinomas, brain tumors, and adrenocortical carcinomas. Indeed, it has been proposed that pediatric ACT is almost diagnostic of a germ line TP53 mutation (9), but clearly alternative factors can contribute to this tumor type (e.g., Beckwith-Wiedemann syndrome, Carney's complex, and multiple endocrine neoplasia type I; ref. 10). Beckwith-Wiedemann syndrome is characterized by the overgrowth of tissues and organs, including the adrenal gland. Beckwith-Wiedemann syndrome is usually sporadic; however, it also occurs as a familial autosomal dominant form linked to the loss of imprinting at the insulin-like growth factor-II (IGF-II) locus on chromosome 11p15.5, resulting in the overproduction of IGF-II (6). The underlying genetic events responsible for the Beckwith-Wiedemann syndrome phenotype are complex, with multiple genes (e.g., KCNQ1 and CDKN1C) being implicated in its etiology (11, 12).
The cooperating factors and signaling pathways that promote the development of childhood ACT are not well defined. Animal studies implicate inhibin-
, a glycoprotein with homology to transforming growth factor-ß, as a suppressor of ACT development (13). Deletion of inhibin- by gene targeting in gonadectomized mice causes fully penetrant ACT by 4 to 5 weeks of age. Consistent with the mouse model, mutation of inhibin- with loss of heterozygosity at chromosome 2q33 was commonly observed in human pediatric ACT (13). Comparative genomic hybridization analysis of pediatric ACT also showed recurrent chromosomal alterations, such as the amplification of chromosome 9q34 (14). Localized within this region is the nuclear orphan receptor steroidogenic factor-1 (SF1, NR5A1), which is required for normal adrenal gland development. Subsequent studies showed that SF1 is amplified and overexpressed in 
90% of pediatric ACT (15, 16). Similarly, both pediatric and adult ACT express elevated levels of IGF-II (17, 18).
Due to the rarity of pediatric ACT, it becomes necessary to consolidate resources to maximize efforts in studying this disease in a comprehensive and thorough manner. We therefore established an International Pediatric Adrenocortical Tumor Registry and Bank at St. Jude Children's Research Hospital.12 More than 250 subjects have enrolled in the registry component since 1990 (the adrenal tissue bank has been in existence since 2000). To identify key factors and signaling pathways that may be involved in adrenocortical tumorigenesis, we conducted an Affymetrix gene expression profiling analysis of pediatric ACT. As we report here, distinct expression signatures have been identified that discriminate between normal adrenal cortex and ACT. In addition, our retrospective analyses identified profiles that may aid in the differential diagnosis of adenoma from carcinoma. Insight into the cell type of origin that gives rise to ACT has also been generated. Our findings provide the basis for identifying signaling pathways that are corrupted during adrenocortical tumorigenesis, with the goal of establishing new therapeutic targets that could be exploited in treating this often fatal disease.
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Materials and Methods |
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Total RNA preparation. Tissue samples were classified according to established histopathologic criteria and verified by two independent pathologists. Total RNA was isolated from 50 to 100 mg of pediatric ACT using the RNeasy RNA Midi-Prep kit (Qiagen, Valencia, CA). Tumors were prepared in a 4°C cold room, sliced into fine pieces using a sterile scalpel, and homogenized with 18- and 19-gauge needles in lysis Buffer RLT (Qiagen) containing ß-mercaptoethanol. Total RNA was isolated by the Animal Tissues protocol following the manufacturer's recommendations. The RNA was resuspended in diethyl pyrocarbonate–treated water, quantified by UV absorbance at 260/280 nm, and stored at –80°C.
cDNA amplification and real-time PCR analysis. cDNA was generated from 1 µg total RNA using the iScript cDNA amplification kit according to the manufacturer's instructions (Bio-Rad Laboratories, Hercules, CA). cDNA was diluted 1:2 using sterile double-distilled water before real-time PCR analysis. The following genes were amplified by real-time PCR using the iQSybrGreen PCR amplification mix (Bio-Rad Laboratories; according to the manufacturer's instructions) and 400 ng per primer: IGF-II, type II 3ß-hydroxysteroid dehydrogenase (HSD3B2), fibroblast growth factor receptor-4 (FGFR4), NURR1, NGF1-B, and nephroblastoma overexpressed (NOV). Ubiquitin was also amplified as a loading control. Each normal adrenal and tumor sample was amplified in triplicate via separate PCR conditions and compared with ubiquitin expression levels using the 
Ct method (19). Primer sequences and PCR conditions are described in Supplementary Table S1.
Western blot analysis. Protein was isolated from normal adrenal cortex and tumor tissues by homogenization in T-PER lysis buffer (Pierce Chemical, Rockford, IL) containing a protease inhibitor cocktail (Roche Diagnostics Corporation, Indianapolis, IN). Total protein (50 µg) was analyzed by SDS-PAGE using the Novex NuPAGE system (Invitrogen, Carlsbad, CA). Proteins were separated by electrophoresis and transferred to 0.45-µm nitrocellulose membranes. Membranes were blocked in TBS-T buffer [10 mmol/L Tris-HCl (pH 7.4), 150 mmol/L NaCl, 0.1% Tween 20] containing 5% nonfat milk and probed with the following primary antibodies: goat polyclonal anti-human IGF-II (1:500; Sigma-Aldrich Chemical, St. Louis, MO), rabbit polyclonal anti-human HSD3B2 (1:500; gift from Dr. C. Richard Parker Jr., University of Alabama, Birmingham, AL), and mouse monoclonal anti-human actin (1:2000; Sigma-Aldrich Chemical). Membranes were washed with TBS-T and hybridized with the following horseradish peroxidase–linked antibodies diluted in TBS-T containing 5% nonfat milk: rabbit anti-goat (1:1,000; Calbiochem, San Diego, CA), donkey anti-rabbit (1:3,000; Amersham Biosciences, Piscataway, NJ), and sheep anti-mouse (1:2,000; Amersham Biosciences). The membranes were washed with TBS-T and developed using Supersignal West Dura chemiluminescence reagent (Pierce Chemical) according to the manufacturer's protocol.
Microarray analysis. The Affymetrix U133A GeneChip was used to collect expression data for 22,215 probe sets on each of 31 samples (18 adrenocortical carcinomas, five adenomas, one undetermined ACT, and seven normal adrenal cortex). Microarray analysis was done in the Hartwell Center Affymetrix core laboratory at St. Jude. High-quality RNA, confirmed by UV spectrophotometry and an Agilent 2100 Bioanalyzer, was processed according to the Affymetrix one-cycle labeling protocol.13 In brief, 5 to 10 µg total RNA was annealed to an oligo-dT(24)-T7 primer to initiate cDNA synthesis. Purified double-stranded cDNA was used as a template to synthesize biotin-labeled cRNA using T7 RNA polymerase. Labeled cRNA (20 µg) was fragmented, added to a mixture containing blocking agents and array controls, and hybridized overnight at 45°C to the gene chip array. Following hybridization, arrays were stringently washed, stained with streptavidin-conjugated phycoerythrin, and scanned using an Affymetrix GeneChip Scanner 3000. Relative expression signals for each gene was calculated using the Affymetrix GCOS software (version 1.4) using the global normalization method where the 2% trimmed mean signal was set to a target value of 500.
Statistical analysis. Microarray signals were summarized and normalized using Affymetrix GCOX software as described above. No probe set was excluded before subsequent statistical analysis because filtering has been found to be of questionable value (20). The Wilcoxon rank-sum test was used to compare median expression between normal and tumor tissues in each probe set (21). Likewise, the rank-sum test was used to compare the median expression level of each probe set between adrenocortical adenomas and carcinomas. To account for multiple testing in each of these analyses, we used a robust method to estimate the false discovery rate (22). These analyses were implemented using S-plus software, version 6.2 for Windows (Microsoft).14 The robust false discovery rate method was implemented using our freely available routines.15
To compare expression profiles in our pediatric ACT samples with data in other reports (23, 24), U133A probe sets were matched by either Genbank accession ID (23) or by the Affymetrix "best match" criteria (24). Fold-change point estimates were computed by exponentiation of the difference of means of log-transformed signals. This estimate of fold change can be interpreted as an estimate of the ratio median expression levels of the two groups. The t distribution was used to compute 95% confidence intervals for the difference of means of log signals; these intervals were transformed into confidence intervals for fold changes by exponentiation. The fold-change confidence intervals are not adjusted for multiple testing.
As measures of how fold changes observed in our study correlated with fold changes observed in other studies, we computed the number of probe sets with a directional agreement (i.e., the fold-change estimates from the two studies were in the same direction) and Kendall et al.'s method (25) with the two sets of fold changes as input. We used a permutation method to assess the statistical significance of the observed values of these measures of agreement. The permutation assessment was done by computing the fold changes on 1,000 data sets, derived by randomly reassigning group labels in our data set to the expression profiles in our data set, and then computing the agreement statistics. We counted the number of permuted data sets in which stronger values of the agreement statistics were observed to obtain the P values.
Estimates of overall and relapse-free survival were computed using the Kaplan-Meier method with SEs determined using the method of Peto et al. (26). Overall survival was defined as the duration from date of diagnosis to date of death with those living at last follow-up considered censored. Relapse-free survival was defined as the duration from date of diagnosis to date of relapse or death with those alive and relapse-free at last follow-up censored.
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Results |
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Gene expression profiling distinguishes ACT from normal adrenal tissue. Gene expression profiles for the ACT and normal adrenal cortex samples were generated using the Affymetrix U133A gene chip, which recognizes 14,500 genes using 22,215 probe sets. We estimate that at least 33% of the probe sets on the array are differentially expressed between tumor and normal tissues; for 1,019 of the probe sets, we detected differences that were significant at P = 0.001 (see Supplementary Table S2). Furthermore, we estimate that 1.5% or fewer of the 1,019 detected differences are false discoveries. Hierarchical clustering analysis was used to visualize the variability between ACT and normal cortex (Fig. 1 ).
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40-fold less than that of normal controls. This finding was confirmed by qRT-PCR and Western blot analysis (Fig. 2C and D).
Moreover, the expression of NURR1 (NR4A2) and NGF1-B (NR4A1), transcriptional regulators of HSD3B2 gene expression (32), were concomitantly lower in the ACT samples (Table 2; and data not shown). The expression of KCNQ1, which encodes a voltage-dependent potassium channel, was also lower (85-fold) in the pediatric ACT samples than in normal adrenal cortex (Table 2). Murine Kcnq1 is preferentially expressed in the cortical zona glomerulosa (33), but not in the adrenal medulla. Taken together, these results suggest that pediatric ACT may arise from either the fetal zone or the more developmentally mature zona reticularis or zona fasciculata.
Comparison between adult and pediatric ACT. Giordano et al. (24) recently identified differences in gene expression patterns between adult ACT and normal tissue using the Affymetrix human U95A gene chip. Independently, Rainey et al. (23) compared the gene expression profiles of normal human fetal and adult adrenal cortex using a cDNA microarray approach. To our knowledge, there have been no published studies to date comparing adult and pediatric ACT gene expression in a comprehensive manner.
To compare expression profiles across studies, we queried our microarray data set for the genes identified as significantly changed in the other two studies. We then used expression values relative to normal tissues within each study (log2 ratio) to compare gene profiles across studies. These analyses showed that the most significant differences identified in the comparison between adult adrenal tumors and normal adult adrenal cortex (24) were remarkably similar to our findings comparing childhood ACT (adenoma and carcinoma) to normal cortex (
= 0.56, P = 0.001; Fig. 3
). Moreover, the observed direction of association was the same for 147 of 153 probe sets in our study corresponding to their reported fold changes (P < 0.001).
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= 0.34, P = 0.022; Fig. 3). Additionally, the direction of association agreed for 99 of 127 probe sets corresponding to genes for which they report fold changes (P = 0.006; Supplementary Table S4). These results indicate that both adult and pediatric ACT resemble fetal tissue with respect to gene expression patterns. Furthermore, our findings suggest that adult and childhood ACT may select for common genetic and biochemical alterations and may be more physiologically related than previously considered. Differences between pediatric adrenocortical carcinoma and adenoma. There are no definitive tests to predict ACT malignant potential. Tumor size is one of the most consistent prognostic indicators in children with completely resected ACT (1), although it is not uncommon for patients with small tumors to experience relapses. We therefore compared gene expression profiles of ACT that were classified by histologic criteria as either adenoma or carcinoma to identify changes that may distinguish between these risk groups.
For 52 probe sets, we detected differences in expression between adrenocortical adenomas and carcinomas that were significant at the P = 0.001 level (Fig. 4 ; Supplementary Table S5). We estimate that 56% or more of the detected differences represent true discoveries. Among this set was a consistent and marked decrease in the expression of major histocompatibility class II genes. Specifically, the median expressions of HLA-DRB1, HLA-DPB1, HLA-DRA, and HLA-DPA1 mRNA levels were 6- to 8-fold lower in pediatric adrenocortical carcinomas than in adenomas. Similar findings have been recently reported by Bornstein and coworkers (34, 35) in a study of adult ACT. HLA-class II expression may therefore serve as a marker for distinguishing between adrenocortical carcinoma and adenoma.
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Discussion |
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Overexpression of IGF-II in pediatric ACT was anticipated based on previously published reports (Fig. 2A and B; Table 2; refs. 18, 24, 28, 36). However, the finding that the majority of the tumors grossly overexpress immature forms of IGF-II was surprising, but not unprecedented based on adult ACT studies (29). Pro-IGF-II must be posttranslationally modified by glycosylation and proteolytic cleavage before its mature, active 7.5-kDa form is secreted (37). Here, we have detected, in the ACT samples, IGF-II proteins ranging from 14 to 22 kDa, but not the 7.5-kDa form, which was readily evident in normal adrenal cortex tissue. It is generally considered that the overexpression of IGF-II in ACT provides a growth advantage that drives tumorigenesis. Consistent with this hypothesis, transgenic mice engineered to express high levels of IGF-II develop adrenal hyperplasia (38) and recombinant IGF-II stimulates human fetal adrenocortical cell proliferation in culture (39). Because the IGF-I receptor is concomitantly up-regulated in the pediatric tumors analyzed here (Supplementary Table S2), it is reasonable to speculate that IGF-II may also play a role in pediatric adrenocortical tumorigenesis and therefore serve as a drug target. However, further consideration must be given as to whether these adrenal tumors secrete an active form of IGF-II that contributes to the growth and survival of these cells.
Interestingly, basic FGF-2 (bFGF-2) suppresses the processing of IGF-II in human ACT cells, thereby blocking its secretion, resulting in a marked accumulation of intracellular IGF-II (40). Consistent with the high levels of partially processed IGF-II protein in the adrenal tumors, FGFR1 and FGFR4, both of which can be activated by bFGF-2, were found by microarray analysis to be significantly up-regulated in the ACT samples (Table 2; Supplementary Table S2). Moreover, because bFGF is a potent angiogenic factor and is mitogenic for fetal adrenal cortex cells (41, 42), the inhibition of the FGFR signaling pathway may represent a rational approach in developing new treatments for pediatric ACT. In support of this concept, 17 of the most significant genes dysregulated in pediatric ACT (Fig. 1; Supplementary Table S2) function within the mitogen-activated protein kinase pathway, including NRAS, an immediate downstream target of FGFR signaling.
The finding that the expression of KCNQ1, HSD3B2, and its corresponding transcriptional regulators NURR1 and NGF1B is markedly lower in pediatric ACT compared with normal adrenal cortex supports the thesis that the tumors originate from either the fetal zone during embryogenesis or the developing zona fasciculata or zona reticularis during the first few years of life. At the very least, the pediatric adrenal tumors share biochemical characteristics of these compartments. Because normal adult tissue is significantly different from the fetal adrenal cortex (23), the remarkable and somewhat unexpected similarity between adult and pediatric ACT implies (Fig. 3; Supplementary Table S3) the existence of an adrenal stem cell that may become corrupted to give rise to the developing tumor. Alternatively, the tumors, whether adult or pediatric, may undergo dedifferentiation as they develop (43).
In the present study, patterns of gene expression have been identified that distinguish adrenocortical carcinomas from adenomas, which is often difficult to assess by standard histopathologic approaches. Interestingly, two adrenocortical carcinoma cases, which have not yet relapsed, segregated with the adrenocortical adenoma group (Fig. 4; Supplementary Table S5 and Fig. S1), underscoring the limitations of the histologic criteria to predict tumor malignant potential. Future prospective studies should determine the usefulness of gene expression analysis in the classification and prognosis of pediatric ACT.
Significant changes in the expression profiles between adrenocortical adenomas and carcinomas included the MHC class II genes, which are largely restricted to hematopoietic lineages. Interestingly, the adrenocortical reticular zone also expresses MHC class II antigens after 4 years of age (34, 35). Based on the age of the patients diagnosed with adrenocortical adenoma, it is reasonable to speculate that the relatively high MHC class II expression reflects an infiltration of immune cells that limits tumor potential (B.F.; data not shown). Conversely, the association of low MHC class II expression in the carcinomas may represent a mechanism to evade immune surveillance, which could contribute to its malignant phenotype (35).
Little is known regarding the pathways and factors that promote pediatric ACT and there is no proven therapy for this rare malignancy other than surgery. Our findings identify potentially important components that may contribute to adrenocortical tumorigenesis. However, the establishment of genetically engineered mice, primary tissue culture cell lines, and/or human ACT xenografts will be required to explore new potential targets, such as FGFR4, IGF-II, and other dysregulated genes identified here. Only through these efforts can advancements in the treatment of pediatric ACT be made.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Dr. Robert Lorsbach for his assistance in processing tissue samples, the Hartwell Center for the Affymetrix U133A GeneChip and biostatistical analyses, Dr. C. Richard Parker, Jr., for his generosity in providing the antihuman HSD3B2 probe, and Dr. Donald D. Samulack for his editorial assistance.
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Footnotes |
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A.N. West and G.A. Neale contributed equally to this work.
12 www.stjude.org. 
13 http://www.affymetrix.com/support/technical/manual/expression_manual.affx.
14 www.splus.com.
15 http://www.stjuderesearch.org/depts/biostats/robustfdr/index.html.
Received 10/12/06. Accepted 11/14/06.
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-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers. J Med Genet 2004;41:354–9.C(T)) method. Methods 2001;25:402–8.[CrossRef][Medline]
5-4 isomerase gene family. Endocr Rev 2005;26:525–82.This article has been cited by other articles:
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  P S H Soon, A J Gill, D E Benn, A Clarkson, B G Robinson, K L McDonald, and S B Sidhu Microarray gene expression and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas Endocr. Relat. Cancer, June 1, 2009; 16(2): 573 - 583. [Abstract] [Full Text] [PDF]
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