help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-0963
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pinto, E. M
Right arrow Articles by Latronico, A. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pinto, E. M
Right arrow Articles by Latronico, A. C.
Related Collections
Right arrow Adrenal and Hypertension
Right arrow Endocrine Oncology
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2976-2981
Copyright © 2005 by The Endocrine Society

Deletion Mapping of Chromosome 17 in Benign and Malignant Adrenocortical Tumors Associated with the Arg337His Mutation of the p53 Tumor Suppressor Protein

Emilia M Pinto, Ana Elisa C. Billerbeck, Maria Candida B. Villares Fragoso, Berenice B. Mendonca and Ana Claudia Latronico

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil

Address all correspondence and requests for reprints to: Ana Claudia Latronico, M.D., Ph.D., Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da USP Av. Dr. Enéas Carvalho de Aguiar, 155, 2° andar, bloco 6, 05403-900, São Paulo, Brasil. E-mail: anacl{at}usp.br.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The human p53 tumor suppressor gene is located at the short arm of chromosome 17. A germinative mutation (Arg337His) in the tetramerization domain of p53 has been frequently identified in Brazilian children with sporadic adrenocortical tumors. Loss of heterozygosity at this region was demonstrated in the majority of the cases. In the present study, we performed deletion mapping of chromosome 17 in 30 adrenocortical tumors from 29 Brazilian patients (15 children and 14 adults). One boy had bilateral adrenocortical tumor. Sixteen patients had the germinative Arg337His mutation. Loss of heterozygosity analysis using six polymorphic microsatellite markers disclosed loss of the entire chromosome 17 in 18 tumors (10 adenomas and eight carcinomas) from 17 patients. The Arg337His mutation was present in 13 of them. Chromosomal instability involving chromosomes 2, 9, and 11 was also found in 47, 47, and 70% of the 17 patients who exhibited chromosome 17 losses, respectively. The concomitant loss of chromosomes 2, 9, 11, and 17 was evidenced exclusively in malignant tumors. Therefore, chromosomal instability involving three or more chromosomes may contribute to define the malignant adrenocortical lesions. In conclusion, we demonstrated a high frequency of biallelic inactivation of p53 derived from two distinct events, the germinative Arg337His mutation and the acquired loss of the entire chromosome 17. In addition, the isolated loss of the entire chromosome 17 did not correlate with aggressive tumor behavior in these patients with adrenocortical tumors.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
LOSS OF HETEROZYGOSITY (LOH) on the short arm of chromosome 17 has been identified in several human cancers (1, 2, 3). It is widely assumed that the LOH occurring frequently at a specific locus implies the existence of a tumor suppressor gene at or near that region (1). In addition, a linkage between LOH and biological parameters related to tumor aggressiveness, such as DNA aneuploidy and rapid cellular proliferation, indicates that somatic deletions are important phenomena in tumor development, with diagnostic and prognostic relevance (4, 5).

The p53 tumor suppressor gene, which encodes a 53-kDa nuclear phosphoprotein, has been assigned to chromosome region 17p13.1 (6). A nucleotide substitution in exon 10 of the p53 gene, leading to a missense Arg337His mutation in the tetramerization domain of p53 tumor suppressor protein was found in a very high frequency (97–78%) in Brazilian children with sporadic adrenocortical tumors (7, 8). This mutation was also identified in 13.5% of adults with adrenocortical tumors (8). LOH of this region was identified in the majority of the studied cases (7, 8). Interestingly, the Arg337His mutation was also identified in blood DNA of asymptomatic first-degree relatives of these patients, suggesting low penetrance for adrenocortical tumor development (8). A comparative study between the structures of the p53 mutant (H337) and the wild-type tetramerization domains revealed that the mutant tetramerization domain adopts a native-like fold but is less stable than the wild type (9). Furthermore, the stability of this mutant is highly sensitive to pH within the physiological range (9). It was speculated that the increased risk to develop adrenocortical tumors in children with this mutation is a consequence of the increased pH levels in apoptotic adrenal cortex cells during the pre- and postnatal development of the adrenal gland (9).

To date, there are no histological or molecular markers that can reliably distinguish benign from malignant adrenocortical tumors, especially in pediatric patients (10). Recently, Wieneke et al. (11) demonstrated that 51 of 74 patients (69%) with histologically malignant-appearing tumors had a benign clinical course, suggesting that the classical histological parameters are not helpful in predicting the biological behavior of such neoplasms in the pediatric population. In a previous study, we demonstrated that the presence of the Arg337His mutation in the tumor suppressor p53 in Brazilian children with adrenocortical tumors was not related to an unfavorable prognosis (8). However, whether the extension of chromosome 17 losses has a prognostic relevance in children with adrenocortical tumors remains unknown. Therefore, we examined deletion mapping of chromosome 17 in children and adult patients with adrenocortical tumors, carriers or not of the Arg337His mutation of p53.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
The study was approved by the Ethics Committee of Hospital das Clínicas, São Paulo, Brazil, and informed written consent was obtained from all patients. We obtained paired genomic DNA samples from blood and tumor specimens of 29 Brazilian patients (22 females and seven males, age ranged from 0.9–52 yr) with adrenocortical tumors. Complete clinical and histopathological features of these patients with and without the Arg337His mutation are shown in Tables 1Go and 2Go, respectively. All patients had functioning tumors (eight virilizing, six Cushing syndrome, 14 mixed, and one feminization). Patient 7 showed bilateral tumor with asynchronic development with an interval of 2 yr, and both tumors were available for DNA analysis. Fifteen patients were under 15 yr of age. Among the 16 patients who carried the Arg337His mutation of p53, 15 of them had the mutation in the heterozygous state and one patient (case 1) in the homozygous state in blood DNA (Table 1Go). Segregation analysis showed that both asymptomatic parents of patient 1 had the Arg337His mutation in the heterozygous state.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical and histopathological features of 16 patients with adrenocortical tumors with the R337H mutation

 

View this table:
[in this window]
[in a new window]
  		TABLE 2. Clinical and histopathological features of 13 patients with adrenocortical tumors without the R337H mutation

 
A precise criterion of malignancy was established by the combination of two or more of the following features: staging of at least III, Weiss score of at least IV, distant metastasis, or fatal evolution. The staging was based on the system originally proposed by MacFarlane and modified by Sullivan (12, 13). The follow-up time for the adrenocortical adenomas ranged from 1–11 yr (mean, 4.6 yr). We classified 11 tumors as malignant lesions in eight adults and three children (Tables 1Go and 2Go). In the pediatric group, we observed that 45% of tumors (5 of 11) had Weiss score of at least IV with benign evolution, confirming that this isolated criterion is not reliable for children’s tumor classification (10, 11).

One hundred sixty unrelated Brazilian Caucasian subjects from the same patients’ geographic regions were also studied as a control group.

DNA analysis

Genomic DNA was extracted from blood and frozen tumor tissue using standard procedures. Six different polymorphic markers covering the entire chromosome 17 were studied: D17S926, VNTRp53, D17S1856, D17S942, D17S1351, and D17S928 (Table 3Go). These markers span a 135.05-cM interval from 17p13.3 to 17q25.3. All markers, except VNTRp53, are dinucleotide repeats (CA)n. The VNTRp53 is a pentanucleotide repeat (AAAAT)n within intron 1 of the human p53 gene (14). The oligonucleotides were selected from the 1996 Généthon Microsatellite Map Database (http://www.genlink.wustl.edu), and forward primers were labeled with fluorescent dye (FAM or TET). Genomic DNA (100 ng) was added to a 50-µl reaction mixture of 1x PCR buffer (50 mM KCl, 1.5 mM MgCl2, and 10 mM Tris/HCl, pH 9.0), 200 µM of each dNTP, 20 pmol of each primer, and 2.5 U Taq DNA polymerase (Amersham Pharmacia, Uppsala, Sweden). The PCR mixture was denatured for 5 min at 94 C and cycled 35 times (94 C for 30 sec, 50–62 C for 30 sec, and 72 C for 30 sec), followed by a 30-min extension at 72 C. Internal size standard TAMRA 350 (Applied Biosystems, Foster City, CA) was added to 2 µl of PCR products and 24 µl of formamide, and those were submitted to capillary electrophoresis in an automatic sequencer (ABI Prism 310 genetic analyzer) followed by GeneScan fragment analysis (Applied Biosystems, Foster City, CA). We applied a criterion for LOH scoring using the ratio of the heights of the allele peaks in the tumor and the blood samples. An allelic imbalance ratio less than 0.5 or more than 2.0 was defined as LOH (Fig. 1Go) (15).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Characterization of the six different microsatellite markers covering the entire chromosome 17

 


View larger version (102K):
[in this window]
[in a new window]
  		FIG. 1. Typical example of LOH categories in adrenocortical tumors. The upper panels show two shaded alleles (heterozygous state) in DNA blood, whereas the bottom panels show the same tumor alleles with retention (A) or loss (B) of heterozygosity.

 
Chromosomal losses involving predominantly chromosomes 2, 9, and 11 have been demonstrated in adrenocortical tumors (16). Based on these studies, we investigated LOH for these chromosomes using polymorphic microsatellite markers in the patients who exhibited loss of chromosome 17. The markers used for chromosome 2 were D2S2211, D2S367, D2S364, and D2S206; for chromosome 9, D9S288, D9S161, D9S273, and D9S164; and for chromosome 11, D11S4046, D11S905, D11S4175, and D11S925. All markers were originated from the ABI PRISM Linkage Mapping Set, version 2.5 (Applied Biosystems).

We investigated the entire coding region (exons 2–11) of the p53 gene throughout PCR amplification followed by automatic sequencing in four patients (cases 18, 24, 27, and 29; Table 2Go). Automatic sequencing and/or fragment analysis performed by digestion with restriction endonuclease HhaI (Invitrogen, Carlsbad, CA) were used for investigation of the germinative Arg337His mutation in genomic DNA from 160 normal individuals.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
LOH analysis for the six markers of chromosome 17 showed loss of the entire chromosome in 18 (10 adenomas and eight carcinomas) of 30 adrenocortical tumors (Fig. 2Go). Patient 7, who had bilateral tumors, showed loss of one copy of chromosome 17 in both tumors. Thirteen tumors (10 adenomas and three carcinomas) had the Arg337His mutation of p53 (Fig. 2AGo). Among the adrenocortical tumors without the Arg337His mutation, only four carcinomas exhibited loss of chromosome 17 (Fig. 2BGo). Different p53 mutations were not identified in these patients, except a known polymorphism at codon 72 (Pro/Pro) in the homozygous state found in patient 18.



View larger version (24K):
[in this window]
[in a new window]
  		FIG. 2. Deletion mapping of chromosome 17 using six different polymorphic markers, in 16 patients (A) with adrenocortical tumors carrying the Arg337His mutation of p53 and in 13 patients (B) without the Arg337His mutation of p53. *, Patients with malignant lesions; black squares, allelic loss; white squares, allelic retention; gray squares, not informative. Patients 2, 4–9, 11–16, 18, 24, 27, and 29 had loss of the entire chromosome 17.

 
Allelic loss at any loci studied was not identified in the other 12 tumors (eight adenomas and four carcinomas), except in one (case 26), who showed allelic loss at VNTRp53 locus and was noninformative for the other five markers.

None of the tumors showed signs of microsatellite instability at any loci analyzed. However, additional chromosomal loss of at least one of the three other chromosomes studied was demonstrated in 12 patients who had already lost chromosome 17. Chromosomal loss involved chromosomes 2, 9, and 11 in 8, 8, and 12 patients, respectively (Table 4Go). Losses of chromosomes 2 and 11 were found in both benign and malignant tumors. In contrast, the concomitant loss of chromosomes 2, 9, 11, and 17 was exclusively found in malignant lesions.


View this table:
[in this window]
[in a new window]
  		TABLE 4. Chromosomal instability involving chromosomes 2, 9, and 11 in 17 patients with adrenocortical tumors and chromosome 17 loss

 
The Arg337His mutation was not found in 320 normal alleles.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
A high incidence of adrenocortical tumors has been reported in Brazil, especially in the south and southwestern regions (17, 18). The identification of the inherited p53 mutation, Arg337His, outside the highly conserved DNA-binding domain of p53 in patients with adrenocortical tumors from these regions, indicates a genetic predisposition in the etiology of the adrenocortical tumors (7, 8). Furthermore, we recently demonstrated that the germinative Arg337His mutation arose from a single common ancestor in the great majority of the Brazilian patients with adrenocortical tumors (19).

The LOH on the short arm of human chromosome 17 is important in the pathogenesis of various malignant tumors, including breast cancers, colorectal carcinomas, lung cancers, glioblastomas, and adrenocortical carcinomas (1, 2, 3). Loss of alleles of 17p was first demonstrated in primary malignant adrenocortical tumors and their metastases but not in benign lesions of the adrenal cortex (20). In addition, the presence of genetic aberrations detected by comparative genomic hybridization revealed losses involving chromosome 17p in approximately 50% of the adrenocortical carcinomas, suggesting that this region might contain genes with a relevant role in the development of adrenocortical carcinomas (21, 22).

In this study, we demonstrated allelic loss through the analysis of six distinct microsatellite markers spanning along chromosome 17 in 29 Brazilian patients with benign and malignant adrenocortical tumors, including 16 patients with the Arg337His mutation of the p53 tumor suppressor protein. A high frequency (81%) of loss of the entire chromosome 17 was evidenced in carriers of the Arg337His mutation with benign and malignant adrenocortical tumors. Interestingly, patient 1, who was homozygous for the germinative Arg337His mutation, did not have loss of chromosome 17. These findings emphasize the contribution of isolated p53 inactivation in adrenocortical tumor development in this patient.

Interestingly, the great majority of Brazilian children with adrenocortical tumors who carried the Arg337His mutation were diagnosed at an age younger than 3 yr (12 of 15 children; Tables 1Go and 2Go). Additionally, some of these patients had a history of virilization since birth or during the first year of life. The elevated frequency of the Arg337His mutation in the pediatric group as well as its very early manifestations suggest that age is an important factor in adrenocortical tumor development. These findings support the hypothesis that childhood adrenocortical tumor may arise as a result of the persistence of the fetal adrenal cell, triggered by defective apoptosis (23).

In a previous study, the high incidence of LOH on chromosome 17p contrasted with the relatively low frequency of somatic p53 gene mutations in adrenocortical tumors (4). Additionally, most of the LOH analysis was restricted to the short arm of chromosome 17. Nevertheless, the patients with the germinative Arg337His mutation had an elevated rate of LOH of the entire chromosome 17. We believe that this discrepancy can be explained by the fact that most of the previous studies analyzed only the hot spot region of the p53 gene (24, 25).

One major problem in the management of adrenocortical tumors is distinguishing localized tumors with malignant behavior from benign ones (5). Gicquel et al. (4) in search of a reliable molecular marker for malignancy assessed three markers, including 17p13 LOH in a large series of adult patients with sporadic adrenocortical tumors. It was demonstrated that 17p13 LOH was a strong predictor of shorter disease-free survival and had an independent prognostic significance (4). These findings, however, were not confirmed in our group of patients with the Arg337His mutation. Among the 18 with loss of chromosome 17, 10 cases had a benign behavior. Therefore, loss of the entire chromosome 17 occurred in both benign and malignant tumors, being even more prevalent in adenomas, showing a lack of correlation between chromosome 17 losses and tumor aggressiveness in these patients. Conversely, in the group of patients without the Arg337His mutation, the loss of chromosome 17 occurred at a lower frequency (30%) and only in malignant lesions.

Chromosomal instability has been observed in both benign and malignant adrenal tumors, indicating defects in the mitogenic machinery (26). Using comparative genomic hybridization, Figueiredo et al. (27) reported gain of 9q34 in eight of nine Brazilian children with sporadic adrenocortical tumors (three adenomas and six carcinomas). The high incidence of 9q34 amplification was confirmed in British children with adrenocortical tumors through the same methodology (28). These previous reports contrast with our findings, which identified loss of chromosome 9q in well-defined adrenocortical carcinomas. We previously demonstrated aneuploidy by fluorescent in situ hybridization in direct preparations of uncultured cells of adrenal carcinoma using six different probes for chromosomes 1, 8, 11, 12, 15, and 17 in one patient from our series (case 4) (29). Based on these previous genetic alterations detected by comparative genomic hybridization and fluorescent in situ hybridization, here we investigated the LOH for chromosomes 2, 9, and 11 in those patients who exhibited loss of chromosome 17 using allele typing with polymorphic microsatellite markers. We observed that 70% of these patients had loss of at least one chromosome. Losses of chromosomes 2 and 11 were seen in both benign and malignant tumors. In contrast, the concomitant loss of chromosomes 2, 9, 11, and 17 was exclusively found in adrenocortical carcinomas. Therefore, chromosomal instability involving three or more chromosomes may contribute to define the malignant adrenocortical lesions. In conclusion, we demonstrated a high frequency of biallelic inactivation of p53 derived from two distinct events, the germinative Arg337His mutation and the acquired loss of the entire chromosome 17. In addition, the isolated loss of the entire chromosome 17 did not correlate with aggressive tumor behavior in these patients with adrenocortical tumors.


   Acknowledgments
 
We thank Drs. Sorahia Domenice and Regina M. Martin for clinical assistance with patients with adrenocortical tumors.


   Footnotes
 
First Published Online March 1, 2005

Abbreviation: LOH, Loss of heterozygosity.

Received May 20, 2004.

Accepted February 18, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Chen LC, Neubauer A, Kurisu W, Waldman FM, Ljung BM, Goodson 3rd W, Goldman ES, Moore 2nd D, Balazs M, Liu E 1991 Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer. Proc Natl Acad Sci USA 88:3847–3851[Abstract/Free Full Text]
  2. Farrand K, Delahunt B, Wang XL, McIver B, Hay ID, Goellner JR, Eberhardt NL, Grebe SK 2002 High resolution loss of heterozygosity mapping of 17p13 in thyroid cancer: Hurthle cell carcinomas exhibit a small 411-kilobase common region of allelic imbalance, probably containing a novel tumor suppressor gene. J Clin Endocrinol Metab 87:4715–4721[Abstract/Free Full Text]
  3. Zhao X, He M, Wan D, Ye Y, He Y, Han L, Guo M, Huang Y, Qin W, Wang MW, Chong W, Chen J, Zhang L, Yang N, Xu B, Wu M, Zuo L, Gu J 2003 The minimum LOH region defined on chromosome 17p13.3 in human hepatocellular carcinoma with gene content analysis. Cancer Lett 190:221–232[CrossRef][Medline]
  4. Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, Bertherat J, Chapuis Y, Duclos JM, Schlumberger M, Plouin PF, Luton JP, Le Bouc Y 2001 Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 61:6762–6767[Abstract/Free Full Text]
  5. Bornstein SR, Stratakis CA, Chrovsos GP 1999 Adrevnocortical tumors: recent advances in basic concepts and clinical management. Ann Intern Med 130:759–771[Abstract/Free Full Text]
  6. Isobe M, Emanuel BS, Givol D, Oren M, Croce CM 1986 Localization of gene for human p53 tumour antigen to band 17p13. Nature 320:84–85[CrossRef][Medline]
  7. Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G, Cat I, Stratakis CA, Sandrini R 2001 An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98:9330–9335[Abstract/Free Full Text]
  8. Latronico AC, Pinto EM, Domenice S, Fragoso MC, Martin RM, Zerbini MC, Lucon AM, Mendonca BB 2001 An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors. J Clin Endocrinol Metab 86:4970–4973[Abstract/Free Full Text]
  9. DiGiammarino EL, Lee AS, Cadwell C, Zhang W, Bothner B, Ribeiro RC, Zambetti G, Kriwacki RW 2002 A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Mol Biol 9:12–16
  10. Mendonca BB, Lucon AM, Menezes CA, Saldanha LB, Latronico AC, Zerbini C, Madureira G, Domenice S, Albergaria MA, Camargo M.H 1995 Clinical, hormonal and pathological findings in a comparative study of adrenocortical neoplasms in childhood and adulthood. J Urol 154:2004–2009[CrossRef][Medline]
  11. Wieneke JA, Thompson LD, Heffess CS 2003 Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am J Surg Pathol 27:867–881[CrossRef][Medline]
  12. Macfarlane DA 1958 Cancer of the adrenal cortex; the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl 23:155–186[Medline]
  13. Sullivan M, Boileau M, Hodges CV 1978 Adrenal cortical carcinoma. J Urol 120:660–665[Medline]
  14. Hahn M, Fislage R, Pingoud A 1995 Polymorphism of the pentanucleotide repeat d(AAAAT) within intron 1 of the human tumor suppressor gene p53 (17p13.1). Hum Genet 95:471–472[Medline]
  15. Shattuck TM, Costa J, Bernstein M, Jensen RT, Chung DC, Arnold A 2002 Mutational analysis of Smad3, a candidate tumor suppressor implicated in TGF-ß and menin pathways, in parathyroid adenomas and enteropancreatic endocrine tumors. J Clin Endocrinol Metab 87:3911–3914[Abstract/Free Full Text]
  16. Koch CA, Pacak K, Chrousos GP2002 The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 87:5367–5384.
  17. Wajchenberg BL, Albergaria Pereira MA, Medonca BB, Latronico AC, Campos Carneiro P, Alves VA, Zerbini MC, Liberman B, Carlos Gomes G, Kirschner MA 2000 Adrenocortical carcinoma: clinical and laboratory observations. Cancer 88:711–736[CrossRef][Medline]
  18. Ribeiro RC, Michalkiewicz EL, Figueiredo BC, DeLacerda L, Sandrini F, Pianovsky MD, Sampaio G, Sandrini R 2000 Adrenocortical tumors in children. Braz J Med Biol Res 33:1225–1234[Medline]
  19. Pinto EM, Billerbeck AEC, Villares MCBF, Domenice S, Mendonca BB, Latronico AC 2004 Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors. Arq Bras Endocrinol Metab, 48:647–650
  20. Yano T, Linehan M, Anglard P, Lerman MI, Daniel LN, Stein CA, Robertson CN, LaRocca R, Zbar B 1989 Genetic changes in human adrenocortical carcinomas. J Natl Cancer Inst 81:518–523[Abstract/Free Full Text]
  21. Kjellman M, Kallioniemi OP, Karhu R, Hoog A, Farnebo LO, Auer G, Larsson C, Backdahl M 1996 Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy. Cancer Res 56:4219–4223[Abstract/Free Full Text]
  22. Sidhu S, Marsh DJ, Theodosopoulos G, Philips J, Bambach CP, Campbell P, Magarey CJ, Russell CF, Schulte KM, Roher HD, Delbridge L, Robinson BG 2002 Comparative genomic hybridization analysis of adrenocortical tumors. J Clin Endocrinol Metab 87:3467–3474[Abstract/Free Full Text]
  23. Wilkin F, Gagné N, Paquette J, Oligny LL, Deal C 2000 Pediatric adrenocortical tumors: molecular events leading to insulin-like growth factor II gene overexpression. J Clin Endocrinol Metab 85:2048–2056[Abstract/Free Full Text]
  24. Reincke M, Karl M, Travis WH, Mastorakos G, Allolio B, Linehan HM, Chrousos GP 1994 p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 78:790–794[Abstract]
  25. Reincke M, Wachenfeld C, Mora P, Thumser A, Jaursch-Hancke C, Abdelhamid S, Chrousos GP, Allolio B 1996 p53 mutations in adrenal tumors: Caucasian patients do not show the exon 4 "hot spot" found in Taiwan. J Clin Endocrinol Metab 81:3636–3638[Abstract]
  26. Dohna M, Reincke M, Mincheva A, Allolio B, Solinas-Toldo S, Lichter P 2000 Adrenocortical carcinoma is characterized by a high frequency of chromosomal gains and high-level amplifications. Genes Chromosomes Cancer 28:145–152[CrossRef][Medline]
  27. Figueiredo BC, Stratakis CA, Sandrini R, DeLacerda L, Pianovsky MA, Giatzakis C, Young HM, Haddad BR 1999 Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab 84:1116–1121[Abstract/Free Full Text]
  28. James LA, Kelsey AM, Birch JM, Varley JM 1999 Highly consistent genetic alterations in childhood adrenocortical tumours detected by comparative genomic hybridization. Br J Cancer 81:300–304[CrossRef][Medline]
  29. Rosenberg C, Della-Rosa VA, Latronico AC, Mendonca BB, Vianna-Morgante AM 1995 Selection of adrenal tumor cells in culture demonstrated by interphase cytogenetics. Cancer Genet Cytogenet 79:36–40[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Vet PatholHome page
M. Bielinska, H. Parviainen, S. Kiiveri, M. Heikinheimo, and D. B. Wilson
REVIEW PAPER: Origin and Molecular Pathology of Adrenocortical Neoplasms
Vet. Pathol., March 1, 2009; 46(2): 194 - 210.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
M. H. S. Costa, A. C. Latronico, R. M. Martin, A. S Barbosa, M. Q Almeida, C. F. P. Lotfi, H. P Lima Valassi, M. Y. Nishi, A. M. Lucon, S. A. Siqueira, et al.
Expression profiles of the glucose-dependent insulinotropic peptide receptor and LHCGR in sporadic adrenocortical tumors
J. Endocrinol., February 1, 2009; 200(2): 167 - 175.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. Q. Almeida, M. C. B. V. Fragoso, C. F. P. Lotfi, M. G. Santos, M. Y. Nishi, M. H. S. Costa, A. M. Lerario, C. C. Maciel, G. E. Mattos, A. A. L. Jorge, et al.
Expression of Insulin-Like Growth Factor-II and Its Receptor in Pediatric and Adult Adrenocortical Tumors
J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3524 - 3531.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
M Volante, C Buttigliero, E Greco, A Berruti, and M Papotti
Pathological and molecular features of adrenocortical carcinoma: an update
J. Clin. Pathol., July 1, 2008; 61(7): 787 - 793.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Libe, L. Groussin, F. Tissier, C. Elie, F. Rene-Corail, A. Fratticci, E. Jullian, P. Beck-Peccoz, X. Bertagna, C. Gicquel, et al.
Somatic TP53 Mutations Are Relatively Rare among Adrenocortical Cancers with the Frequent 17p13 Loss of Heterozygosity
Clin. Cancer Res., February 1, 2007; 13(3): 844 - 850.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pinto, E. M
Right arrow Articles by Latronico, A. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pinto, E. M
Right arrow Articles by Latronico, A. C.
Related Collections
Right arrow Adrenal and Hypertension
Right arrow Endocrine Oncology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals