ELSEVIER
Molecular and Cellular Endocrinology
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Vesicular you Celular Endocrinology
Review
Differences in the molecular mechanisms of adrenocortical tumorigenesis between children and adults
André M. Faria ª, Madson Q. Almeida a,b,*
a Unidade de Suprarrenal e Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM-42, Hospital das Clínicas e, Brazil
b Instituto do Câncer (ICESP), da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
ARTICLE INFO
Article history: Available online 14 October 2011
Keywords:
Adrenocortical tumors
Children
p53
IGF2
IGF1R
SF1
ABSTRACT
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. The incidence of pediatric adrenocortical tumors (ACT) is remarkably high in Southern Brazil, where it is estimated to be 15 times greater than the world occurrence, due to a high frequency of a germline mutation (p.R337H) of the TP53 gene. Differently from adults, pediatric adrenocortical neoplasms with apparently poor prognosis based on histopathological features have often a good clinical outcome. A high Weiss score is definitely not a good predictor of survival in children, but it is much more discriminative of a poor outcome in adult tumors. Besides important differences in prognosis, adrenocortical tumorigenesis has distinct patterns between children and adults. In this review, we summarize recent data from ours and other Institutions, showing that the prognostic importance of molecular markers is striking different between pediatric and adult ACT. Although the majority of pediatric ACT are associated with p.R337H germline mutation, it is not a predictor of poor outcome in children and adolescents with ACT. On the other side, TP53 somatic mutations define a subgroup of adult ACC with different tumorigenesis and unfavorable prognosis. IGF system has a central role in the malignant phenotype of ACT, but in adult tumors it is mediated by IGF2 over-expression and in pediatric tumors by IGF1R over-expression. Finally, SF1 over-expression is associated with decreased overall survival and recurrence-free survival in adult ACC, but not in the pedi- atric group. In conclusion, discriminating benign and malignant behavior is more challenging in pediatric ACT than in adult tumors.
2011 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction 52
2. Clinicopathological aspects and outcome of pediatric and adult adrenocortical tumors.
53
3. Molecular pathogenesis of adrenocortical tumors
53
3.1. TP53 gene and 17p13 locus
53
3.2. IGF2 and its receptor (IGF1R)
54
3.3. Steroidogenic factor 1 (SF1)
55
4. Concluding remarks and perspectives.
56
References 56
1. Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy, that accounts for only 0.05-0.2% of all human cancers, with an estimated incidence of 0.5-2 per million per year in adults (Allolio
and Fassnacht, 2006). In children, the frequency is even smaller, with only about 25 new cases of ACC being diagnosed in the USA each year. Nevertheless, the incidence of pediatric adrenocortical tumors (ACT) is remarkably high in Southern Brazil, where it is estimated to be 15 times greater than the world occurrence, due to a high frequency of a germline mutation (p.R337H) of the P53 tumor suppressor gene (Latronico et al., 2001; Ribeiro et al., 2001; Sandrini et al., 1997). Beyond the age of onset, pediatric ACT differ from adult tumors in many other ways (Almeida and Latronico, 2007).
* Corresponding author. Address: Av. Dr. Enéas de Carvalho Aguiar, 155, 2º andar, Bloco 6, São Paulo, SP 05403-900, Brazil. Tel .: +55 11 3069 7512; fax: +55 11 3069 7519.
Differently from adults, pediatric adrenocortical neoplasms with apparently poor prognosis based on histopathological fea- tures have often a favorable clinical outcome (Mendonca et al., 1995; Wieneke et al., 2003). To date, few molecular markers are helpful to predict poor prognosis in children with ACT (Allolio and Fassnacht, 2006; Almeida et al., 2008; Almeida and Latronico, 2007). In the last decade, considerable advances toward under- standing the molecular mechanisms of adrenocortical tumorigene- sis have mainly been made in ACT of adults from distinct ethnicities (de Fraipont et al., 2005; de Reynies et al., 2009; Gicquel et al., 1997; Giordano et al., 2009, 2003; Tissier et al., 2005). Some of these studies have recently inspired the molecular analysis of ACT of children and adolescents, most of them from Brazilian ori- gin (Almeida et al., 2008, 2010; Figueiredo et al., 2005; Latronico et al., 2001; Ribeiro et al., 2001; West et al., 2007).
2. Clinicopathological aspects and outcome of pediatric and adult adrenocortical tumors
Approximately 60% of children with ACT are diagnosed before 4 years old (Michalkiewicz et al., 2004). At presentation, viriliza- tion is the most common syndrome in children with ACT. Isolated signs of Cushing syndrome are infrequent, occurring most often in combination with signs of increased androgen secretion (Sandrini et al., 1997). In adults, ACT are classically diagnosed under two cir- cumstances: first, in symptomatic patients with steroid excess (Cushing syndrome, Conn syndrome or hyperandrogenism in wo- men) or with symptoms related to the tumor mass; second, and more frequently, they are discovered as incidentalomas (Allolio and Fassnacht, 2006; Latronico and Chrousos, 1997).
The early manifestations of the disease (12% of the cases are diagnosed during the first year of life), the reports of ACT diag- nosed during the neonatal period and the predominance of viriliz- ing tumors suggest that pediatric adrenocortical neoplasms may arise from the fetal zone of the fetal adrenal cortex (Ishimoto and Jaffe, 2011; Michalkiewicz et al., 2004). The fetal adrenal gland rapidly grows through cell proliferation and angiogenesis at the gland periphery, cell migration, hypertrophy, and apoptosis. In terms of steroidogenesis, the fetal adrenal cortex is characterized by extensive production of dehydroepiandrosterone and its sulfate. Soon after birth, fetal zone undergoes a rapid involution, with a de- crease in androgen secretion. After fetal zone regression, adult definitive zones will be most probably originated from the defini- tive zone of the fetal adrenal (Ishimoto and Jaffe, 2011).
The pathological diagnosis of ACT should be performed by an experienced pathologist (Allolio and Fassnacht, 2006). Differentia- tion between benign and malignant adrenal lesions is based on macroscopic features (tumor weight, hemorrhage, breached or in- tact tumor capsule) and microscopic diagnostic criteria with the Weiss score, the most widely used tool (Aubert et al., 2002; Lau and Weiss, 2009; Weiss, 1984). Nuclear atypia, atypical and fre- quent mitoses (more than five of 50 high-power fields), vascular and capsular invasion, and necroses are suggestive of malignancy in adult ACT (Allolio and Fassnacht, 2006; Fassnacht et al., 2009).
Since 1995, Mendonca and others have reported that children with ACT have a more favorable outcome than adults and Weiss score is not a good predictor of prognosis in the pediatric group (Mendonca et al., 1995; Sandrini et al., 1997; Wajchenberg et al., 2000). This observation has been confirmed in a large clinicopath- ologic analysis of 83 children with ACT, where 69% of patients with apparently poor prognosis based on the histopathological features had a favorable outcome (Wieneke et al., 2003). Based on these evi- dence, pediatric ACT were then classified as clinically benign or clinically malignant tumors. In addition, vena cava invasion, necro- sis and increased mitotic activity (>15 mitotic figures/20 high
power fields) independently suggested malignant clinical behavior in multivariate analysis (Wieneke et al., 2003).
In adult patients, the prognostic parameters associated with shorter survival were older age at diagnosis, cortisol hypersecre- tion and initial stage III or IV (Abiven et al., 2006). Data from the International Pediatric Adrenocortical Tumor Registry demon- strated that patients with localized disease, age between 0 and 3 years, virilization alone, disease stage I, absence of spillage dur- ing surgery, and tumor weight <200 g were associated with a greater probability of disease-free survival (Michalkiewicz et al., 2004).
The outcome analysis of patients with ACT from our Institution according to the Weiss criteria illustrates an obvious difference be- tween children and adults (Fig. 1). A high Weiss score (≥3) was definitely not a good predictor of survival in children, whereas it was much more discriminative of a poor outcome in adult tumors. A Weiss score ≤2 was useful to exclude high-risk tumors, but it represented a smaller subgroup of tumors in children. Due to the limitations of histopathological parameters to define high-risk pediatric ACT, we do not recommend the use of Weiss score to de- fine pediatric adrenocortical adenomas and carcinomas. We, there- fore, consider that it is more appropriated to employ the terms clinically benign and clinically malignant (associated with local invasion, recurrence and/or metastases) to classify ACT in the pedi- atric group, as suggested by Wieneke et al., 2003.
3. Molecular pathogenesis of adrenocortical tumors
There are currently few therapeutic options for patients with adrenocortical cancer, and new insights into the pathogenesis of this lethal disease are urgently needed (Allolio and Fassnacht, 2006; Fassnacht and Allolio, 2009). The study of rare genetic syn- dromes associated with ACT has greatly contributed to the elucida- tion of sporadic adrenocortical tumorigenesis. Pediatric ACTs are more frequently associated with Li Fraumeni, Li Fraumeni-like and Beckwith-Wiedemann syndromes. Besides important differ- ences in prognosis, adrenocortical tumorigenesis has distinct pat- terns between children and adults.
3.1. TP53 gene and 17p13 locus
p53 function is almost always compromised in tumor cells, usu- ally as a result of somatic mutations, which occur in approximately half of all human cancers and constitute a cornerstone in tumori- genesis (Brosh and Rotter, 2009; Vogelstein et al., 2000). The fre- quencies of reported TP53 mutations vary considerably between cancer types, ranging from ~10% in haematopoietic malignancies (Peller and Rotter, 2003) to 50-70% in ovarian (Schuijer and Berns, 2003), colorectal (Iacopetta, 2003) and head and neck (Blons and Laurent-Puig, 2003) cancers.
Whereas somatic TP53 mutations contribute to sporadic cancer, germline TP53 mutations cause a rare type of cancer predisposition known as Li-Fraumeni syndrome (LFS). This rare familial cancer syndrome is characterized by a high incidence of sarcoma diag- nosed early in life and at least two first-degree relatives with can- cer occurring before the age of 45 years, such as breast cancer and other diverse neoplasms, particularly brain tumors, leukemia and adrenocortical carcinomas (Malkin et al., 1990).
In Southern Brazil, a recurrent TP53 germline mutation, p.R337H, was detected in families with cancer predisposition (Achatz et al., 2007; Garritano et al., 2010; Palmero et al., 2008). This germline mutation was first identified in 98% of unrelated children with ACT originated from Southern Brazil (Ribeiro et al., 2001). The p.R337H mutation was also present in 78% of children with sporadic ACT in another Brazilian series (Latronico et al.,
Children with ACT
Adults with ACT
A
1.0
B
1.0
Weiss < 3 (n=12)
Weiss < 3 (n= 41)
0.8
0.8
* p < 0.0001
Survival
Weiss ≥ 3 (n= 27)
0.6
Survival
0.6
* p = 0.08
Weiss ≥ 3 (n= 30)
0.4
0.4
0.2
0.2
0
0
0
50
100
150
200
250
0
50
100
150
200
250
300
Time (m)
Time (m)
| TP53 mutation | n | |
|---|---|---|
| Children | ||
| Varley et al. (1999) | Somatic p.R337H | 1/14 (7%) |
| Germline p.P152L | 6/14 (43%) | |
| Germline p.R158H | 3/14 (21%) | |
| Chompret et al. (2000) | Germline p.R337H, R273L | 2 Cases |
| Ribeiro et al. (2001) | Germline p.R337H | 35/36 (98%) |
| Latronico et al. (2001) | Germline p.R337H | 21/27 (78%) |
| West et al. (2006) | Germline p.R175L | 1 Case |
| Adults | ||
| Reincke et al. (1994) | Somatic | 0/5 ACA |
| 3/16 ACC (19%) | ||
| Latronico et al. (2001) | Germline p.R337H | 6 (3 ACA; 3 ACC)/ 46 (13%) |
| Ragazzon et al. (2010) | Somatic | 9/51 ACC (17.6%) |
| Poor outcome |
ACA, adenomas; ACC, carcinomas.
2001) (Table 1). Furthermore, the p.R337H mutation was not re- stricted to the pediatric group, as it was also found in 13% of adult patients with ACT (Latronico et al., 2001). More recently, P53 mutations were also screened in 45 Brazilian unrelated individuals with family histories fulfilling the clinical definitions of Li-Frau- meni-like syndrome (Achatz et al., 2007). The germline p.R337H mutation was found in 46% of the patients harboring TP53 muta- tions, and was associated with a wide spectrum of tumors, includ- ing breast cancers (30%), brain cancers (11%), soft tissue sarcomas (10.7%) and adrenocortical tumors (8.9%) (Achatz et al., 2007). The p.R337H mutation has been originated in the Brazilian population through a founder effect (Garritano et al., 2010; Pinto et al., 2004).
Although the majority of pediatric ACT are associated with p.R337H germline mutation, this mutation was not a predictor of outcome in children and adolescents with ACT (Latronico et al., 2001; Pinto et al., 2005). However, we should also emphasize that not all TP53 mutations are functionally equivalent and different TP53 mutations may have different influence on the clinical out- come of pediatric ACT (West et al., 2006). On the other hand, TP53 mutations are mostly somatic in adult ACT and represent a
later step in tumorigenesis (Gicquel et al., 2001; Ragazzon et al., 2010; Reincke et al., 1994) (Table 1). TP53 somatic mutations de- fined a subgroup of ACC with different tumorigenesis and poor out- come (Ragazzon et al., 2010).
17p13 loss of heterozygosity was a prognostic marker of poor outcome in adults with ACT (Gicquel et al., 2001). 17p13 LOH was demonstrated in 30% of ACA and in 80% of ACC, and it was independently associated with recurrence in the multivariate anal- ysis (Gicquel et al., 2001). Interestingly, 17p13 LOH did not always correlate with the presence of TP53 mutation (Libe et al., 2007). Differently from adults, 17p13 LOH was not associated with poor prognosis in pediatric ACT (Pinto et al., 2005).
3.2. IGF2 and its receptor (IGF1R)
The IGF signaling pathway has many important roles in normal cell growth and development (Samani et al., 2007). All of the com- ponents of the IGF system (IGFs, receptors, and binding proteins) are expressed by human fetal adrenals (Ilvesmaki et al., 1993). The IGF2 gene, which is located on chromosome 11p15, encodes a fetal growth factor that is expressed exclusively from the pater- nally inherited allele. Genetic or epigenetic defects in the im- printed 11p15 region can increase IGF2 expression. Structural abnormalities at the 11p15 locus, particularly uniparental paternal isodisomy, were initially described in 37% of adults with sporadic ACT (Gicquel et al., 1994). In a large adult series of 82 ACT, abnor- malities of the 11p15 region and/or IGF2 gene over-expression were demonstrated in 93% of malignant tumors and in only 9% of benign tumors (Gicquel et al., 1997). Genome profiling analysis identified IGF2 up-regulation as a relevant alteration in adult ACC (de Fraipont et al., 2005; Giordano et al., 2003).
In contrast to adult tumors, IGF2 was over-expressed in both clinically bening and malignant pediatric ACT (Almeida et al., 2008; West et al., 2007; Wilkin et al., 2000). IGF2 exerts its mito- genic effects through interaction with IGF1 receptor (IGF1R) (Logie et al., 1999). Thus, over-expression of IGF2 and/or IGF1R may trig- ger a cascade of molecular events that can ultimately lead to malignancy (Samani et al., 2007). We previously demonstrated an over-expression (>2-fold increase) of IGF1R gene in pediatric
ACT (Almeida et al., 2008). IGF1R over-expression was significantly correlated with malignant behavior in children. These findings suggest that the IGF system has a central role in the malignant phenotype of ACT, but in adult tumors it is mediated by IGF2 over-expression and in pediatric tumors by IGF1R over-expression. Therefore, IGF1R is a potential prognostic marker for children with ACT. Additionally, a selective IGF-IR kinase inhibitor had anti-tu- mor effects in vitro (Almeida et al., 2008). IGF1R inhibition blocked cell proliferation in a dose and time-dependent manner through a significant increase of apoptosis in NCIH295 cells and in a pediatric ACT cell line (Almeida et al., 2008). Another study demonstrated that IGF1R inhibition also reduced tumor growth in vivo, and the combination with mitotane significantly enhanced tumor growth suppression (Barlaskar et al., 2009). IGF1R targeting therapies are now being evaluated in adult ACC (Haluska et al., 2010). Because of the importance of IGF1-R over-expression in the molecular path- ogenesis of pediatric ACT, clinical trials with IGF1R targeting ther- apies are also being considered for children with metastatic ACT.
More recently, Doghman and colleagues confirmed IGF1R over- expression in pediatric ACT and showed that mTOR signaling was activated in these tumors (Doghman et al., 2010). The microRNAs mir-99a and mir-100 were among the most down-regulated microRNAs in pediatric tumors when compared to normal adrenals (Doghman et al., 2010). Downregulation of mir100 in adrenocorti-
cal cancer cells promoted a significant increase in IGF1R expres- sion, showing that mir100 downregulation is one of the mechanisms to explain IGF1R over-expression in pediatric ACT.
3.3. Steroidogenic factor 1 (SF1)
SF-1 is an orphan member of the nuclear receptor family of transcription factors and plays an important role in endocrine function, including the regulation of steroid hydroxylases, develop- ment and function of the adrenal cortex and male sexual differen- tiation (Parker and Schimmer, 1997). SF-1 maps to 9q33.3, a chromosomal region associated with amplification in pediatric adrenocortical tumors (Figueiredo et al., 1999). SF-1 dosage regu- lated compensatory adrenal growth following unilateral adrenal- ectomy in mice (Beuschlein et al., 2002). Furthermore, increased SF-1 dosage promoted cell proliferation and triggers tumorigenesis in mice (Doghman et al., 2007).
An increased SF-1 copy number was detected in 8 out of 9 ACT diagnosed in Brazilian children using fluorescence in situ hybridiza- tion, suggesting an association between SF-1 gene amplification and pediatric adrenocortical tumorigenesis (Figueiredo et al., 2005). Recently, we assessed SF-1 staining in a cohort of 103 ACT from 36 children and 67 adults, and analyzed gene amplification in 38 tumors (Almeida et al., 2010) (Fig. 2). SF1 amplification was
A
B
+
9
90
120
150
180
210
240
270
300
330
360
390
420
Exon 5
Exon 3
Exon 4
1500
Exon 1
Exon 6
1200
900
600
300
0
Normal adrenal gland
1600
1200
800
400
0
Pediatric ACT with SF1 amplification
| Markers | Children ACT | Adult ACT |
|---|---|---|
| Weiss score ≥ 3 | No | Yes |
| Ki67 | No | Yes |
| TP53 mutations | No (germline p.R337H) | Yes (somatic |
| P53 mutations) | ||
| 17p13 LOH | No | Yes |
| IGF2 over-expression | No | Yes |
| 11p15 LOH | No | Yes |
| IGF1R over-expression | Yes | No |
| SF1 amplification | No | No |
| SF1 over-expression | No | Yes |
| DGL7-PINK1 expression | NA | Yes |
| BUB1B-PINK1 expression | NA | Yes |
ACT, adrenocortical tumors; LOH, loss of heterozygosity; NA, not available.
analyzed by multiple ligation-dependent probe amplification (MLPA) and real-time PCR. Increased SF1 copy number was identi- fied in 47% of pediatric ACT and in only 10% of adult tumors. The fre- quency of SF1 gene amplification was similar in clinically benign and malignant pediatric ACT. A strong nuclear SF1 expression was detected in 56% of the pediatric and in 19% of adult ACT. SF1 expres- sion was also not correlated with functional status of adrenocortical tumors, supporting the concept that in adrenal tumor cells SF1 functions are more related to modulation of cell proliferation and apoptosis than to steroidogenesis (Doghman et al., 2007). Interest- ingly, a strong SF1 staining was also identified in 29% of pediatric ACT without SF1 amplification, indicating that additional mecha- nisms other than gene amplification can increase SF1 expression.
In a recent study, strong SF1 protein expression significantly correlated with poor clinical outcome in a very expressive cohort of adult ACC (Sbiera et al., 2010). In contrast to children, adult pa- tients with ACC and a strong SF1 expression had a significant de- crease in overall survival and recurrence-free survival. Since the frequency of SF1 gene amplification in adult ACC is very low (Al- meida et al., 2010), SF1 over-expression in this context might be caused by other mechanisms, such as transcriptional regulation or post-translational modifications.
4. Concluding remarks and perspectives
Discriminating benign and malignant behavior is more chal- lenging in pediatric ACT than in adult tumors. In contrast to adults, prognostic factors are not well established in children with ACT (Table 2). Transcriptome analysis has already identified relevant transcriptome differences not only between adenoma and carci- noma but also between two sets of carcinoma in adult individuals with very different outcomes (de Reynies et al., 2009). However, the only reported transcriptome study of pediatric ACT did not dis- criminate malignant behavior using unsupervised clustering meth- ods (West et al., 2007). Therefore, additional transcriptome studies of pediatric ACT are needed to provide a better understanding of the mechanisms of tumorigenesis. We believe that further infor- mation should come from the integration of transcriptomes and deep-sequencing of pediatric ACT, providing novel molecular ther- apeutic targets and predictors of poor outcome, which can hope- fully help in the selection of high-risk pediatric ACT.
References
Abiven, G., Coste, J., Groussin, L., Anract, P., Tissier, F., Legmann, P., Dousset, B., Bertagna, X., Bertherat, J., 2006. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J. Clin. Endocrinol. Metab. 91, 2650-2655.
Achatz, M.I., Olivier, M., Calvez, F.L., Martel-Planche, G., Lopes, A., Rossi, B.M., Ashton-Prolla, P., Giugliani, R., Palmero, E.I., Vargas, F.R., Rocha, J.C., Vettore, A.L.,
Hainaut, 2007. The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett. 245, 96-102. Allolio, B., Fassnacht, M., 2006. Clinical review: adrenocortical carcinoma: clinical update. J. Clin. Endocrinol. Metab. 91, 2027-2037.
Almeida, M.Q., Latronico, A.C., 2007. The molecular pathogenesis of childhood adrenocortical tumors. Horm. Metab. Res. 39, 461-466.
Almeida, M.Q., Fragoso, M.C., Lotfi, C.F., Santos, M.G., Nishi, M.Y., Costa, M.H., Lerario, A.M., Maciel, C.C., Mattos, G.E., Jorge, A.A., Mendonca, B.B., Latronico, A.C., 2008. Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. J. Clin. Endocrinol. Metab. 93, 3524- 3531.
Almeida, M.Q., Soares, I.C., Ribeiro, T.C., Fragoso, M.C., Marins, L.V., Wakamatsu, A., Ressio, R.A., Nishi, M.Y., Jorge, A.A., Lerario, A.M., Alves, V.A., Mendonca, B.B., Latronico, A.C., 2010. Steroidogenic factor 1 overexpression and gene amplification are more frequent in adrenocortical tumors from children than from adults. J. Clin. Endocrinol. Metab. 95, 1458-1462.
Aubert, S., Wacrenier, A., Leroy, X., Devos, P., Carnaille, B., Proye, C., Wemeau, J.L., Lecomte-Houcke, M., Leteurtre, E., 2002. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am. J. Surg. Pathol. 26, 1612-1619.
Barlaskar, F.M., Spalding, A.C., Heaton, J.H., Kuick, R., Kim, A.C., Thomas, D.G., Giordano, T.J., Ben-Josef, E., Hammer, G.D., 2009. Preclinical targeting of the type I insulin-like growth factor receptor in adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 94, 204-212.
Beuschlein, F., Mutch, C., Bavers, D.L., Ulrich-Lai, Y.M., Engeland, W.C., Keegan, C., Hammer, G.D., 2002. Steroidogenic factor-1 is essential for compensatory adrenal growth following unilateral adrenalectomy. Endocrinology 143, 3122- 3135.
Blons, H., Laurent-Puig, P., 2003. TP53 and head and neck neoplasms. Hum. Mutat. 21, 252-257.
Brosh, R., Rotter, V., 2009. When mutants gain new powers: news from the mutant p53 field. Nat. Rev. Cancer 9, 701-713.
Chompret, A., Brugieres, L., Ronsin, M., Gardes, M., Dessarps-Freichey, F., Abel, A., Hua, D., Ligot, L., Dondon, M.G., Bressac-de Paillerets, B., Frebourg, T., Lemerle, J., Bonaiti-Pellie, C., Feunteun, J., 2000. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer 82, 1932-1937.
de Fraipont, F., El Atifi, M., Cherradi, N., Le Moigne, G., Defaye, G., Houlgatte, R., Bertherat, J., Bertagna, X., Plouin, P.F., Baudin, E., Berger, F., Gicquel, C., Chabre, O., Feige, J.J., 2005. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic acid microarrays identifies several candidate genes as markers of malignancy. J. Clin. Endocrinol. Metab. 90, 1819- 1829.
de Reynies, A., Assie, G., Rickman, D.S., Tissier, F., Groussin, L., Rene-Corail, F., Dousset, B., Bertagna, X., Clauser, E., Bertherat, J., 2009. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J. Clin. Oncol. 27, 1108-1115.
Doghman, M., Karpova, T., Rodrigues, G.A., Arhatte, M., De Moura, J., Cavalli, L.R., Virolle, V., Barbry, P., Zambetti, G.P., Figueiredo, B.C., Heckert, L.L., Lalli, E., 2007. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol. Endocrinol. 21, 2968-2987.
Doghman, M., El Wakil, A., Cardinaud, B., Thomas, E., Wang, J., Zhao, W., Peralta-Del Valle, M.H., Figueiredo, B.C., Zambetti, G.P., Lalli, E., 2010. Regulation of insulin- like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res. 70, 4666-4675.
Fassnacht, M., Allolio, B., 2009. Clinical management of adrenocortical carcinoma. Best Pract. Res. Clin. Endocrinol. Metab. 23, 273-289.
Fassnacht, M., Johanssen, S., Quinkler, M., Bucsky, P., Willenberg, H.S., Beuschlein, F., Terzolo, M., Mueller, H.H., Hahner, S., Allolio, B., 2009. Limited prognostic value of the 2004 International Union against cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 115, 243-250.
Figueiredo, B.C., Stratakis, C.A., Sandrini, R., DeLacerda, L., Pianovsky, M.A., Giatzakis, C., Young, H.M., Haddad, B.R., 1999. Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J. Clin. Endocrinol. Metab. 84, 1116-1121.
Figueiredo, B.C., Cavalli, L.R., Pianovski, M.A., Lalli, E., Sandrini, R., Ribeiro, R.C., Zambetti, G., DeLacerda, L., Rodrigues, G.A., Haddad, B.R., 2005. Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors. J. Clin. Endocrinol. Metab. 90, 615-619.
Garritano, S., Gemignani, F., Palmero, E.I., Olivier, M., Martel-Planche, G., Le Calvez- Kelm, F., Brugieres, L., Vargas, F.R., Brentani, R.R., Ashton-Prolla, P., Landi, S., Tavtigian, S.V., Hainaut, P., Achatz, M.I., 2010. Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect. Hum. Mutat. 31, 143-150.
Gicquel, C., Bertagna, X., Schneid, H., Francillard-Leblond, M., Luton, J.P., Girard, F., Le Bouc, Y., 1994. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J. Clin. Endocrinol. Metab. 78, 1444-1453.
Gicquel, C., Raffin-Sanson, M.L., Gaston, V., Bertagna, X., Plouin, P.F., Schlumberger, M., Louvel, A., Luton, J.P., Le Bouc, Y., 1997. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J. Clin. Endocrinol. Metab. 82, 2559-2565.
Gicquel, C., Bertagna, X., Gaston, V., Coste, J., Louvel, A., Baudin, E., Bertherat, J., Chapuis, Y., Duclos, J.M., Schlumberger, M., Plouin, P.F., Luton, J.P., 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.
Giordano, T.J., Thomas, D.G., Kuick, R., Lizyness, M., Misek, D.E., Smith, A.L., Sanders, D., Aljundi, R.T., Gauger, P.G., Thompson, N.W., Taylor, J.M., Hanash, S.M., 2003. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am. J. Pathol. 162, 521-531.
Giordano, T.J., Kuick, R., Else, T., Gauger, P.G., Vinco, M., Bauersfeld, J., Sanders, D., Thomas, D.G., Doherty, G., Hammer, G., 2009. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin. Cancer Res. 15, 668-676.
Haluska, P., Worden, F., Olmos, D., Yin, D., Schteingart, D., Batzel, G.N., Paccagnella, M.L., de Bono, J.S., Gualberto, A., Hammer, G.D., 2010. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother. Pharmacol. 65, 765-773.
Iacopetta, B., 2003. TP53 mutation in colorectal cancer. Hum. Mutat. 21, 271-276. Ilvesmaki, V., Blum, W.F., Voutilainen, R., 1993. Insulin-like growth factor binding proteins in the human adrenal gland. Mol. Cell. Endocrinol. 97, 71-79.
Ishimoto, H., Jaffe, R.B., 2011. Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocr. Rev. 32, 317-355. Latronico, A.C., Chrousos, G.P., 1997. Extensive personal experience: adrenocortical tumors. J. Clin. Endocrinol. Metab. 82, 1317-1324.
Latronico, A.C., Pinto, E.M., Domenice, S., Fragoso, M.C., Martin, R.M., Zerbini, M.C., Lucon, A.M., Mendonca, B.B., 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.
Lau, S.K., Weiss, L.M., 2009. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum. Pathol. 40, 757-768.
Libe, R., Groussin, L., Tissier, F., Elie, C., Rene-Corail, F., Fratticci, A., Jullian, E., Beck- Peccoz, P., Bertagna, X., Gicquel, C., Bertherat, J., 2007. Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. Clin. Cancer Res. 13, 844-850.
Logie, A., Boulle, N., Gaston, V., Perin, L., Boudou, P., Le Bouc, Y., Gicquel, C., 1999. Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line. J. Mol. Endocrinol. 23, 23-32.
Malkin, D., Li, F.P., Strong, L.C., Fraumeni Jr., J.F., Nelson, C.E., Kim, D.H., Kassel, J., Gryka, M.A., Bischoff, F.Z., Tainsky, M.A., et al., 1990. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233-1238.
Mendonca, B.B., Lucon, A.M., Menezes, C.A., Saldanha, L.B., Latronico, A.C., Zerbini, C., Madureira, G., Domenice, S., Albergaria, M.A., Camargo, M.H., et al., 1995. Clinical, hormonal and pathological findings in a comparative study of adrenocortical neoplasms in childhood and adulthood. J. Urol. 154, 2004-2009.
Michalkiewicz, E., Sandrini, R., Figueiredo, B., Miranda, E.C., Caran, E., Oliveira-Filho, A.G., Marques, R., Pianovski, M.A., Lacerda, L., Cristofani, L.M., Jenkins, J., Rodriguez-Galindo, C., Ribeiro, R.C., 2004. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J. Clin. Oncol. 22, 838-845.
Palmero, E.I., Schuler-Faccini, L., Caleffi, M., Achatz, M.I., Olivier, M., Martel-Planche, G., Marcel, V., Aguiar, E., Giacomazzi, J., Ewald, I.P., Giugliani, R., Hainaut, P., Ashton-Prolla, P., 2008. Detection of R337H, a germline TP53 mutation predisposing to multiple cancers, in asymptomatic women participating in a breast cancer screening program in Southern Brazil. Cancer Lett. 261, 21-25. Parker, K.L., Schimmer, B.P., 1997. Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr. Rev. 18, 361-377.
Peller, S., Rotter, V., 2003. TP53 in hematological cancer: low incidence of mutations with significant clinical relevance. Hum. Mutat. 21, 277-284.
Pinto, E.M., Billerbeck, A.E., Villares, M.C., Domenice, S., Mendonca, B.B., Latronico, A.C., 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.
Pinto, E.M., Billerbeck, A.E., Fragoso, M.C., Mendonca, B.B., Latronico, A.C., 2005. Deletion mapping of chromosome 17 in benign and malignant adrenocortical tumors associated with the Arg337His mutation of the p53 tumor suppressor protein. J. Clin. Endocrinol. Metab. 90, 2976-2981.
Ragazzon, B., Libe, R., Gaujoux, S., Assie, G., Fratticci, A., Launay, P., Clauser, E., Bertagna, X., Tissier, F., de Reynies, A., Bertherat, J., 2010. Transcriptome analysis reveals that p53 and {beta}-catenin alterations occur in a group of aggressive adrenocortical cancers. Cancer Res. 70, 8276-8281.
Reincke, M., Karl, M., Travis, W.H., Mastorakos, G., Allolio, B., Linehan, H.M., Chrousos, G.P., 1994. P53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J. Clin. Endocrinol. Metab. 78, 790-794.
Ribeiro, R.C., Sandrini, F., Figueiredo, B., Zambetti, G.P., Michalkiewicz, E., Lafferty, A.R., DeLacerda, L., Rabin, M., Cadwell, C., Sampaio, G., Cat, I., Stratakis, C.A., 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.
Samani, A.A., Yakar, S., LeRoith, D., Brodt, P., 2007. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr. Rev. 28, 20-47.
Sandrini, R., Ribeiro, R.C., DeLacerda, L., 1997. Childhood adrenocortical tumors. J. Clin. Endocrinol. Metab. 82, 2027-2031.
Sbiera, S., Schmull, S., Assie, G., Voelker, H.U., Kraus, L., Beyer, M., Ragazzon, B., Beuschlein, F., Willenberg, H.S., Hahner, S., Saeger, W., Bertherat, J., Allolio, B., Fassnacht, M., 2010. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J. Clin. Endocrinol. Metab. 95, E161-171. Schuijer, M., Berns, E.M., 2003. TP53 and ovarian cancer. Hum. Mutat. 21, 285-291. Tissier, F., Cavard, C., Groussin, L., Perlemoine, K., Fumey, G., Hagnere, A.M., Rene- Corail, F., Jullian, E., Gicquel, C., Bertagna, X., Vacher-Lavenu, M.C., Perret, C., Bertherat, J., 2005. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 65, 7622-7627.
Varley, J.M., McGown, G., Thorncroft, M., James, L.A., Margison, G.P., Forster, G., Evans, D.G., Harris, M., Kelsey, A.M., Birch, J.M., 1999. Are there low-penetrance TP53 Alleles? Evidence from childhood adrenocortical tumors. Am. J. Hum. Genet. 65, 995-1006.
Vogelstein, B., Lane, D., Levine, A.J., 2000. Surfing the p53 network. Nature 408, 307- 310.
Wajchenberg, B.L., Albergaria Pereira, M.A., Medonca, B.B., Latronico, A.C., Campos Carneiro, P., Alves, V.A., Zerbini, M.C., Liberman, B., Carlos Gomes, G., Kirschner, M.A., 2000. Adrenocortical carcinoma: clinical and laboratory observations. Cancer 88, 711-736.
Weiss, L.M., 1984. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am. J. Surg. Pathol. 8, 163-169.
West, A.N., Ribeiro, R.C., Jenkins, J., Rodriguez-Galindo, C., Figueiredo, B.C., Kriwacki, R., Zambetti, G.P., 2006. Identification of a novel germ line variant hotspot mutant p53-R175L in pediatric adrenal cortical carcinoma. Cancer Res. 66, 5056-5062.
West, A.N., Neale, G.A., Pounds, S., Figueredo, B.C., Rodriguez Galindo, C., Pianovski, M.A., Oliveira Filho, A.G., Malkin, D., Lalli, E., Ribeiro, R., Zambetti, G.P., 2007. Gene expression profiling of childhood adrenocortical tumors. Cancer Res. 67, 600-608.
Wieneke, J.A., Thompson, L.D., Heffess, C.S., 2003. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. Am. J. Surg. Pathol. 27, 867-881.
Wilkin, F., Gagne, N., Paquette, J., Oligny, L.L., Deal, C., 2000. Pediatric adrenocortical tumors: molecular events leading to insulin-like growth factor II gene overexpression. J. Clin. Endocrinol. Metab. 85, 2048-2056.