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Molecular and Cellular Endocrinology
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VAIchefar and Cellular Endocrinology
Review
Molecular epidemiology of adrenocortical tumors in southern Brazil
Gislaine Custódio a,c, Heloisa Komechen a,b, Francisco R.O. Figueiredoª, Natasha D. Fachin ª, Mara A.D. Pianovski “, Bonald C. Figueiredo a,b,c,d,*
a Pelé Pequeno Príncipe Research Institute, Av. Silva Jardim, 1632, Água Verde, Curitiba, Paraná, Brazil
b Pequeno Príncipe Faculties, Av. Iguaçu, 333, Rebouças, Curitiba, Paraná, Brazil
“Center for Molecular Genetics and Pediatric Cancer Research, Av. Agostinho Leão Júnior, 400, Alto da Glória, Curitiba, Paraná, Brazil
d Department of Community Health, Federal University of Paraná, Rua Padre Camargo, 280, 7º andar, Alto da Glória, Curitiba, Paraná, Brazil
ARTICLE INFO
Article history:
Received 7 June 2011 Received in revised form 17 October 2011 Accepted 17 October 2011 Available online 25 October 2011
Keywords:
TP53 mutation
Adrenocortical tumour Arg337His
ABSTRACT
The high frequency of TP53 R337H carriers in southern Brazil is responsible for the highest known inci- dence of childhood adrenocortical tumor (ACT). Our aims were to examine other contributing mutations, age-related risk factors, epidemiological differences in ACT and to shed light on a method for increasing the survival rate of children. The fetal zone of the adrenal cortex is believed to be one of the tissues most susceptible to adenoma or carcinoma formation due to loss of p53 function. The founder germline R337H mutation is found in 95% of ACTs of young children, a much greater proportion than in adults. Despite intense educational campaigns about the high incidence of ACT in Paraná State, advanced cases remain common. Four advanced ACT cases (4/5) were admitted to a single institution in the first 6 months of 2011 in Paraná State, none of the families knew about ACT, and 2 reported no familial cancer syndrome. Curative resection is possible when a small ACT is detected early.
@ 2011 Published by Elsevier Ireland Ltd.
Contents
1. The bimodal age distribution of adrenocortical tumor (ACT) incidence 44
2. Tissue susceptibility
45
3. P53 loss of function and other genetic alterations.
47
4. Early ACT diagnosis and disease-free survival
48
5. Concluding remarks 49
Conflict of interest 49
Acknowledgements 49
References
49
1. The bimodal age distribution of adrenocortical tumor (ACT) incidence
The worldwide incidence of adrenocortical tumors (ACTs) in children under 15 years of age is 0.3 per million per year (Altekruse et al., 2009; Ries et al., 1999). The incidence of adrenal cortical car-
cinoma (ACC) in adults is 1.7-2.0 per million per year, and both carcinomas and benign tumors occur most frequently between the ages of 30 and 50 (Bornstein et al., 1999; Brennan, 1987). Remarkably, the high frequency of adrenal cortical adenomas (ACA) among adults (Song et al., 2008) is not observed among chil- dren. In line with this dramatic difference in frequency, Wieneke et al. (2003) identified 96 cases of pediatric ACT (only 9 ACA and 74 ACC) in a review of 4772 benign and malignant primary adrenal neoplasms (including all ages) in the files of the Endocrine Registry at the Armed Forces Institute of Pathology during the period 1965- 1997. From these 96 records, the authors presented 83 cases (50 girls and 33 boys), ranging in age from 4 months to 19 years (median 4 years), which seemed to be a biphasic age distribution:
Abbreviations: ACC, adrenocortical carcinoma; ACT, adrenocortical tumors; LOH, loss of heterozygosity; CEDM, cisplatin, etoposide, doxorubicin, and mitotane; HPP, Hospital Pequeno Príncipe, Brazil.
* Corresponding author at: Pelé Pequeno Príncipe Research Institute, 1632 Av. Silva Jardim, Água Verde, Curitiba, Paraná 80.250-200, Brazil. Tel .: + 55 41 33101038; fax: +55 41 33221446.
E-mail address: bonaldf@pelepequenoprincipe.org.br (B.C. Figueiredo).
0303-7207/$ - see front matter @ 2011 Published by Elsevier Ireland Ltd. doi:10.1016/j.mce.2011.10.019
with 53% of the cases in children under the age of 5, 10% between the ages of 5 and 10 years and 37% presenting in those over the age of 10 years.
The endemic germline TP53 R337H mutation described in southern Brazil and the south of southeastern Brazil (Latronico et al., 2001; Ribeiro et al., 2001; Seidinger et al., 2011) is responsi- ble for an incidence of ACT in children that is at least 15 times higher (Pianovski et al., 2006b) than in other countries. Pinto et al. (2004) have demonstrated that the frequency of germline R337H mutation is due to common ancestry. Furthermore, we have analyzed many carriers and we never found one case of de novo R337H mutation (Figueiredo et al., 2006). The large series of child- hood ACTs reported by the International Adrenocortical Registry (IPACTR), most of which are from Brazil (Michalkiewicz et al., 2004), show an age distribution similar to that of other countries (Hartley et al., 1987; Kleihues et al., 1997; Liou and Kay, 2000; Wieneke et al., 2003), with an age peak of diagnosis in the first 5 years of life. This suggests that age of ACT onset in very young children is not influenced by differences in socioeconomic, envi- ronmental, genetic, or epigenetic background among different pop- ulations. An extensive review of 21 series of childhood ACT (n = 412) from different countries (variable cultural, ethnical and socioeconomic backgrounds) presented similar median age of diagnosis (mainly <5 years), but remarkably with impressive de- lays in ACT diagnosis, ranging from 1 to 60 months (Liou and Kay, 2000). Despite improved medical care and education for the population in many countries, the delay in diagnosis is still the main cause of advanced stages of the disease and the low survival rate.
The young age of the individuals with ACC and germline TP53 mutations contrasts with that of adult patients with ACC (more fre- quently associated with somatic mutations), which has a broad age distribution in adults (Barzilay and Pazianos, 1989; Wajchenberg et al., 2000; Wooten and King, 1993). One hypothesis for the pre- dominance of somatic mutations in adults (Ohgaki et al., 1993; Reincke et al., 1994) is that it may be related to the aging process and/or to longer exposure of adults to environmental factors.
An extensive review of 1891 ACC cases, including patients of all ages, published in the worldwide English literature from 1952 to 1992, revealed that ACC was more common in women (58.6%) than in men (41.4%) corresponding to the second age peak in the fifth decade of life (Wooten and King, 1993). These authors reported that the median age for diagnosis of functional tumors (24 years) was much lower than that for nonfunctional tumors (47 years). Remarkably, the largest review on ACC in adult Americans (pa- tients younger than 18 years of age at the time of diagnosis were excluded), of cases obtained from a nationwide cancer registry (The National Cancer Data Base, NCDB), was reported by Bilimoria et al. (2008). These authors presented data from 3982 patients, the majority of whom were female (58.2%), with a median age at diag- nosis of 55 years. The most important discrepancy between these 2 studies (worldwide vs. USA) is the difference in the median age at diagnosis. In agreement with the American series, Johanssen et al., 2010 have reported a similar median age (52 years, ranging from 16 to 86 years) for ACC cases with diagnosis in the years of 1998 to 2009 in Germany (62.5% women). Mean age at diagnosis re- ported in 15 small series from different types of services and coun- tries ranged from 20 years to 54 years, and such wide variation may be due to differences in the characteristics of each service (re- viewed by Wajchenberg et al., 2000). However, further study to examine the impacts of race/ethnicity, socioeconomic level, educa- tional level, environmental factors, and other factors on the age of ACC diagnosis in these populations is necessary. For example, the American patients were predominantly white (84.7%) and lived in areas with median incomes and education levels above the na- tional median (Bilimoria et al., 2008); these conditions are most
probably not typical of those of the majority of the Brazilian pa- tients. The reason for a lower average age for ACC in adult patients from Brazil is not due to the R337H mutation because it was found in only 13.5% (5/37) of the adult cases (Latronico et al., 2001).
Approximately 60-75% of the ACCs in adults are functional, pro- ducing predominantly glucocorticoids, while the remaining tumors are silent (Almeida et al., 2010; Wooten and King, 1993). The dis- tinction between ACA and ACC in children is not as clear as that de- fined by the Weiss score (based on nine histopathological alterations) in adults (Lau and Weiss, 2009).
2. Tissue susceptibility
Li-Fraumeni syndrome (LFS) has been defined as occurring in families with a proband with sarcoma at less than 45 years of age, a first-degree relative younger than 45 years with any cancer, and an additional first- or second-degree relative in the same line- age with any cancer before 45 years of age or with a sarcoma at any age (Li et al., 1988). Given that most cases of familial cancer do not meet the criteria for LFS, partial sets of the criteria were proposed to constitute a Li-Fraumeni-like syndrome (LFL). LFS is a complex familial cancer syndrome that was first defined based on epidemi- ological and clinical data (Li and Fraumeni, 1969); TP53 germline mutation was later found to be one of the main underlying causes (Malkin et al., 1990; Srivastava et al., 1990). ACC in children is al- most pathognomonic for a TP53 germline mutation (Sameshima et al., 1992; Kleihues et al., 1997).The profile of familial clustering of certain tumor types is more likely to reflect the penetrance of the germline TP53 mutation, ranging from high-penetrance TP53 mutations (Kleihues et al., 1997) that cause classical LFS to low- penetrance mutations such as R337H (Figueiredo et al., 2006) that cause diverse-cancer-prone families. However, for low-penetrance germline TP53 mutations such as R337H, it seems insufficient to describe all of these families as LFS or LFL; the more complex clus- tering of families requires other subtypes of familial syndromes, and we propose type 1 (classic LFS), type 2 (without sarcoma, cor- responding to LFL as proposed by Birch in 1994), type 3 (LFL with at least 1 or 2 tumor types as proposed by Chompret et al., 2001) and type 4 (when a low-penetrance germline TP53 mutation has been inherited by several family members of all ages and genera- tions but no case of cancer has yet been diagnosed). In our experi- ence, the families with the germline R337H mutation fall predominantly into types 3 and 4 but may also present as type 2 (Figueiredo et al., 2006). To date, we have found only 1 R337H-po- sitive family that meets the criteria for type 1; however, we have not ruled out in this family the possibility that other mutations in TP53 or other genes are responsible for the phenotype in this case. The first type of cancer reported in a type 4 family will usually depend on the type of service (pediatric or adult clinic) doing the reporting; in our case (Pediatric Hospital), this would be repre- sented more frequently by childhood cases of ACT or choroid plexus carcinoma. Long-term observation of many families has al- lowed us to estimate that the risk of ACT in R337H carriers is, remarkably, at least 15 times higher in early childhood than in adulthood. In addition, none of the 30 families with germline R337H mutation exhibited any adult ACT (Figueiredo et al., 2006).
The differences in cancer phenotypes (cancer type, age of onset, penetrance, etc.) are associated with a large spectrum of genetic alterations: mutations inactivating p53 (of which >80% are in the DNA-binding domain (DBD); 50% of all human tumors have such a mutation) (Petitjean et al., 2007; Vousden and Lu, 2002). Many studies of the TP53 R337H allele have shown different phenotypes in different families, and these observations are summarized in Table 1.
| Cellular, molecular, demographic, and clinical characteristics | References | |
|---|---|---|
| Mean age of ACT diagnosis (R337H- positive only) | Mean age = 3.18 + 2.43 (+SD) years; median age = 2.1 years (0.7-10.8 years of age) (n = 41). The age at which clinical manifestations were first reported (0.2-1.4 years earlier) should be considered a more accurate estimate of age of ACT onset | Figueiredo et al. (2006) and unpublished data |
| R337H origin | R337H is the most common germline mutation in the IARC database (http://www.iarc.fr/); the de novo mutation rate (0%) is consistent with founder effect/common ancestry for the entire population of R337H carriers in southern and southeastern Brazil | http://www.iarc.fr/; Pinto et al. (2004), Figueiredo et al. (2006) |
| Family history of cancer with the R337H genotype | LFS, 0%; LFLª, 22% for association with a second tumor in a first- or second-degree relative or 30% for association with families without any type of cancer | Figueiredo et al. (2006) |
| Frequency of R337H in cancers Gene profiling (of children mostly carrying the R337H mutation and adults with other genotypes) | Childhood ACT (93-95%), adult ACT (13.5%), choroid plexus carcinoma in children (63-65%), osteosarcoma (7%), breast carcinoma (3%). Germline R337H mutation has also been detected in stomach and intestinal cancers in adults and in glioblastomas and neuroblastomas in children | Ribeiro et al. (2001), Latronica et al. (2001) Figueiredo et al. (2006), Custódio et al. (2011), Seidinger et al. (2011) |
| The childhood R337H-positive carcinoma "signature" does not seem to differ significantly from that of the adult profile or from other p53 genotypes, but the profile of the carcinoma seems to differ from that of ACA in children and adults. Almost all pediatric and adult ACTs have IGF-2 as the single most upregulated transcript | Giordano et al., 2003, Velázquez-Fernández et al., 2005, West et al. (2006), Ragazzon et al. (2011) | |
| Cooperative events in ACT formation | Loss of IGF-2 imprinting triggering activation of the IGF-2/IGF- 1R pathway; SF-1 amplification and overexpression of the SF-1 protein; mutations in the alpha inhibin subunit (Inh-a associated with loss of heterozygosity (LOH) were observed in children with ACT and indicated that Inh-o functions as a tumor suppressor of ACT | Beuschlein et al. (2002), Longui et al. (2004), Figueiredo et al. (2005), Pianovski et al. (2006a), Looyenga and Hammer (2006), Doghman et al. (2007, 2010), El Wakil et al. (2011) |
| Race of southern Brazilian R337H carriers with ACT | White, mainly European (Portuguese, Italian, German, Polish, and Ukrainian), 77%; mixed (mulatto, black, Brazilian Indian native), 21%; Asian (0%) | Ribeiro et al. (2001), Figueiredo et al. (2006) |
| Geographic distribution of R337H in childhood ACT in Brazil | Most frequent in southern Brazil and the southern part of southeast Brazil (93%). R337H has not yet been found in northern and northeastern Brazil; intermediate frequencies (30-50%) of R337H-positive ACT were found in the north of southeastern Brazil | Michalkiewicz et al. (2004), Barreto et al. (2001), unpublished data |
| Clinical presentation in children | Virilization (V, 55%), Cushing's syndrome (CS, 5.5%), mixed (V + CS)b (29.2%), and nonfunctional tumor (10.2%) from IPACTRC; see also Fig. 1 and Table 2 for comparisons with ACT in adults | Michalkiewicz et al. (2004) |
| ACT Histology (pediatric and adult ACTs with different genotypes) | Carcinoma (89.7%) and adenoma (10.3%) according to data from IPACTR (R337H is found in both types). In contrast to adults, histological features do not correlate with clinical outcome in pediatric patients. There are no specific prognostic markers for childhood ACT | Michalkiewicz et al. (2004) (most are R337H-positive); Bergadá et al. (1996), Venara et al. (1998) |
| LOH with any TP53 germline mutation in ACT | LOH occurs in 95-100% of all R337H-positive ACCs and ACAs in children. It was observed in most ACC cases with more penetrant TP53 mutations in adults but was reported to be rare in ACAs | Ribeiro et al. (2001), Figueiredo et al. (2006), Seidinger et al. (2011), Gicquel et al. (2001) |
| Response to CEDM Socioeconomic level | Approximately 10% survival in pediatric patients with stage III and IV or approximately 55% survival (average for all stages in IPACTR" data). Most of these children were found to be positive for germline R337H Low family income (US$350-880 per 3-5 people per month) in Paraná state (where frequency of R337H and ACT incidence is very high) | Zancanella et al. (2006), Michalkiewicz et al. (2004) Kiesel et al. (in preparation) |
a According to Birch (1994). CEDM = cisplatin, etoposide, doxorubicin, and mitotane therapy.
b Indicates clinical and/or laboratory evidence of abnormal production of more than one hormone, including aldosterone (Conn’s syndrome) or estrogen (feminization).
” IPACTR = International Pediatric Adrenocortical Tumor Registry (n = 254), including 79.9% (n = 203) cases from southern and southeastern Brazil.
In most countries (with the exception of southern Brazil), ACT cases in children are more frequently observed in populations with familial cancer; half of the families affected by pediatric ACT have fulfilled the diagnostic criteria for classic LFS. The incidence of ACC in LFS was 3.6%, in contrast to the higher frequencies of bone or soft-tissue sarcomas (24.2%), breast cancers (24.0%), and brain tu- mors (12.0%) observed (Kleihues et al., 1997). In addition to the or- gan-specific differences in susceptibility, these authors detected differences in the mean ages of TP53 mutation carriers at the time
of diagnosis: 5 years of age for ACC, 16 years for sarcomas, 25 years for brain tumors, and 37 years for breast cancers. In contrast to the phenotype described for classic LFS (50% of the malignancies occurring by 30 years of age) (Lustbader et al., 1992), 36% (11/30) of families carrying the R337H mutation had no member present with cancer other than ACT before 30 years of age (Figueiredo et al., 2006). The germline TP53 R337H mutation was reported in approximately 95% of ACTs and 65% of choroid plexus carcinomas in young children (<5 years), 7% of osteosarcomas in adolescents,
and 3% of breast cancers in young women (Assumpção et al., 2008; Custódio et al., 2011; Michalkiewicz et al., 2004; Ribeiro et al., 2001; Seidinger et al., 2011).
In order to explain the differing susceptibility of the adrenal cortex over time, 2 critical periods (fetal zone cell death and the aging process in the reticular zone) have been postulated to foster cell stress and molecular changes, which could be a more appropri- ate environment for tumor development (Fig. 1). The levels of the adrenal androgens decline as the fetal zone regresses due to pro- grammed cell death (reviewed by Keegan and Hammer, 2002). The proximity of the final events in the fetal zone (FZ), under in- tense changes, to the age of ACT diagnosis some time before or first years after birth (Isaacs, 2010) could be related to different growth rates of ACT or to small differences in ages of ACT onset. Since most childhood ACT cases from southern Brazil are caused by the germ- line R337H mutation, the hypothesis of a monoclonal ACT would seem to be more likely to arise from the FZ in children.
Levels of dehydroepiandrosterone (DHEA) and its sulfate metabolite DHEAS increase slowly in the first decade and more rapidly during adrenarche and puberty, peak around the age of
A
ACT susceptibility “time zones”
FETAL ZONE CELL DEATH
ADRENOPAUSE
Birth
5th year
5th decade
B
ACT (%)
1
R337H-related (-)
Age
ACT susceptibility ratio among R337H carriers Children : adults = 15:1
C
Androgens
Glucocorticoids
| Children | Adults | |
|---|---|---|
| Virilizing | 58% | 9% |
| Cushing's | 8% | 48% |
| Mixed | 33% | 18% |
| NF | 0% | 25% |
Fig. 1. Cartoon illustrating age-related predisposition to ACT in different cell types (A), the upper part of the panel depicts the two main time periods postulated to have higher susceptibility to ACT (the fetal zone and the period of aging-related reduced androgen synthesis leading to adrenopause); (B), the increase in incidence of ACT cases due to R337H occurs predominantly during the first years of life due to abnormalities in the fetal zone, where the malignant clones are generated. The dashed line represents other causes of ACT; (C), the hormonal status of most ACT cases in an R337H hotspot region in southeastern Brazil is given according to age (as an example, percentages from clinical data reported by Almeida et al., 2010) to illustrate the differences between children and adults.
20 years, and within 2 years begin to decrease linearly in both sexes to reach pre-adrenarche levels in most men and women by the ninth decade (Nawata et al., 2002; Yamaji and Ibayashi, 1969). Decreased production of DHEA and DHEAS from the reticu- lar zone (RZ) may be related to decreased 17,20-lyase activity, accumulation of peroxidated lipids in the RZ, and relative atrophy of the RZ with aging (Takayanagi et al., 1986). At the end of the fifth decade, DHEAS levels reach an intermediary value between the maximal and minimal levels (around 100 µg/dL), and levels in wo- men are more frequently lower than in men (reviewed by Nawata et al., 2004), which could be related to higher prevalence of ACC found among women than in men. It has been proposed that the typical signs of adrenopause are due to accelerated decline of DHEA accompanied by a relative excess of cortisol (Alesci et al., 2001; Valenti, 2002), but stable cortisol levels during adrenopause have also been proposed (Nawata et al., 2004). The strong correla- tion between FZ production of DHEA and the predominantly viri- lizing syndrome in ACTs of young children does not hold true for the profile of the RZ (similar to the FZ) and the symptoms of ACTs in adults. Adult ACTs more frequently present as Cushing’s syn- drome or are nonfunctional. Therefore, the degenerative changes that occur in the RZ during adrenopause do not seem to dramati- cally increase the susceptibility to tumors with a predominantly androgenic phenotype. Alternatively, metabolic stress and the degenerative process that occurs during adrenopause could be fac- tor-mediated, e.g., through oxygen radicals or nitric oxide. There is circumstantial evidence that oxidative metabolism in the mito- chondria can produce reactive oxygen species (ROS). ROS may cause oxidized nucleobases, DNA strand breaks, and mutagenesis (reviewed by Maynard et al., 2009). Nitric oxide, which is produced by nitric oxide synthase in the context of chronic inflammatory states (Ohshima and Bartsch, 1994), could influence adjacent cells from other adrenal cortical zones to undergo inactivation of tumor suppressor genes and/or activation of oncogenes, resulting in be- nign and malignant transformations. If this hypothesis were cor- rect, the peak of adrenopause, during which the changes in the RZ are most intense, would contribute with other, more important tumorigenic factors to influence the age of ACT onset. Therefore, we speculate that the differences in peak age of adult ACT diagno- sis in different countries (Almeida et al., 2010; Bilimoria et al., 2008; Wajchenberg et al., 2000; Wooten and King, 1993) could be influenced by differences in the age of adrenopause as well as other genetic and epigenetic differences.
3. P53 loss of function and other genetic alterations
Cell cycle and apoptosis regulation by p53 involve a complex network of downstream genes that are essential for suppressing tumor formation; there are therefore several ways in which cell stress can cause DNA damage and cell transformation, and the exact result may depend on the degree of mutational p53 inactiva- tion (Brosh and Rotter, 2009; Oren, 2003) or mutations in p53-dependent genes. Twenty-three independent inherited TP53 mutations within and outside of the DBD were identified in 48 pediatric ACT samples from the IPACTR tissue bank. The majority of the mutations occurred in 6 hotspot codons, and only 3 muta- tions (Arg175His, Arg273Cys, and Arg337His) were detected more than once (Pinto et al., 2011). We have found 100% loss of the wild- type allele in ACTs from patients who inherited the R337H germ-line mutation (Ribeiro et al., 2001; Figueiredo et al., 2006), which is consistent with the classical 2-hit mechanism of cancer proposed by Knudson (1971). The ultimate mechanism of p53 loss seems to be the destabilization of p53 tetramerization due to increased pH- and temperature-sensitivity of its binding to DNA, as described by DiGiammarino et al. (2002).
| Institution | Period | N | Gender | Median Age/ Range (years) | Clinical manifestations (%) | Hotspot Region for R337H? | R337H % | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Only V | Only CS | M | NF | All V | All CS | |||||||
| HC-UFPR (PR) (Pereira et al., 2004) | 1966-2003 | 125 | F> M | 4/1-19 | 51 | 1.6 | 42 | 4.8 | 93 | 43.6 | Yes | 93 |
| CID Boldrini (SP) (Hirose et al., 2005) | 1980-2004 | 78 | F > M | <18 | 71 | 6.4 | 11.5 | 10.3 | 82.5 | 17.9 | Yes | a |
| Santa Casa (SP) (Longui et al., 2004) | NA | 46 | F> M | 2/0.4-13.4 | 65 | 2.2 | 32.6 | NA | 97.6 | 34.8 | Yes | 84.8 |
| HCFMRPreto (SP) (Tucci et al., 2005) | 1975-2003 | 34 | F> M | 3/1-17 | 55 | 11.8 | 29.4 | 2.9 | 84.4 | 41.2 | Yes | NA |
| HC/USP (SP) (Almeida et al., 2010) | NA | 36 | F> M | NA/2.2-4.6 | 58 | 8.3 | 33.3 | 0 | 91.3 | 41.6 | Yes | NA |
| IPACTR-ACT Registry (Michalkiewicz et al., 2004); 80% from Brazil | NA | 254 | F > M | 3.2/0-19 | 55 | 5.5 | 29.2 | 10.2 | 84.2 | 34.7 | Yes | NA |
| HSR (BA) (Barreto et al., 2001) | 1981-2004 | 6 | F> M | <12 | 16 | 33 | 0 | 33 | 16 | 33 | No | 0 |
HC-UFPR (PR) = Hospital at Clínicas at Universidade Federal do Paraná (Paraná); CID Boldrini (SP) = Centro Infantil Domingos Boldrini in Campinas (São Paulo); Santa Casa (SP) = Hospital Santa Casa in São Paulo (São Paulo); HCFMRPreto (SP) = Hospital de Clínicas at Faculdade de Medicina in Ribeirão Preto (São Paulo); HC/USP (SP) = Hospital das Clínicas in São Paulo (São Paulo); IPACTR = International Pediatric Adrenocortical Tumor Registry; HSR = Hospital São Rafael at Universidade Federal da Bahia; N = Number of cases; PR = Paraná State (in southern Brazil); SP = São Paulo State (in southeastern Brazil); V = Virilizing syndrome; CS = Cushings Syndrome; M = Mixed-type syndrome (V + CS); NF = Non-functional; BA = Bahia State (in northern Brazil).
a In another recent study using the same group of patients it was found that 93% (65/70) of ACT cases were R337H-positive (Seidinger et al., 2011).
Other contributing genetic changes were detected in ACTs (Table 1), suggesting that inheritance of R337H and loss of p53 function are not the only determinants of ACT, but it is rare to find a childhood ACT without the R337H mutation. Many genetic alter- ations in various chromosomal regions (2, 11p15, 11q, and 17p13) and genes (IGF-II, TP53, B-catenin, and MC2R) have been implicated in ACC development (reviewed by Libe et al., 2007a; Fassnacht et al., 2011). Further genetic or epigenetic alterations that compro- mise p53 function or are unrelated to p53 have been reported (Figueiredo et al., 2006; Longui et al., 2004; Weisz et al., 2007; Yan and Chen, 2010; Zambetti, 2007).
High-throughput genome-wide expression assays yielded very similar transcriptome results and therefore did not define distinct “signatures” for pediatric and adult carcinomas, although they helped identify markers for malignant tumors that differ from those of ACA (Giordano et al., 2003, 2009; Velázquez-Fernández et al., 2005; West et al., 2006; reviewed by Ragazzon et al., 2011). These studies provided important insights into the candi- date markers that could be used to predict clinical outcomes. The clinical presentation of most ACTs is strongly related to the partic- ular hormonal identity of the adrenal cortical cells. Although ACCs display uncontrolled growth and accumulate genomic changes over time, they usually maintain their original steroidogenic pro- files. Relapsing cases tend to reproduce the hormone levels of the primary tumor, consistent with a relatively well-preserved steroi- dogenic function. In addition to intrinsic tissue factors (Kleihues et al., 1997), susceptibility during the final stage of the fetal zone and loss of p53 function may link the early age of ACT onset with androgen overproduction. Consistent with this hypothesis, chil- dren very frequently present with virilization, a feature of the fetal zone clone (Fig. 1 and Table 2).
Despite the incomplete penetrance of Arg337His in pediatric ACT (considering only families with ACTs) (Figueiredo et al., 2006), the diagnosis of an ACT in a young child in southern Brazil or in the south of southeastern Brazil, even in families with no his- tory of cancer, is almost pathognomonic for the germline R337H mutation (Pianovski et al., 2006b; Ribeiro et al., 2001). Previous re- ports on rare ACT cases in children from Argentina found p53 inac- tivation in <20% of cases (Bergadá et al., 1996; Venara et al., 1998); however, these studies assayed p53 activity by immunohistochem- istry, which is not highly reliable as an indicator of the presence of mutations. These children (0.4-15.6 years of age) presented with virilization with (55%) or without (45%) Cushing’s syndrome, which suggests that there is no definite relationship between the genotype (TP53 or other mutation) and the clinical course. The fre- quency of Cushing’s syndrome in children with ACT increases with age, consistent with the higher prevalence of Cushing’s in adult
ACT patients. In the United States and Europe, TP53 germline muta- tions have been observed in 50-80% of children with sporadic ACC (Varley et al., 1999; Wagner et al., 1994). In contrast, TP53 muta- tions are found in only 25% of adult ACCs and are usually somatic (Ohgaki et al., 1993; Reincke et al., 1994). The heterogeneity of genotypes and the various clinical presentations between children and adults may reflect different cell types and mechanisms leading to tumor development. Interestingly, in a French study of 36 adults (aged 44.7 + 16.2 years (mean + SD)) with sporadic ACT who were selected for 17p13 loss of heterozygosity (LOH), 33% of the tumors had TP53 mutations and 44% had an intragenic LOH (VNTR1 mar- ker), which did not always correlate with the presence of a TP53 mutation (Gicquel et al., 2001; Libè et al., 2007b). These authors have proposed that other suppressor candidates exist and that instability in 17p13 occurs early in adrenocortical cancer develop- ment. They also confirmed the finding of previous studies that TP53 mutations are associated with more aggressive and advanced tu- mors. However, the clinical manifestations, which were typical for adults, were not specific for any one of the genotypes (negative or positive for TP53 inactivation mutation).
4. Early ACT diagnosis and disease-free survival
Given that almost all ACTs in children from southern Brazil are related to the inherited R337H mutation and that this genotype is more frequently associated with aggressive and advanced tumors, it is imperative to make the diagnosis of ACT as soon as possible. However, low socioeconomic and education levels and the limita- tions of the public health system tend to delay ACT diagnosis for the majority of these families. This may account for the high over- all mortality rate for ACT in Brazilian children, which is probably very similar to the 45.8% reported for 254 ACT cases from IPACTR, in which most cases are from southern Brazil (Michalkiewicz et al., 2004). Only a small percentage (<0.1%) of the estimated number of R337H-positive families in southern Brazil are aware of the inher- ited R337H mutation, have received genetic counseling, and are prepared for the possibility of cancer. Villani et al. (2011) have demonstrated the feasibility of a protocol for the detection of asymptomatic neoplasms in individuals with germline TP53 muta- tions, lending support to the use of early genetic testing and sur- veillance of individuals from families with LFS. Interestingly, the follow-up was not restricted to ACT, but encompassed all of the cancer types especially common in LFS. An equivalent ACT protocol for use in children would require only a short follow-up period to detect most cases of ACT. Since a substantial number of families from southern Brazil are not LFL and have no familial history of
any type of cancer, we are not able to select individuals for genetic testing based on their family histories of cancer (Figueiredo et al., 2006). Considering approximately 15 new cases of ACT in children under the age of 5 occur in Paraná state (population 10.5 million) each year, and more than 95% of the ACTs are positive for the R337H mutation (Pianovski et al., 2006b; Ribeiro et al., 2001), an interesting option that could potentially increase the survival rate would be a simple PCR-RFLP R337H test (Custódio et al., 2011) for all newborns and a surveillance protocol for those positive for R337H.
The largest exclusively pediatric hospital in Brazil is Hospital Pequeno Principe (HPP) in Curitiba, the capital of Paraná. Despite an intense media campaign and internet resources (www.cura- dotca.org.br, web site for a cure for ACT) organized and funded by this hospital for the last 5 years, the population (mainly from rural areas) is not aware of the possibility of carrying the R337H mutation. By way of illustration, 4 of 5 R337H-positive children admitted to HPP in the first 6 months of 2011 had advanced ACT, and none of the parents knew anything about either the disease or the mutation. All five families reported clinical manifestations 8 months to almost 4 years before diagnosis. Education for the gen- eral population and intensive training for new health professionals about the risk, signs, and symptoms of ACT should be systemati- cally employed in this region. However, a more definitive efficient option for early diagnosis of ACT would be genetic screening of all newborns in Paraná state and surveillance of those testing positive for R337H.
R337H-negative ACT cases in children are rare in southern Bra- zil, and some may still be attributed to migration of ancestors from more remote states. Based on several ACT cases identified in differ- ent parts of Brazil (unpublished data), the frequency of R337H car- riers is inversely proportional to the distance from Paraná and São Paulo states (located in southern Brazil), and we predict that it would be very difficult to find any R337H carrier or case of child- hood ACT more than 1000 miles to the north from these states. Remarkably, all five reported childhood ACT cases (Table 2) from Hospital São Rafael (located in the state of Bahia in northern Brazil, were negative for R337H. In our experience, the older the patient (above 8 years of age), the greater the probability of an R337H- negative genotype, which is in line with the observation that the incidence is at least 15 times higher at early ages (Fig. 1). The difference between younger and older children should be taken into account when considering the differences in the frequencies of the R337H mutation. This TP53 allele is a good candidate marker to differentiate the two classes of ACT (positive and negative for R337H, or the childhood and the adult type of ACT), with all of their differences in clinical manifestations, histopathology, and outcome.
5. Concluding remarks
The hypothesis that the adrenal fetal zone is much more sus- ceptible than any other part of the adrenal gland or other tissue to cancer formation caused by the germline R337H mutation is very likely correct. This is consistent with the lower ACT incidence and differences in clinical manifestations in adults. Likewise, the R337H mutation is less common in other types of tumors in chil- dren and adults than in ACT. Considering the time reported with clinical signs and symptoms before diagnosis by most studies, ACT onset in children occurs much earlier than the peak of diagno- sis shown in Fig. 1, suggesting that more than 80% of the newborns with ACT would be identified before the age of 3. Based on these observations, neonatal screening and surveillance would be the most efficient strategy for early diagnosis of ACT, allowing curative resection and higher rates of disease-free survival than treatment
with mitotane (o,p’-DDD) in combination with chemotherapy, which has a less than 10% cure rate (Zancanella et al., 2006).
Conflict of interest
The authors declare no potential conflicts of interest with re- spect to the authorship and/or publication of this article.
Acknowledgements
This work was supported in part by CAPES (Nanobiotechnology grant 2009) and CNRS/LIA (2011), Araucária Foundation (Paraná, 375 and 043/2010), and by the American Lebanese Syrian Associ- ated Charities (ALSAC).
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