Combined expression of BUB1B, DLGAP5, and PINK1 as predictors of poor outcome in adrenocortical tumors: validation in a Brazilian cohort of adult and pediatric patients

in European Journal of Endocrinology
(Correspondence should be addressed to M C B V Fragoso; Email: mariafragoso@uol.com.br)

Background

A recent microarray study identified a set of genes whose combined expression patterns were predictive of poor outcome in a cohort of adult adrenocortical tumors (ACTs). The difference between the expression values measured by qRT-PCR of DLGAP5 and PINK1 genes was the best molecular predictor of recurrence and malignancy. Among the adrenocortical carcinomas, the combined expression of BUB1B and PINK1 genes was the most reliable predictor of overall survival. The prognostic and molecular heterogeneity of ACTs raises the need to study the applicability of these molecular markers in other cohorts.

Objective

To validate the combined expression of BUB1B, DLGAP5, and PINK1 as outcome predictor in ACTs from a Brazilian cohort of adult and pediatric patients.

Patients and methods

BUB1B, DLGAP5, and PINK1 expression was assessed by quantitative PCR in 53 ACTs from 52 patients – 24 pediatric and 28 adults (one pediatric patient presented a bilateral asynchronous ACT).

Results

DLGAP5–PINK1 and BUB1B–PINK1 were strong predictors of disease-free survival and overall survival, respectively, among adult patients with ACT. In the pediatric cohort, these molecular predictors were only marginally associated with disease-free survival but not with overall survival.

Conclusion

This study confirms the prognostic value of the combined expression of BUB1B, DLGAP5, and PINK1 genes in a Brazilian group of adult ACTs. Among pediatric ACTs, other molecular predictors of outcome are required.

Abstract

Background

A recent microarray study identified a set of genes whose combined expression patterns were predictive of poor outcome in a cohort of adult adrenocortical tumors (ACTs). The difference between the expression values measured by qRT-PCR of DLGAP5 and PINK1 genes was the best molecular predictor of recurrence and malignancy. Among the adrenocortical carcinomas, the combined expression of BUB1B and PINK1 genes was the most reliable predictor of overall survival. The prognostic and molecular heterogeneity of ACTs raises the need to study the applicability of these molecular markers in other cohorts.

Objective

To validate the combined expression of BUB1B, DLGAP5, and PINK1 as outcome predictor in ACTs from a Brazilian cohort of adult and pediatric patients.

Patients and methods

BUB1B, DLGAP5, and PINK1 expression was assessed by quantitative PCR in 53 ACTs from 52 patients – 24 pediatric and 28 adults (one pediatric patient presented a bilateral asynchronous ACT).

Results

DLGAP5–PINK1 and BUB1B–PINK1 were strong predictors of disease-free survival and overall survival, respectively, among adult patients with ACT. In the pediatric cohort, these molecular predictors were only marginally associated with disease-free survival but not with overall survival.

Conclusion

This study confirms the prognostic value of the combined expression of BUB1B, DLGAP5, and PINK1 genes in a Brazilian group of adult ACTs. Among pediatric ACTs, other molecular predictors of outcome are required.

Introduction

Adrenocortical tumors (ACTs) are common neoplasms with a prevalence of at least 3% in a population over the age of 50 years (1). Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy, with a 5-year survival lower than 35% in most populations (2). In adults, the differential diagnosis between an adrenocortical adenoma (ACA) and a localized ACC rely on the presence of at least three of nine histological Weiss criteria (3). However, in some cases, the diagnosis of malignancy is not straightforward. ACCs in children and adolescents constitute only 0.2% of all pediatric malignancies (4, 5). A remarkably high annual incidence of ACTs has been reported in children younger than 15 years from Southern Brazil, where a high prevalence of a germline mutation of the TP53 tumor suppressor (p.R337H) was identified (6, 7). In contrast to adults, pediatric ACTs with apparently poor prognosis based on the histopathological features often have a better clinical outcome (8).

ACTs are heterogeneous neoplasms with incompletely understood pathogenesis. Different transcriptome analyses confirmed IGF2 overexpression in the majority of adult ACCs (9, 10). In contrast, a single microarray analysis of pediatric ACTs did not discriminate ACAs and ACCs using unsupervised clustering (11). IGF2 and FGFR4 were similarly expressed in both benign and malignant pediatric ACTs (11, 12). Interestingly, IGF1R gene, whose product mediates the mitogenic effects of IGF2, was overexpressed in metastatic pediatric ACCs (12, 13).

Recently, de Reyniès et al. (14) identified genes in a microarray study that robustly discriminated adult ACAs and ACCs and identified two clusters of ACCs with distinct outcomes. They identified and validated that the combined expression levels of three genes were strong predictors of overall survival and disease-free survival. Accordingly, the difference between the expression values of discs large associated protein 7 (DLGAP5) and PTEN-induced putative kinase 1 (PINK1; ΔCT DLGAP5–ΔCT PINK1) was a strong predictor of recurrence and malignancy and the difference between the expression values of budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) and PINK1CT BUB1B–ΔCT PINK1) was a reliable predictor of overall survival (14). These new molecular markers identified in a European population of patients may provide important predictors for the diagnosis and the management of adult ACTs. However, it needs to be validated in other groups of adult patients and studied in pediatric ACTs, whose molecular pathogenesis is clearly different from adult tumors (5).

In the current study, we investigated the prognostic value of the combined expression of DLGAP5, BUB1B, and PINK1 genes in an adult cohort of Brazilian patients with ACTs. In addition, we examined for the first time whether the same molecular markers can predict outcome in pediatric ACTs.

Materials and methods

The study was approved by the Ethics Committee of the Hospital das Clinicas, Sao Paulo, Brazil, and informed written consent was obtained from all patients and/or parents. Clinical and pathological data were retrospectively recorded. The study cohort consisted of 52 patients (24 pediatric and 28 adults) evaluated in our Institution from 1990 to 2010 (see Tables 1 and 2). The mean follow-up period in pediatric and adult groups was 80.4 and 65.8 months respectively. Endocrine work-up was performed in all patients.

Table 1

Clinical and molecular data of pediatric adrenocortical tumor patients.

PatientSexAge (years)Size (cm)StageaWeissBUB1–PINK1DLGAP5–PINK1Recurrence/metastasisDFS (months)OutcomeFollow-up (months)
1F0.906.00II38.23907.9830No99.00Alive99.00
2F0.988.50III5−1.60670.2600On follow-up6.00Alive65.57
3F1.253.70I53.97334.3300No24.80Alive24.80
4F1.584.00I33.55676.6150No26.15Alive26.15
6M1.724.00I4−1.8467−0.3433No164.10Alive164.10
7M2.006.50II40.0740−2.7520No174.00Alive174.00
9F2.005.00I4−0.36900.7790No84.00Alive84.00
10F2.084.00I4−1.2450−1.3540No79.00Alive60.00
11F2.103.00I1−1.54800.3840No148.00Alive148.00
13F2.423.80I5−1.37171.0333No74.60Alive74.60
14F2.442.50IN/A5.47676.7067No72.40Alive72.40
15F2.525.20II7−1.92001.1100No100.77Alive100.77
16M2.592.00I54.30005.6300No155.83Alive155.83
17F2.873.50I20.97600.4740No167.17Alive167.17
19M3.208.00III71.1750−1.3310On follow-up3.00CRD12.00
20M4.888.50III6−1.08831.6583On follow-up15.00Alive127.97
21F6.077.00II7−2.21000.6633On follow-up10.00CRD15.80
22F9.326.00IV7−1.58830.1117At diagnosisCRD15.33
23M9.414.50I26.75306.7770No96.00Alive96.00
25F15.1720.00IV7−1.14000.9333At diagnosisCRD21.50
26F16.704.00I36.17338.0100No25.20Alive25.20
27F17.2015.00II45.08005.7830No115.00Alive115.00
28M17.329.00III53.455011.2000No60.00Alive60.00
29F17.4710.00IV8−0.9110−2.7570At diagnosisCRD6.93

DFS, disease-free survival; CRD, cancer-related death.

According to MacFarlane system.

Table 2

Clinical and molecular data of adult adrenocortical tumor patients.

PatientSexAge (years)Size (cm)StageaWeissBUB1–PINK1DLGAP5–PINK1Recurrence/metastasisDFS (months)OutcomeFollow-up (months)
30F19.0013.00III8−2.4760−3.2280On follow-up 8.00CRD10.00
31F22.0013.00IV7−0.51331.3000At diagnosisCRD12.00
32F22.4414.50II8−1.6100−0.5800On follow-up1.00CRD15.00
33F22.816.00III51.9060−0.7210On follow-up4.00Alive14.77
34F22.8214.00IV61.38333.2200At diagnosisCRD15.20
35F23.544.00I24.27337.4500No28.40Alive28.40
36F24.003.00I26.06204.9720No159.00Alive159.00
37F26.005.50II16.23106.2500No64.00Alive64.00
38F26.882.50I27.52009.3233No90.97Alive90.97
41F28.8812.00IV4−7.3617−2.5000At diagnosisCRD28.30
42F29.005.00I07.60507.1930No160.00Alive160.00
43M29.6119.00IV8−4.1533−1.1867At diagnosisCRD8.00
44M30.009.60III40.2250−3.0130On follow-up4.00CRD12.00
45F30.4812.00III6−0.24671.7267On follow-up4.00CRD12.00
46F35.002.00I35.33306.6650No102.00Alive102.00
47F35.563.00I07.58339.3633No54.12Alive54.17
48F35.736.00II11.77674.0000No121.43Alive121.43
50F37.602.50I27.32009.7267No202.83Alive202.83
51F39.002.50I05.72806.0770No93.00Alive93.00
52F41.002.80I15.13004.6500No143.00Alive143.00
53F41.361.80I06.46678.2000No43.17Alive43.17
54F43.4518.00IV83.14005.4233At diagnosisCRD35.37
56F45.1910.00III77.788310.5417No128.50Alive128.50
57F47.003.50I18.16007.4840No84.00Alive84.00
58F47.695.00I0−11.9350−3.7350No79.30Alive79.30
59M54.004.50I46.96907.2920No25.00Alive25.00
62F64.063.50I06.55008.0783No45.97Alive45.97
63F65.326.00II42.66674.2567No54.73Alive54.73

DFS, disease-free survival; CRD, cancer-related death.

According to MacFarlane system.

In the pediatric group, 20 out of 24 cases were classified as ACC according to Weiss criteria (Weiss score ≥3). However, only eight patients presented an advanced tumor stage (MacFarlane III or IV) at diagnosis and/or poor clinical outcome. Among adult ACTs, 14 cases were classified as ACAs (Weiss score <3) and 14 as ACCs (Weiss score ≥3). Metastases were diagnosed by systematic imaging investigations mainly abdominal and chest computed tomography (CT) scans; bone scintigraphy in appropriated cases, magnetic resonance imaging, and more recently in selected cases with positron emission CT scan. All patients were submitted to unilateral adrenalectomy except one pediatric patient who presented a bilateral asynchronous ACT (15). Histopathological diagnosis, tumor weight, size, and Weiss scores were determined for each tumor specimen. Death related to ACC progression occurred in five pediatric and nine adult patients, within a mean time of 15.67 months (6.9–35.4) after the diagnosis. The germline TP53 mutation p.R337H was studied in 21 pediatric and 20 adult patients. In pediatric patients, it was identified in 13 (62%). In adults, two patients (10%) were carriers of TP53 p.R337H germline mutations in heterozygous state (6).

RNA extraction and quantitative real-time PCR

Total RNA was extracted from the frozen tumor fragments stored in liquid nitrogen using TRIzol (Invitrogen) reagent method. The RNA integrity and concentration were evaluated by agarose gel electrophoresis (1%) and spectrophotometry. cDNA was generated using the High Capacity cDNA Archive kit for RT (Applied Biosystems, Foster City, CA, USA). Quantitative real-time PCR was performed in the ABI PRISM 7000 Sequence Detector using TaqMan gene expression assays (Applied Biosystem). The assay IDs were BUB1B, Hs00177821_m1; PINK1, Hs00260868_m1; and DLGAP5, Hs007323_m1. A cycle threshold (CT) value in the linear range of amplification was selected for each sample in triplicate and normalized to human beta glucuronidase (GUSB) endogenous control gene (4326320E). The differences of ΔCtCT DLGAP5–ΔCT PINK1) and (ΔCT BUB1B–ΔCT PINK1) were correlated with clinical and pathological parameters.

Statistical analyses

All statistical analyses were performed with the MedCalc Software (version 11.6.1.0; MedCalc Software BVBA, Brussels, Belgium). The adjusted cutoff values for (ΔCT DLGAP5–ΔCT PINK1) and (ΔCT BUBB1–ΔCT PINK1) were established by the receiver operating characteristic (ROC) curve method (see below). Univariate analysis was performed using Kaplan–Meyer curves and log-rank test statistics for comparison. A P value <0.05 was considered significant.

Results

DLGAP5–PINK1 and disease-free survival

According to de Reyniès et al. (14), the subtraction of expression level of DLGAP5 and PINK1 (DLGAP5–PINK1) in ACTs could discriminate between malignant and benign tumors and was a predictor of disease-free survival. Accordingly, a sample is predicted to be malignant if (DLGAP5–PINK1) <6.95. To find out whether similar results could be achieved in our cohort, we performed a Kaplan–Meyer survival analysis applying the same cutoff value to 23 adult patients with no evidence of residual disease or metastasis after surgery (absence of metastatic disease on preoperative evaluation and R0 surgical excision). All patients who remained disease free were followed for at least 24 months. The difference in disease-free survival between the two groups (DLGAP5–PINK <6.95 and DLGAP5–PINK ≥6.95) was significant (log-rank P=0.0315). However, the performance of the molecular marker was apparently inferior to a Weiss score >2 in prognosis prediction (log-rank P=0.0016; Fig. 1A). We wondered whether applying a different cutoff value would improve the discriminative performance of the molecular marker. To select the best possible cutoff for our adult cohort, we applied the ROC curve analysis method. To build up the curve, we divided the 28 adult patients in two groups: i) unfavorable outcome (metastasis on diagnosis or recurrent/metastatic disease on follow-up; n=10) and ii) favorable outcome (patients with no evidence of recurrence/metastasis after at least 24 months of follow-up; n=18). The greatest area under the curve (AUC) value was obtained with a cutoff of ≤3.22 (AUC=0.922, P=1.25×10−12). This optimized cutoff value defined two groups of patients with significantly different disease-free survival (log-rank P=6.12×10−6; Fig. 1B).

Figure 1

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Figure 1

DLGAP5–PINK1 as a predictor of disease-free survival. In 23 adult patients with no evidence of residual disease after surgery, a sample is predicted to present a poor outcome if the subtraction of Ct values of DLGAP5–PINK1 is <3.22. The molecular predictor of malignancy was at least as accurate as Weiss score (panels A and B). Among 21 pediatric patients, both the Weiss score and the molecular predictor could not discriminate groups with different outcomes, even after adjusting the cutoff for the best possible performance (panels C and D).

Citation: European Journal of Endocrinology 166, 1; 10.1530/EJE-11-0806

The next question was whether the molecular predictor was also discriminative in a pediatric cohort. To address this issue, we applied the adult cohort optimal cutoff value of ≤3.22 to a cohort of 21 pediatric patients with no evidence of residual disease after surgery. We observed a marginally significant difference in disease-free survival (log-rank P=0.0629). Adjusting the cutoff value for the pediatric cohort did not improve its performance (log-rank P=0.0629; Fig. 1D). As previously reported, in pediatric patients, a Weiss score >2 is not a reliable predictor of malignancy (Fig. 1C).

BUB1B–PINK1 as a predictor of overall survival in ACCs

de Reyniès et al. (14) have demonstrated that the combined expression of BUB1B–PINK1 was the best predictor of overall survival in a cohort of histologically malignant ACTs. Accordingly, a sample was predicted to have a poor prognosis if (BUB1B–PINK1) <6.32. Applying the same cutoff values to 14 adult patients with histologically indeterminate or malignant ACTs (Weiss score ≥2), we could observe two groups with distinct survival time (log-rank P=0.037). However, this molecular predictor was outperformed by the MacFarlane staging (log-rank P=0.007; Fig. 2A). To select the best possible cutoff for (BUB1B–PINK1) in our adult cohort, we applied the ROC curve analysis method as described in the previous section. All patients that did not present an adverse outcome were followed for at least 60 months in this analysis. The greatest AUC value was obtained with a cutoff of ≤3.14 (AUC=0.907, P=1.07×10−6). This adjusted cutoff value leads to a better prediction of overall survival (log-rank P=4.56×10−4; Fig. 2B). In the pediatric cohort with histologically indeterminate or malignant ACTs (n=19), however, this molecular predictor was not associated with a statistically significant difference in overall survival, even after adjusting for the best possible cutoff value (log-rank P=0.146; Fig. 2D). In the pediatric group, tumor stage remains the only significant parameter associated with overall survival (log-rank P=0.015; Fig. 2C).

Figure 2

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Figure 2

BUB1B–PINK1 as a predictor of overall survival. Among 14 adult ACTs with a potentially malignant histology (Weiss ≥2), the difference between expression values of BUB1B and PINK1 ≤3.14 was at least similar to MacFarlane staging in predicting a fatal outcome (panels A and B). Among 19 pediatric patients, however, only staging was associated to a fatal outcome.

Citation: European Journal of Endocrinology 166, 1; 10.1530/EJE-11-0806

Discussion

ACC is a rare neoplasm with a dismal prognosis. Although the main prognostic factor is tumor stage, even localized disease (MacFarlane I and II) has a high relapse rate. The differential diagnosis between localized ACCs and adenomas is crucial and relies on a score of histological features (Weiss score), which has important drawbacks. To overcome the limitations of Weiss score, in the last few years, many authors have recently searched for molecular markers of malignancy. Among these, unsupervised hierarchical clustering of gene expression signatures has provided new insights into the identification of different groups of ACCs with distinct outcomes (14, 16). Giordano et al. (16) showed that cluster analysis revealed two subtypes of ACCs that reflected tumor proliferation, as measured by mitotic counts and cell cycle genes. de Reyniès et al. (14) also identified a subclassification of ACC based on the gene expression profile. Therefore, these two microarray-based assessment studies demonstrated that molecular signatures can robustly predict poor outcome with higher accuracy than morphological parameters (14, 16). However, these studies are difficult to perform and, consequently, unsuitable to the clinical practice. To overcome this limitation, de Reyniès et al. (14) identified three genes for which the combined expression values were highly associated with outcomes. According to their data, the difference in the expression values of DLGAP5–PINK1 and BUB1B–PINK1 were strong predictors of recurrence and overall survival, respectively, in adult ACT patients. DLGAP5 and BUB1B are overexpressed in ACCs. The former is involved in stem cell pluripotency and carcinogenesis (17, 18) and the latter controls mitotic checkpoint and chromosomal segregation during mitosis (18, 19). PINK1 gene, which is regulated by the PTEN gene and is involved with mitochondrial integrity, was found to be downregulated in ACTs (20). The authors suggested that due to its accuracy and simplicity, these molecular predictors would be relevant to clinical practice.

In order to validate these findings, we studied the expression values of the same genes in ACTs from Brazilian patients. In the adult cohort, our results were quite similar as those reported (14), in which the molecular markers were strong predictors of recurrence and survival, with an accuracy at least comparable to clinical and histological parameters, if not better. It is noteworthy that five out of 13 cases of our adult cohort with a Weiss score ≥2 and R0 tumor resection presented a relapse on follow-up. The molecular predictor (DLGAP5–PINK1) ≤3.22 correctly identified all cases as ‘non-recurrent’ and ‘recurrent’ (Fig. 3). In spite of the limited number of cases, these data are promising, suggesting that the molecular marker goes beyond clinical and histological information in prognosis prediction.

Figure 3

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Figure 3

DLGAP5–PINK1 in 13 adult ACCs in which a R0 resection could be achieved. A cutoff value of 3.22 (dashed line) correctly classified all cases as ‘recurrent’ or ‘non-recurrent’. Open circles: individual values; Filled squares: Mean values. Error bars: 95% CI.

Citation: European Journal of Endocrinology 166, 1; 10.1530/EJE-11-0806

The differences in cutoff values of DLGAP5–PINK1 and BUB1B–PINK1 between our study and those reported by de Reyniès et al. (14) may be related to methodological issues. Nevertheless, external validation is important when there is inter-tumor heterogeneity; notably, both studies corroborate the reliability of these molecular markers in the clinical evaluation of adult ACT. In addition, we first employed these new molecular markers to predict outcome in a cohort of pediatric ACTs diagnosed in Brazilian patients. In this group of patients, these molecular markers were not good discriminators of outcome, although a marginally significant trend could be observed in disease-free survival curves (Fig. 1D).

In conclusion, we validated the prognostic value of the combined expression of BUB1B, DLGAP5, and PINK1 genes in a different group of adult ACTs and reinforced its potential applicability to clinical practice. For pediatric patients, according to our data, these molecular markers are still lacking sufficient discriminatory efficiency and other markers need to be identified.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 200069/2009-8) from São Paulo, Brasil, and Laboratory of Endocrine Pathophysiology, Centre de Recherche du CHUM (CRCHUM), Canada.

References

  • 1

    BarzonLSoninoNFalloFPaluGBoscaroM. Prevalence and natural history of adrenal incidentalomas. European Journal of Endocrinology2003149273285. doi:10.1530/eje.0.1490273.

  • 2

    AllolioBFassnachtM. Clinical review: adrenocortical carcinoma: clinical update. Journal of Clinical Endocrinology and Metabolism20069120272037. doi:10.1210/jc.2005-2639.

  • 3

    WeissLMMedeirosLJVickeryALJr. Pathologic features of prognostic significance in adrenocortical carcinoma. American Journal of Surgical Pathology198913202206. doi:10.1097/00000478-198903000-00004.

  • 4

    SandriniRRibeiroRCDeLacerdaL. Childhood adrenocortical tumors. Journal of Clinical Endocrinology and Metabolism19978220272031. doi:10.1210/jc.82.7.2027.

  • 5

    AlmeidaMQLatronicoAC. The molecular pathogenesis of childhood adrenocortical tumors. Hormone and Metabolic Research200739461466. doi:10.1055/s-2007-981476.

  • 6

    RibeiroRCSandriniFFigueiredoBZambettiGPMichalkiewiczELaffertyARDeLacerdaLRabinMCadwellCSampaioGCatIStratakisCASandriniR. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. PNAS20019893309335. doi:10.1073/pnas.161479898.

  • 7

    LatronicoACPintoEMDomeniceSFragosoMCMartinRMZerbiniMCLuconAMMendoncaBB. An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors. Journal of Clinical Endocrinology and Metabolism20018649704973. doi:10.1210/jc.86.10.4970.

  • 8

    WienekeJAThompsonLDHeffessCS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. American Journal of Surgical Pathology200327867881. doi:10.1097/00000478-200307000-00001.

  • 9

    de FraipontFEl AtifiMCherradiNLe MoigneGDefayeGHoulgatteRBertheratJBertagnaXPlouinPFBaudinEBergerFGicquelCChabreOFeigeJJ. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic acid microarrays identifies several candidate genes as markers of malignancy. Journal of Clinical Endocrinology and Metabolism20059018191829. doi:10.1210/jc.2004-1075.

  • 10

    GiordanoTJThomasDGKuickRLizynessMMisekDESmithALSandersDAljundiRTGaugerPGThompsonNWTaylorJMHanashSM. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. American Journal of Pathology2003162521531. doi:10.1016/S0002-9440(10)63846-1.

  • 11

    WestANNealeGAPoundsSFigueredoBCRodriguez GalindoCPianovskiMAOliveira FilhoAGMalkinDLalliERibeiroRZambettiGP. Gene expression profiling of childhood adrenocortical tumors. Cancer Research200767600608. doi:10.1158/0008-5472.CAN-06-3767.

  • 12

    AlmeidaMQFragosoMCLotfiCFSantosMGNishiMYCostaMHLerarioAMMacielCCMattosGEJorgeAAMendoncaBBLatronicoAC. Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. Journal of Clinical Endocrinology and Metabolism20089335243531. doi:10.1210/jc.2008-0065.

  • 13

    DoghmanMEl WakilACardinaudBThomasEWangJZhaoWPeralta-Del ValleMHFigueiredoBCZambettiGPLalliE. Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Research20107046664675. doi:10.1158/0008-5472.CAN-09-3970.

  • 14

    de ReyniesAAssieGRickmanDSTissierFGroussinLRene-CorailFDoussetBBertagnaXClauserEBertheratJ. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. Journal of Clinical Oncology20092711081115. doi:10.1200/JCO.2008.18.5678.

  • 15

    Lima LdeOLerarioAMAlencarGABritoLPAlmeidaMQDomeniceSLatronicoACMendoncaBBFragosoMC. Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor. Arquivos Brasileiros de Endocrinologia e Metabologia2011557277. doi:10.1590/S0004-27302011000100010.

  • 16

    GiordanoTJKuickRElseTGaugerPGVincoMBauersfeldJSandersDThomasDGDohertyGHammerG. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clinical Cancer Research200915668676. doi:10.1158/1078-0432.CCR-08-1067.

  • 17

    GudmundssonKOThorsteinssonLSigurjonssonOEKellerJROlafssonKEgelandTGudmundssonSRafnarT. Gene expression analysis of hematopoietic progenitor cells identifies Dlg7 as a potential stem cell gene. Stem Cells20072514981506. doi:10.1634/stemcells.2005-0479.

  • 18

    AssieGGuillaud-BatailleMRagazzonBBertagnaXBertheratJClauserE. The pathophysiology, diagnosis and prognosis of adrenocortical tumors revisited by transcriptome analyses. Trends in Endocrinology and Metabolism201021325334. doi:10.1016/j.tem.2009.12.009.

  • 19

    WangQLiuTFangYXieSHuangXMahmoodRRamaswamyGSakamotoKMDarzynkiewiczZXuMDaiW. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood200410312781285. doi:10.1182/blood-2003-06-2158.

  • 20

    UnokiMNakamuraY. Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene20012044574465. doi:10.1038/sj.onc.1204608.

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Figures

  • View in gallery

    DLGAP5–PINK1 as a predictor of disease-free survival. In 23 adult patients with no evidence of residual disease after surgery, a sample is predicted to present a poor outcome if the subtraction of Ct values of DLGAP5–PINK1 is <3.22. The molecular predictor of malignancy was at least as accurate as Weiss score (panels A and B). Among 21 pediatric patients, both the Weiss score and the molecular predictor could not discriminate groups with different outcomes, even after adjusting the cutoff for the best possible performance (panels C and D).

  • View in gallery

    BUB1B–PINK1 as a predictor of overall survival. Among 14 adult ACTs with a potentially malignant histology (Weiss ≥2), the difference between expression values of BUB1B and PINK1 ≤3.14 was at least similar to MacFarlane staging in predicting a fatal outcome (panels A and B). Among 19 pediatric patients, however, only staging was associated to a fatal outcome.

  • View in gallery

    DLGAP5–PINK1 in 13 adult ACCs in which a R0 resection could be achieved. A cutoff value of 3.22 (dashed line) correctly classified all cases as ‘recurrent’ or ‘non-recurrent’. Open circles: individual values; Filled squares: Mean values. Error bars: 95% CI.

References

1

BarzonLSoninoNFalloFPaluGBoscaroM. Prevalence and natural history of adrenal incidentalomas. European Journal of Endocrinology2003149273285. doi:10.1530/eje.0.1490273.

2

AllolioBFassnachtM. Clinical review: adrenocortical carcinoma: clinical update. Journal of Clinical Endocrinology and Metabolism20069120272037. doi:10.1210/jc.2005-2639.

3

WeissLMMedeirosLJVickeryALJr. Pathologic features of prognostic significance in adrenocortical carcinoma. American Journal of Surgical Pathology198913202206. doi:10.1097/00000478-198903000-00004.

4

SandriniRRibeiroRCDeLacerdaL. Childhood adrenocortical tumors. Journal of Clinical Endocrinology and Metabolism19978220272031. doi:10.1210/jc.82.7.2027.

5

AlmeidaMQLatronicoAC. The molecular pathogenesis of childhood adrenocortical tumors. Hormone and Metabolic Research200739461466. doi:10.1055/s-2007-981476.

6

RibeiroRCSandriniFFigueiredoBZambettiGPMichalkiewiczELaffertyARDeLacerdaLRabinMCadwellCSampaioGCatIStratakisCASandriniR. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. PNAS20019893309335. doi:10.1073/pnas.161479898.

7

LatronicoACPintoEMDomeniceSFragosoMCMartinRMZerbiniMCLuconAMMendoncaBB. An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors. Journal of Clinical Endocrinology and Metabolism20018649704973. doi:10.1210/jc.86.10.4970.

8

WienekeJAThompsonLDHeffessCS. Adrenal cortical neoplasms in the pediatric population: a clinicopathologic and immunophenotypic analysis of 83 patients. American Journal of Surgical Pathology200327867881. doi:10.1097/00000478-200307000-00001.

9

de FraipontFEl AtifiMCherradiNLe MoigneGDefayeGHoulgatteRBertheratJBertagnaXPlouinPFBaudinEBergerFGicquelCChabreOFeigeJJ. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic acid microarrays identifies several candidate genes as markers of malignancy. Journal of Clinical Endocrinology and Metabolism20059018191829. doi:10.1210/jc.2004-1075.

10

GiordanoTJThomasDGKuickRLizynessMMisekDESmithALSandersDAljundiRTGaugerPGThompsonNWTaylorJMHanashSM. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. American Journal of Pathology2003162521531. doi:10.1016/S0002-9440(10)63846-1.

11

WestANNealeGAPoundsSFigueredoBCRodriguez GalindoCPianovskiMAOliveira FilhoAGMalkinDLalliERibeiroRZambettiGP. Gene expression profiling of childhood adrenocortical tumors. Cancer Research200767600608. doi:10.1158/0008-5472.CAN-06-3767.

12

AlmeidaMQFragosoMCLotfiCFSantosMGNishiMYCostaMHLerarioAMMacielCCMattosGEJorgeAAMendoncaBBLatronicoAC. Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. Journal of Clinical Endocrinology and Metabolism20089335243531. doi:10.1210/jc.2008-0065.

13

DoghmanMEl WakilACardinaudBThomasEWangJZhaoWPeralta-Del ValleMHFigueiredoBCZambettiGPLalliE. Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Research20107046664675. doi:10.1158/0008-5472.CAN-09-3970.

14

de ReyniesAAssieGRickmanDSTissierFGroussinLRene-CorailFDoussetBBertagnaXClauserEBertheratJ. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. Journal of Clinical Oncology20092711081115. doi:10.1200/JCO.2008.18.5678.

15

Lima LdeOLerarioAMAlencarGABritoLPAlmeidaMQDomeniceSLatronicoACMendoncaBBFragosoMC. Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor. Arquivos Brasileiros de Endocrinologia e Metabologia2011557277. doi:10.1590/S0004-27302011000100010.

16

GiordanoTJKuickRElseTGaugerPGVincoMBauersfeldJSandersDThomasDGDohertyGHammerG. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clinical Cancer Research200915668676. doi:10.1158/1078-0432.CCR-08-1067.

17

GudmundssonKOThorsteinssonLSigurjonssonOEKellerJROlafssonKEgelandTGudmundssonSRafnarT. Gene expression analysis of hematopoietic progenitor cells identifies Dlg7 as a potential stem cell gene. Stem Cells20072514981506. doi:10.1634/stemcells.2005-0479.

18

AssieGGuillaud-BatailleMRagazzonBBertagnaXBertheratJClauserE. The pathophysiology, diagnosis and prognosis of adrenocortical tumors revisited by transcriptome analyses. Trends in Endocrinology and Metabolism201021325334. doi:10.1016/j.tem.2009.12.009.

19

WangQLiuTFangYXieSHuangXMahmoodRRamaswamyGSakamotoKMDarzynkiewiczZXuMDaiW. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood200410312781285. doi:10.1182/blood-2003-06-2158.

20

UnokiMNakamuraY. Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene20012044574465. doi:10.1038/sj.onc.1204608.

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