Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors

Arlt, Wiebke; Biehl, Michael; Taylor, Angela E.; Hahner, Stefanie; Libé, R.; Hughes, Beverly; Schneider, Petra; Smith, D. J.; Stiekema, Han; Krone, Nils; Porfiri, Emilio; Opocher, Giuseppe; Bertherat, Jérôme; Mantero, Franco; Allolio, Bruno; Terzolo, Massimo; Nightingale, Peter; Shackleton, Cedric; Bertagna, Xavier; Fassnacht, Martin; Stewart, Paul M.

doi:10.1210/jc.2011-1565

Cited by 387 publications

(315 citation statements)

References 36 publications

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“…However, larger studies, requiring multicentre collaborations, due to the rare incidence of ACCs, will be necessary to fully validate the predictive value of these specific epigenetic changes and to also validate the required cutoff values for malignancy. These results should be compared with urine steroid metabolomics, a recently introduced new potential preoperative marker for malignancy in adrenal tumours (Arlt et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas

Creemers

Koetsveld

Kemenade

et al. 2016

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Discrimination of ACCs from adrenocortical adenomas (ACAs) is challenging on both imaging and histopathological grounds. High IGF2 expression is associated with malignancy, but shows large variability. In this study, we investigate whether specific methylation patterns of IGF2 regulatory regions could serve as a valuable biomarker in distinguishing ACCs from ACAs. Pyrosequencing was used to analyse methylation percentages in DMR0, DMR2, imprinting control region (ICR) (consisting of CTCF3 and CTCF6) and the H19 promoter. Expression of IGF2 and H19 mRNA was assessed by realtime quantitative PCR. Analyses were performed in 24 ACCs, 14 ACAs and 11 normal adrenals. Using receiver operating characteristic (ROC) analysis, we evaluated which regions showed the best predictive value for diagnosis of ACC and determined the diagnostic accuracy of these regions. In ACCs, the DMR0, CTCF3, CTCF6 and the H19 promoter were positively correlated with IGF2 mRNA expression (P < 0.05). Methylation in the most discriminating regions distinguished ACCs from ACAs with a sensitivity of 96%, specificity of 100% and an area under the curve (AUC) of 0.997 ± 0.005. Our findings were validated in an independent cohort of 9 ACCs and 13 ACAs, resulting in a sensitivity of 89% and a specificity of 92%. Thus, methylation patterns of IGF2 regulatory regions can discriminate ACCs from ACAs with high diagnostic accuracy. This proposed test may become the first objective diagnostic tool to assess malignancy in adrenal tumours and facilitate the choice of therapeutic strategies in this group of patients.

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Section: Discussionmentioning

confidence: 99%

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas

Creemers

Koetsveld

Kemenade

et al. 2016

Endocrine-Related Cancer

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“…Most recent data using urinary steroid hormone metabolomics showed characteristic patterns of steroid secretion and metabolism in ACC samples. 10 The histological diagnosis of malignancy is also often difficult 11 and novel markers of malignancy are intensively searched for using bioinformatics approaches to establish an early and specific differential diagnosis between ACC and ACA.…”

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confidence: 99%

Analysis of circulating microRNAs in adrenocortical tumors

Szabó

Luconi

Szabó

et al. 2014

Laboratory Investigation

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Differential diagnosis of adrenocortical adenoma (ACA) and carcinoma is of pivotal clinical relevance, as the prognosis and clinical management of benign and malignant adrenocortical tumors (ACTs) is entirely different. Circulating microRNAs (miRNAs) are promising biomarker candidates of malignancy in several tumors; however, there are still numerous technical problems associated with their analysis. The objective of our study was to investigate circulating miRNAs in ACTs and to evaluate their potential applicability as biomarkers of malignancy. We have also addressed technical questions including the choice of profiling and reference gene used. A total of 25 preoperative plasma samples obtained from patients with ACAs and carcinomas were studied by microarray and quantitative real-time PCR. None of the three miRNAs (hsa-miR-192, hsa-mir-197 and hsa-miR-1281) found as differentially expressed in plasma samples in our microarray screening could be validated by quantitative real-time PCR. In contrast, of the selected eight miRNAs reported in the literature as differentially expressed in ACT tissues, five (hsa-miR-100, hsa-miR-181b, hsa-miR-184, hsa-miR-210 and hsamiR-483-5p) showed a statistically significant overexpression in adrenocortical cancer vs adenoma when normalized on hsa-miR-16 as a reference gene. Receiver operator characteristic analysis of data revealed that the combination of dCT hsa-miR-210 -dCT hsa-miR-181b and dCT hsa-miR-100 /dCT hsa-miR-181b showed the highest diagnostic accuracy (area under curve 0.87 and 0.85, respectively). In conclusion, we have found significant differences in expression of circulating miRNAs between ACAs and carcinomas, but their diagnostic accuracy is not yet high enough for clinical application. Further studies on larger cohorts of patients are needed to assess the diagnostic and prognostic potential application of circulating miRNA markers.

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“…Os autores concluíram que a metabolômica dos esteroides urinários é uma ferramenta de biomarcador sensível e específico para discriminar tumores adrenais benignos de malignos. Esse teste, sensível, específico, rápido, de baixo custo e de triagem diagnóstica, poderá no futuro, potencialmente, eliminar a necessidade de imagens frequentes no acompanhamento de pacientes com TAC (8).…”

Section: Descritoresunclassified

Tumores adrenocorticais na criança: da abordagem clínica à avaliação molecular

Antonini

Colli²,

Ferro

et al. 2011

Arq Bras Endocrinol Metab

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sumárioTumores do córtex adrenal (TCA) são mais frequentes em crianças, mas podem ocorrer em qualquer faixa etária. São classificados como funcionantes, não funcionantes (predominam no adulto), e mistos. O diagnóstico é baseado na avaliação clínica, hormonal e exames de imagem. Em crianças, o método de escolha para diferenciar entre benigno ou maligno é a classificação baseada no estadiamento do tumor. Alguns marcadores moleculares merecem destaque: além de mutações inativadoras no gene supressor tumoral TP53, há evidências de envolvimento do IGF2 em 90% de TAC malignos, e mutações no éxon 3 do gene CTNNB1 foram encontradas em 6% dos TAC pediátricos. Além disso, microRNAs podem atuar como reguladores negativos da expressão gênica e participar da tumorigênese adrenocortical. Métodos para análise da expressão gênica permitem identificar TCA com prognóstico bom ou ruim, e espera-se que esses estudos possam facilitar o desenvolvimento de drogas para tratar pacientes de acordo com as vias de sinalização específicas que estiverem alteradas. Arq Bras Endocrinol Metab. 2011;55(8):599-606 Descritores Tumor do córtex adrenal; doenças da adrenal; fatores de crescimento; proteína supressora de tumor P53; biologia molecular summArY Adrenocortical tumors (ACT) are more frequent during childhood, but they can appear at any age. ACTs can be classified in functioning, nonfunctioning (mainly observed in adults) and mixed. The diagnosis is based on clinical, biochemical findings and imaging. In children, in order to classify ACT as benign or malignant, tumor staging classification is recommended. Regarding molecular markers some studies should be taken into account: besides TP53 mutations, previous studies have also provided evidences of IGF2 involvement in 90% of the malignant ACT. Mutations altering exon 3 of CTNNB1 gene have been found in 6% of childhood ACTs. In addition, microRNAs can act as negative regulators of gene expression by targeting mRNA controlling cell growth, differentiation and apoptosis and have been implicated in adrenal tumorigenesis. High-throughput methods to analyze genome-wide expression have been developed over the last decade and identified a subset of tumors with good or poor prognosis. In the future, these studies can provide the basis of specific drug development, which can treat patients according to specific altered signaling pathway. Arq Bras Endocrinol Metab. 2011;55(8):599-606 Keywords Adrenal cortex tumor; adrenal gland diseases; molecular biology growth factors; tumor suppressor protein P53 iNTroDuÇÃo O s tumores adrenocorticais (TAC) apresentam incidência bimodal, sendo mais comuns nos primeiros cinco anos de vida e entre a 4ª e 5ª décadas de vida. Em todas as faixas etárias esses tumores são mais frequentes no sexo feminino (1,2). Sua incidência varia de acordo com a região geográfica, sendo dez a quinze vezes mais elevada no Sul e Sudeste do Brasil, onde ocorrem apro-

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Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors

Cited by 387 publications

References 36 publications

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas

Methylation of IGF2 regulatory regions to diagnose adrenocortical carcinomas

Analysis of circulating microRNAs in adrenocortical tumors

Tumores adrenocorticais na criança: da abordagem clínica à avaliação molecular

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