MARIA CANDIDA BARISSON VILLARES FRAGOSO | Universidade de São Paulo (original) (raw)

Papers by MARIA CANDIDA BARISSON VILLARES FRAGOSO

Cancer Management and Research, 2014

Complete clinical and molecular data of all samples used in this study.

Results of differentially expressed genes analysis on ACC-TCGA CIMP-high v. non-CIMP-high and res... more Results of differentially expressed genes analysis on ACC-TCGA CIMP-high v. non-CIMP-high and results of gene ontology analysis on ACC-TCGA CIMP-high v. non-CIMP-high.

Results of G0S2 targeted bisulfite sequencing.

Results of DMRcate analysis on ACC-TCGA non-CIMP-high v. CIMP-high.

This compiled PDF includes Supplementary Tables S3, S4, S6, S7, and S8, as follows: Supp. Table S... more This compiled PDF includes Supplementary Tables S3, S4, S6, S7, and S8, as follows: Supp. Table S3. G0S2 hypermethylation predicts CIMP-high. Supp. Table S4. Clinical characteristics of FMUSP+UM ACC and ACA Cohorts. Supp. Table S6. EpiTect accurately measures binary G0S2 methylation status. Supp. Table S7. Hypermethylation and silencing of G0S2 is heterogeneous in recurrent, metastatic, and non-treatment naive carcinomas. Supp. Table S8. BUB1B-PINK1 can predict any history of metastasis in patients with G0S2 Unmethylated ACC.

Endocrine, 2021

Janaina Petenuci ● Gustavo F. C. Fagundes ● Anna Flavia F. Benedetti ● Augusto G. Guimaraes ● Ana... more Janaina Petenuci ● Gustavo F. C. Fagundes ● Anna Flavia F. Benedetti ● Augusto G. Guimaraes ● Ana Caroline F. Afonso ● Flavia T. Mota ● Aurea Luiza F. Magalhães ● George B. Coura-Filho ● Maria Claudia N. Zerbini ● Sheila Siqueira ● Fabio L. M. Montenegro ● Victor Srougi ● Fabio Y. Tanno ● Jose Luis Chambo ● Marcela S. S. Ferrari ● Joao Evangelista Bezerra Neto ● Maria Adelaide A. Pereira ● Ana Claudia Latronico ● Maria Candida B. V. Fragoso ● Berenice B. Mendonca ● Ana O. Hoff ● Madson Q. Almeida 1,9

The Endocrine Society's 92nd Annual Meeting, June 19–22, 2010 - San Diego, 2010

Oncotarget, Jan 11, 2015

Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DIC... more Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak D...

Journal of the Endocrine Society

Background Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosi... more Background Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require hospital environment due to the risks involved. Methods We evaluated the diagnostic performance of oral 80 mg furosemide in 64 PA patients and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, 2h and 3h after the oral furosemide. In addition, the oral furosemide test was compared with two other confirmatory tests: furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all PA patients. Results The cut-off of 7.6 µU/mL for DRC at 2h after oral furosemide had a sensitivity of 92%, specificity of 82% and accuracy of 90% for PA diagnosis. In five out of six controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these six controls with low-renin hypertension, the DRC cut-off of 10 µU/mL at 2h after oral furo...

Cancer Research

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex without curative medical th... more Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex without curative medical therapies. CIMP-high is an aggressive ACC molecular subtype defined by global CpG island hypermethylation with paradoxical activation of adrenal differentiation (driven by master transcription factor SF1) and stemness (driven by β-catenin). We show DNA hypermethylation redistributes histone methyltransferase EZH2 and its mark, H3K27me3. EZH2 inhibition remains lethal to CIMP-high ACC cells, erasing transcriptional programs without altering DNA methylation. We reconcile this phenomenon by discovery of two nuclear complexes, SF1/β-catenin and EZH2/β-catenin, present in physiology and persistent through advanced ACC. We find SF1/β-catenin is a chromatin-bound complex that controls the ACC super-enhancer landscape, while EZH2/β-catenin is restricted to off-chromatin pools. EZH2 inhibition purges SF1/β-catenin from chromatin, sparing EZH2/β-catenin, inducing dedifferentiation and restraining AC...

Journal of the Endocrine Society, 2020

Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). P... more Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). PA subtypes include aldosterone-producing adenomas (APA) and bilateral adrenal hyperplasia. To date, few PA patients with bilateral adenomas have been reported, but only one case was well characterized by anatomopathological analysis and clinical outcome after adrenal sparing surgery (1). Clinical case: A 53-year-old woman was referred to investigate resistant HT and hypokalemia. (3.0 mEq/L). PA screening revealed aldosterone (A) of 37.9 ng/dL, renin (R) < 1.6 (4.4-46.1 mUI/L), A/R ratio of 24.8. Confirmatory testing confirmed PA diagnosis: seated saline infusion test (A= 83.3 ng/dL) and intravenous furosemide test (R= 3.1 mUI/L; positive test <13 mUI/L). Hypercortisolism investigation revealed a non-suppressible cortisol after an overnight 1 mg low-dose dexamethasone suppression [cortisol (C)= 2.9 μg/dL and dexamethasone= 701 (˃130 ng/dL)], and normal urinary free cortisol, midnigh...

Journal of the Endocrine Society, 2020

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA subtypes includ... more Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA subtypes include bilateral hyperplasia and unilateral PA, typically aldosterone-producing adenomas. Adrenal venous (AV) sampling (AVS) is a key step to define PA subtype and guide PA management. According current PA guidelines, most PA patients should undergo AVS, which is a challenging procedure, especially in terms of successfully cannulating the right AV. The aim of this study was to report a single tertiary center experience with AVS in PA patients. We retrospectively evaluated 84 AVS from 1984 to 2019. Sequential AVS was performed by an experienced interventional radiologist. AV and inferior vena cava (IVC) samples were obtained under cosyntropin continuous infusion. Successful catheterization was defined by a selectivity index [SI= AV/IVC cortisol (C) concentrations] ≥5. Unilateral disease was defined by a lateralization index [LI= aldosterone (A)/C ratio in the dominant AV divided by A/C in the ...

Journal of the Endocrine Society, 2020

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from chromaffin ce... more Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from chromaffin cells. At least 30% of PPGL patients have hereditary predisposition. PPGLs in children are more often hereditary, multiple and extra-adrenal. To date, more than 14 tumor-susceptibility genes have been reported: Cluster 1 or hypoxic (VHL, SDHB, SDHD, SDHC, SDHA, SDHAF2, FH, ENGL1 and HIF2A) and cluster 2 (RET, NF1, TMEM127 and MAX). The aim of this study was to evaluate clinical and molecular aspects of a Brazilian cohort of pediatric patients with PPGLs. Out of 262 patients with PPGLs, 26 (9 %) were diagnosed before 19 yrs of age (16 males and 10 females), with a median age of 14.5 yrs (range, 4 to 18). Genetic investigation was performed in 19 patients: 14 by automated Sanger sequencing (VHL, SDHB, SDHD and RET genes) and 5 by a custom next-generation sequencing (NGS) panel including all genes previously associated with germline mutations in PPGLs. Median tumor size was 5.5 cm (1.7 to 16)...

Journal of the Endocrine Society, 2020

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising... more Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells. More than 30% of patients with PPGLs have a hereditary predisposition. Malignancy in PPGLs is defined by the presence of local invasion or metastasis in nonchromaffin tissues. Germline SDHB mutations are found in approximately 40% of malignant PPGLs, mainly paragangliomas (PGLs). However, SDHB mutations are not a prognostic factor in malignant PPGLs. To date, no genotype-phenotype correlation has been reported in malignant PPGLs associated with SDHB mutations. Aim: To investigate clinical and imaging features of patients with malignant PGLs harboring germline SDHB exon 1 deletion or splicing site mutation. Methods: We retrospectively evaluated 22 unrelated individuals with malignant PPGLs. Six out of 22 (27%) malignant PPGLs harbored germline SDHB mutations. Three patients had SDHB exon 1 deletion and 3 splicing site mutation (2 with c.201-2A>G and one with c.4...

The Journal of Clinical Endocrinology & Metabolism, 2020

Context Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approxi... more Context Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. Objective To investigate SOAT1 protein expression as a marker of treatment response to mitotane. Patients A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. Setting Retrospective study at 12 ACC referral centers. Main outcome measure Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). Results Sixty-one of 135 patients (45%) with adjuvant mitotane treatment ha...

The Journal of Clinical Endocrinology & Metabolism, 2019

ContextPrimary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT rem... more ContextPrimary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear.ObjectiveTo determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA.MethodsWe retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases.ResultsKCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu...

Clinical Cancer Research, 2019

Purpose: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; howe... more Purpose: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, “CIMP-high.” We sought to identify a biomarker that faithfully captures this subgroup. Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/nonprimary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR. R...

Cancer Management and Research, 2014

Complete clinical and molecular data of all samples used in this study.

Results of differentially expressed genes analysis on ACC-TCGA CIMP-high v. non-CIMP-high and res... more Results of differentially expressed genes analysis on ACC-TCGA CIMP-high v. non-CIMP-high and results of gene ontology analysis on ACC-TCGA CIMP-high v. non-CIMP-high.

Results of G0S2 targeted bisulfite sequencing.

Results of DMRcate analysis on ACC-TCGA non-CIMP-high v. CIMP-high.

This compiled PDF includes Supplementary Tables S3, S4, S6, S7, and S8, as follows: Supp. Table S... more This compiled PDF includes Supplementary Tables S3, S4, S6, S7, and S8, as follows: Supp. Table S3. G0S2 hypermethylation predicts CIMP-high. Supp. Table S4. Clinical characteristics of FMUSP+UM ACC and ACA Cohorts. Supp. Table S6. EpiTect accurately measures binary G0S2 methylation status. Supp. Table S7. Hypermethylation and silencing of G0S2 is heterogeneous in recurrent, metastatic, and non-treatment naive carcinomas. Supp. Table S8. BUB1B-PINK1 can predict any history of metastasis in patients with G0S2 Unmethylated ACC.

Endocrine, 2021

Janaina Petenuci ● Gustavo F. C. Fagundes ● Anna Flavia F. Benedetti ● Augusto G. Guimaraes ● Ana... more Janaina Petenuci ● Gustavo F. C. Fagundes ● Anna Flavia F. Benedetti ● Augusto G. Guimaraes ● Ana Caroline F. Afonso ● Flavia T. Mota ● Aurea Luiza F. Magalhães ● George B. Coura-Filho ● Maria Claudia N. Zerbini ● Sheila Siqueira ● Fabio L. M. Montenegro ● Victor Srougi ● Fabio Y. Tanno ● Jose Luis Chambo ● Marcela S. S. Ferrari ● Joao Evangelista Bezerra Neto ● Maria Adelaide A. Pereira ● Ana Claudia Latronico ● Maria Candida B. V. Fragoso ● Berenice B. Mendonca ● Ana O. Hoff ● Madson Q. Almeida 1,9

The Endocrine Society's 92nd Annual Meeting, June 19–22, 2010 - San Diego, 2010

Oncotarget, Jan 11, 2015

Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DIC... more Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak D...

Journal of the Endocrine Society

Background Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosi... more Background Confirmatory tests represent a fundamental step in primary aldosteronism (PA) diagnosis, but they are laborious and often require hospital environment due to the risks involved. Methods We evaluated the diagnostic performance of oral 80 mg furosemide in 64 PA patients and 22 with primary hypertension (controls). Direct renin concentration (DRC) was measured before, 2h and 3h after the oral furosemide. In addition, the oral furosemide test was compared with two other confirmatory tests: furosemide upright test (FUT) and saline infusion test (SIT) or captopril challenge test (CCT) in all PA patients. Results The cut-off of 7.6 µU/mL for DRC at 2h after oral furosemide had a sensitivity of 92%, specificity of 82% and accuracy of 90% for PA diagnosis. In five out of six controls with low-renin hypertension, which might represent a PA spectrum, renin remained suppressed. Excluding these six controls with low-renin hypertension, the DRC cut-off of 10 µU/mL at 2h after oral furo...

Cancer Research

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex without curative medical th... more Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal cortex without curative medical therapies. CIMP-high is an aggressive ACC molecular subtype defined by global CpG island hypermethylation with paradoxical activation of adrenal differentiation (driven by master transcription factor SF1) and stemness (driven by β-catenin). We show DNA hypermethylation redistributes histone methyltransferase EZH2 and its mark, H3K27me3. EZH2 inhibition remains lethal to CIMP-high ACC cells, erasing transcriptional programs without altering DNA methylation. We reconcile this phenomenon by discovery of two nuclear complexes, SF1/β-catenin and EZH2/β-catenin, present in physiology and persistent through advanced ACC. We find SF1/β-catenin is a chromatin-bound complex that controls the ACC super-enhancer landscape, while EZH2/β-catenin is restricted to off-chromatin pools. EZH2 inhibition purges SF1/β-catenin from chromatin, sparing EZH2/β-catenin, inducing dedifferentiation and restraining AC...

Journal of the Endocrine Society, 2020

Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). P... more Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). PA subtypes include aldosterone-producing adenomas (APA) and bilateral adrenal hyperplasia. To date, few PA patients with bilateral adenomas have been reported, but only one case was well characterized by anatomopathological analysis and clinical outcome after adrenal sparing surgery (1). Clinical case: A 53-year-old woman was referred to investigate resistant HT and hypokalemia. (3.0 mEq/L). PA screening revealed aldosterone (A) of 37.9 ng/dL, renin (R) < 1.6 (4.4-46.1 mUI/L), A/R ratio of 24.8. Confirmatory testing confirmed PA diagnosis: seated saline infusion test (A= 83.3 ng/dL) and intravenous furosemide test (R= 3.1 mUI/L; positive test <13 mUI/L). Hypercortisolism investigation revealed a non-suppressible cortisol after an overnight 1 mg low-dose dexamethasone suppression [cortisol (C)= 2.9 μg/dL and dexamethasone= 701 (˃130 ng/dL)], and normal urinary free cortisol, midnigh...

Journal of the Endocrine Society, 2020

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA subtypes includ... more Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA subtypes include bilateral hyperplasia and unilateral PA, typically aldosterone-producing adenomas. Adrenal venous (AV) sampling (AVS) is a key step to define PA subtype and guide PA management. According current PA guidelines, most PA patients should undergo AVS, which is a challenging procedure, especially in terms of successfully cannulating the right AV. The aim of this study was to report a single tertiary center experience with AVS in PA patients. We retrospectively evaluated 84 AVS from 1984 to 2019. Sequential AVS was performed by an experienced interventional radiologist. AV and inferior vena cava (IVC) samples were obtained under cosyntropin continuous infusion. Successful catheterization was defined by a selectivity index [SI= AV/IVC cortisol (C) concentrations] ≥5. Unilateral disease was defined by a lateralization index [LI= aldosterone (A)/C ratio in the dominant AV divided by A/C in the ...

Journal of the Endocrine Society, 2020

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from chromaffin ce... more Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from chromaffin cells. At least 30% of PPGL patients have hereditary predisposition. PPGLs in children are more often hereditary, multiple and extra-adrenal. To date, more than 14 tumor-susceptibility genes have been reported: Cluster 1 or hypoxic (VHL, SDHB, SDHD, SDHC, SDHA, SDHAF2, FH, ENGL1 and HIF2A) and cluster 2 (RET, NF1, TMEM127 and MAX). The aim of this study was to evaluate clinical and molecular aspects of a Brazilian cohort of pediatric patients with PPGLs. Out of 262 patients with PPGLs, 26 (9 %) were diagnosed before 19 yrs of age (16 males and 10 females), with a median age of 14.5 yrs (range, 4 to 18). Genetic investigation was performed in 19 patients: 14 by automated Sanger sequencing (VHL, SDHB, SDHD and RET genes) and 5 by a custom next-generation sequencing (NGS) panel including all genes previously associated with germline mutations in PPGLs. Median tumor size was 5.5 cm (1.7 to 16)...

Journal of the Endocrine Society, 2020

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising... more Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells. More than 30% of patients with PPGLs have a hereditary predisposition. Malignancy in PPGLs is defined by the presence of local invasion or metastasis in nonchromaffin tissues. Germline SDHB mutations are found in approximately 40% of malignant PPGLs, mainly paragangliomas (PGLs). However, SDHB mutations are not a prognostic factor in malignant PPGLs. To date, no genotype-phenotype correlation has been reported in malignant PPGLs associated with SDHB mutations. Aim: To investigate clinical and imaging features of patients with malignant PGLs harboring germline SDHB exon 1 deletion or splicing site mutation. Methods: We retrospectively evaluated 22 unrelated individuals with malignant PPGLs. Six out of 22 (27%) malignant PPGLs harbored germline SDHB mutations. Three patients had SDHB exon 1 deletion and 3 splicing site mutation (2 with c.201-2A>G and one with c.4...

The Journal of Clinical Endocrinology & Metabolism, 2020

Context Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approxi... more Context Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. Objective To investigate SOAT1 protein expression as a marker of treatment response to mitotane. Patients A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. Setting Retrospective study at 12 ACC referral centers. Main outcome measure Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). Results Sixty-one of 135 patients (45%) with adjuvant mitotane treatment ha...

The Journal of Clinical Endocrinology & Metabolism, 2019

ContextPrimary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT rem... more ContextPrimary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure <140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear.ObjectiveTo determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA.MethodsWe retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases.ResultsKCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu...

Clinical Cancer Research, 2019

Purpose: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; howe... more Purpose: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, “CIMP-high.” We sought to identify a biomarker that faithfully captures this subgroup. Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/nonprimary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR. R...