@article{LacombeSoaresMarianietal.2020, author = {Lacombe, Amanda Meneses Ferreira and Soares, Iber{\^e} Cauduro and Mariani, Beatriz Marinho de Paula and Nishi, Mirian Yumie and Bezerra-Neto, Jo{\~a}o Evangelista and Charchar, Helaine da Silva and Brondani, Vania Balderrama and Tanno, Fabio and Srougi, Victor and Chambo, Jos{\´e} Luiz and Costa de Freitas, Ricardo Miguel and Mendonca, Berenice Bilharinho and Hoff, Ana O. and Almeida, Madson Q. and Weigand, Isabel and Kroiss, Matthias and Zerbini, Maria Claudia Nogueira and Fragoso, Maria Candida Barisson Villares}, title = {Sterol O-acyl transferase 1 as a prognostic marker of adrenocortical carcinoma}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {1}, issn = {2072-6694}, doi = {10.3390/cancers12010247}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200857}, year = {2020}, abstract = {Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0-4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5\% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5\% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95\% 1.26-3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95\% 1.09-4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.}, language = {en} } @article{OregliaSbieraFassnachtetal.2020, author = {Oreglia, Maurine and Sbiera, Silviu and Fassnacht, Martin and Guyon, Laurent and Denis, Josiane and Cristante, Justine and Chabre, Olivier and Cherradi, Nadia}, title = {Early postoperative circulating miR-483-5p is a prognosis marker for adrenocortical cancer}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers12030724}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203227}, year = {2020}, abstract = {We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years; NR3yrs) from patients with poor prognosis (recurrence or death within 3 years after surgery; R < 3yrs). We conducted a single-center retrospective analysis using sera from 48 patients with ACC that were initially non-metastatic and treated by surgery. Sera sampled within 3 months after surgery were available in 26 patients. MiR-483-5p absolute circulating levels were measured using quantitative PCR. Thirteen patients showed a recurrence before 3 years (=R < 3yrs). Thirteen patients showed no recurrence within 3 years, including 11 patients with a follow-up longer than 3 years (=NR3yrs). Serum miR-483-5p levels were higher in R < 3yrs than in NR3yrs: 1,541,990 ± 428,377 copies/mL vs. 388,457 ± 62,169 copies/mL (p = 0.002). Receiver operating characteristic analysis showed that a value of 752,898 copies/mL distinguished R < 3yrs from NR3yrs with 61.5\% sensitivity (CI 31.6-86.1) and 100\% specificity (CI 71.5-100) with an area under the curve of 0.853. Patients with a value below this threshold had a significantly longer recurrence-free and overall survival. In multivariate analysis, miR-483-5p provided the single best prognostic value for recurrence-free survival (RFS) (hazard ratio (HR) for recurrence 5.98, p < 0.011) but not for overall survival. Our study suggests that serum miR-483-5p is a potent early post-operative biomarker for ACC prognosis that might be a better predictor of RFS than currently used markers.}, language = {en} } @article{DoghmanBouguerraFinettiDurandetal.2020, author = {Doghman-Bouguerra, Mabrouka and Finetti, Pascal and Durand, Nelly and Parise, Ivy Zort{\´e}a S. and Sbiera, Silviu and Cantini, Giulia and Canu, Letizia and Hescot, S{\´e}gol{\`e}ne and Figueiredo, Mirna M. O. and Komechen, Heloisa and Sbiera, Iuliu and Nesi, Gabriella and Paci, Angelo and Al Ghuzlan, Abir and Birnbaum, Daniel and Baudin, Eric and Luconi, Michaela and Fassnacht, Martin and Figueiredo, Bonald C. and Bertucci, Fran{\c{c}}ois and Lalli, Enzo}, title = {Cancer-testis antigen FATE1 expression in adrenocortical tumors is associated with a pervasive autoimmune response and is a marker of malignancy in adult, but not children, ACC}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers12030689}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203211}, year = {2020}, abstract = {The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.}, language = {en} } @article{ChifuHeinzeFussetal.2020, author = {Chifu, Irina and Heinze, Britta and Fuss, Carmina T. and Lang, Katharina and Kroiss, Matthias and Kircher, Stefan and Ronchi, Cristina L. and Altieri, Barbara and Schirbel, Andreas and Fassnacht, Martin and Hahner, Stefanie}, title = {Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma}, series = {Frontiers in Endocrinology}, volume = {11}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2020.597878}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216494}, year = {2020}, abstract = {Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50\% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=-0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.}, language = {en} } @article{AltieriSbieraHerterichetal.2020, author = {Altieri, Barbara and Sbiera, Silviu and Herterich, Sabine and De Francia, Silvia and Della Casa, Silvia and Calabrese, Anna and Pontecorvi, Alfredo and Quinkler, Marcus and Kienitz, Tina and Mannelli, Massimo and Canu, Letizia and Angelousi, Anna and Chortis, Vasileios and Kroiss, Matthias and Terzolo, Massimo and Fassnacht, Martin and Ronchi, Cristina L.}, title = {Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers12020359}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200565}, pages = {359}, year = {2020}, abstract = {Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2\% vs 51.7\%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55\% of patients with CYP2B6*6 vs. 28.2\% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6\%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.}, language = {en} }