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Abstract The adrenal glands are paired endocrine organs that produce steroid hormones and catecholamines required for life. Adrenocortical carcinoma (ACC) is a rare and often fatal cancer of the peripheral domain of the gland, the adrenal cortex. Recent research in adrenal development, homeostasis, and disease have refined our understanding of the cellular and molecular programs controlling cortical growth and renewal, uncovering crucial clues into how physiologic programs are hijacked in early and late stages of malignant neoplasia. Alongside these studies, genome-wide approaches to examine adrenocortical tumors have transformed our understanding of ACC biology, and revealed that ACC is composed of distinct molecular subtypes associated with favorable, intermediate, and dismal clinical outcomes. The homogeneous transcriptional and epigenetic programs prevailing in each ACC subtype suggest likely susceptibility to any of a plethora of existing and novel targeted agents, with the caveat that therapeutic response may ultimately be limited by cancer cell plasticity. Despite enormous biomedical research advances in the last decade, the only potentially curative therapy for ACC to date is primary surgical resection, and up to 75% of patients will develop metastatic disease refractory to standard-of-care adjuvant mitotane and cytotoxic chemotherapy. A comprehensive, integrated, and current bench-to-bedside understanding of our field’s investigations into adrenocortical physiology and neoplasia is crucial to developing novel clinical tools and approaches to equip the one-in-a-million patient fighting this devastating disease. Graphical Abstract Graphical Abstract

Abstract Background Adrenal tumors are found in up to 40% of patients with multiple endocrine neoplasia type 1 (MEN1). However, adrenocortical carcinomas (ACC) and primary aldosteronism (PA) are rare in MEN1. Case A 48-year-old woman known to have primary hyperparathyroidism and hypertension with hypokalemia was referred for a right complex 8-cm adrenal mass with a 38.1 SUVmax uptake on 18F-FDG PET/CT. PA was confirmed by saline suppression test (aldosterone 1948 pmol/L-1675 pmol/L; normal range [N]: <165 post saline infusion) and suppressed renin levels (<5 ng/L; N: 5-20). Catecholamines, androgens, 24-hour urinary cortisol, and pituitary panel were normal. A right open adrenalectomy revealed a concomitant 4-cm oncocytic ACC and a 2.3-cm adrenocortical adenoma. Immunohistochemistry showed high expression of aldosterone synthase protein in the adenoma but not in the ACC, supporting excess aldosterone production by the adenoma. Genetic analysis After genetic counseling, the patient underwent genetic analysis of leucocyte and tumoral DNA. Sequencing of MEN1 revealed a heterozygous germline pathogenic variant in MEN1 (c.1556delC, p.Pro519Leufs*40). The wild-type MEN1 allele was lost in the tumoral DNA of both the resected adenoma and carcinoma. Sequencing analysis of driver genes in PA revealed a somatic pathogenic variant in exon 2 of the KCNJ5 gene (c.451G>A, p.Gly151Arg) only in the aldosteronoma. Conclusion To our knowledge, we describe the first case of adrenal collision tumors in a patient carrying a germline pathogenic variant of the MEN1 gene associated with MEN1 loss of heterozygosity in both oncocytic ACC and adenoma and a somatic KCNJ5 pathogenic variant leading to aldosterone-producing adenoma. This case gives new insights on adrenal tumorigenesis in MEN1 patients.

While immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy, identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows in vitro and in vivo activity but is overall limited due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 induces complete responses in DLK1 + ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated transdifferentiation. This work identifies DLK1 as an immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC and supports an active phase I clinical trial targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms (NCT06041516). Adrenocortical carcinoma (ACC) has limited treatment options and few tumor-specific targets. Here the authors report that the Notch ligand DLK1 is highly expressed in ACC acting as a regulator of tumor cell plasticity and chemoresistance, and that DLK1 can be targeted with an antibody drug conjugate.

Adrenal tumors, such as adrenocortical carcinoma (ACC), adrenocortical adenoma (ACA), and pheochromocytoma (PCC) are complex diseases with unclear causes and treatments. Mitochondria and mitochondrial-derived peptides (MDPs) are crucial for cancer cell survival. The primary aim of this study was to analyze samples from different adrenal diseases, adrenocortical carcinoma, adrenocortical adenoma, and pheochromocytoma, and compare them with normal adrenal tissue to determine whether the expression levels of the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) gene and protein vary between different types of adrenal tumors compared to healthy controls using qPCR, ELISA, and IHC methods. Results showed decreased MOTS-c mRNA expression in all adrenal tumors compared to controls, while serum MOTS-c protein levels increased in ACA and PCC but not in ACC. The local distribution of MOTS-c protein in adrenal tissue was reduced in all tumors. Notably, MOTS-c protein expression declined with ACC progression (stages III and IV) but was unrelated to patient age or sex. Tumor size and testosterone levels positively correlated with MOTS-c mRNA but negatively with serum MOTS-c protein. Additionally, serum MOTS-c protein correlated positively with glucose, total cholesterol, HDL, LDL, and SHGB levels. These findings suggest disrupted expression of MOTS-c in the spectrum of adrenal diseases, which might be caused by mechanisms involving increased mitochondrial dysfunction and structural changes in the tissue associated with disease progression. This study provides a detailed examination of MOTS-c mRNA and protein in adrenal tumors, indicating the potential role of MDPs in tumor biology and progression.

Adrenocortical carcinoma (ACC) is an aggressive and rare neoplasm that originates in the cortex of the adrenal gland. The disease is associated with heterogeneous but mostly poor outcomes and lacks effective pharmaceutical treatment options. Multi-omics studies have defined the landscape of molecular alterations in ACC. Specific molecular signatures can be detected in body fluids, potentially enabling improved diagnostic applications for patients with adrenal tumours. Importantly, pan-molecular data sets further reveal a spectrum within ACC, with three major subgroups that have different disease outcomes. These new subgroups have value as prognostic biomarkers. Research has revealed that the p53–RB and the WNT–β-catenin pathways are common disease drivers in ACC. However, these pathways remain difficult to target by therapeutic interventions. Instead, a unique characteristic of ACC is steroidogenic differentiation, which has emerged as a potential treatment target, with several agents undergoing preclinical or clinical investigations. Finally, a large proportion of ACC tumours have genetic profiles that are associated with promising therapeutic responsiveness in other cancers. All these opportunities now await translation from the laboratory into the clinical setting, thereby offering a real potential of improved survival outcomes and increased quality of life for patients with this serious condition.Adrenocortical carcinoma (ACC) is a rare and aggressive neoplasm that arises in the adrenal gland cortex. This Review highlights how genomics can be used to stratify ACC and potentially improve clinical care, outcomes and patient quality of life.

Adrenocortical carcinoma (ACC) is a rare type of tumor with a poor prognosis. Ferroptosis is a relatively novel form of programmed cell death driven by iron-dependent lipid peroxidation accumulation. Recent evidence suggests that IFNγ facilitates erastin-induced ferroptosis, which contributed to anticancer therapy in various types of cancer. However, it has remained elusive whether the regulation of IFNγ on ferroptosis has a positive role in the treatment of ACC. Thus, the aim of the present study was to explore the effects of IFNγ on erastin-induced ferroptosis in the ACC cell line NCI-H295R and investigate the underlying mechanisms. Cell viability was assessed using a Cell Counting Kit-8 assay, an ethynyldioxyuridine proliferation assay and Live/Dead staining. The levels of iron, reactive oxygen species, lipid peroxidation and mitochondrial damage were also assessed. Western blot and reverse transcription-quantitative PCR analyses were used to determine the underlying molecular mechanisms involved in the erastin-induced ferroptosis of NCI-H295R cells. The results suggested that IFNγ promoted erastin-induced ferroptotic cell death. Furthermore, IFNγ enhanced erastin-induced ferroptosis, as evidenced by the accumulation of iron, as well as the increase in lipid peroxidation and promotion of mitochondrial damage. Further analysis suggested that IFNγ enhanced ferroptosis by suppressing the expression of solute carrier family 7 member 11, an important negative regulator of ferroptosis, and this was achieved via activation of the JAK/STAT pathway in NCI-H295R cells. The present study provided experimental evidence on the activity and mechanism of ferroptosis enhanced by IFNγ in ACC and may give critical insight into the immunotherapeutic management of ACC.

Adrenocortical carcinoma is a rare malignancy with an annual worldwide incidence of 1–2 cases per 1 million and a 5-year survival rate of <60%. Although adrenocortical carcinoma is rare, such rare cancers account for approximately one third of patients diagnosed with cancer annually. In the past decade, there have been considerable advances in understanding the molecular basis of adrenocortical carcinoma. The genetic events associated with adrenocortical carcinoma in adults are distinct from those of paediatric cases, which are often associated with germline or somatic TP53 mutations and have a better prognosis. In adult primary adrenocortical carcinoma, the main somatic genetic alterations occur in genes that encode proteins involved in the WNT–β-catenin pathway, cell cycle and p53 apoptosis pathway, chromatin remodelling and telomere maintenance pathway, cAMP–protein kinase A (PKA) pathway or DNA transcription and RNA translation pathways. Recently, integrated molecular studies of adrenocortical carcinomas, which have characterized somatic mutations and the methylome as well as gene and microRNA expression profiles, have led to a molecular classification of these tumours that can predict prognosis and have helped to identify new therapeutic targets. In this Review, we summarize these recent translational research advances in adrenocortical carcinoma, which it is hoped could lead to improved patient diagnosis, treatment and outcome.Adrenocortical carcinoma is a rare endocrine cancer with a dismal survival rate and limited therapeutic options. This Review outlines the recent advances that have been made in the understanding of the molecular basis of adrenocortical carcinoma and what this means for the diagnosis and treatment of patients with this cancer type.

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 hsa-miR-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 dCThsa-miR-210 - dCThsa-miR-181b and dCThsa-miR-100/dCThsa-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.

Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37–57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs. Adrenocortical cancer (ACC) is a rarely diagnosed and aggressive cancer whose metastatic form has been scarcely studied. Here, the authors study primary and metastatic ACC to investigate genomic heterogeneity, discovering higher mutation rates in metastatic lesions and novel recurrent mutations.

Adrenocortical carcinoma is a rare heterogeneous neoplasm with an incompletely understood pathogenesis and a poor prognosis. No general consensus on the diagnostic and therapeutic measures for adrenocortical carcinoma exists, but collaborative efforts have substantially advanced the field. This Review provides an updated approach to the patient with suspected adrenocortical carcinoma and discusses etiology, diagnosis and treatment options. Adrenocortical carcinoma is a rare heterogeneous neoplasm with an incompletely understood pathogenesis and a poor prognosis. Previous studies have identified overexpression of insulin-like growth factor 2 (IGF-2) and constitutive activation of β-catenin as key factors involved in the development of adrenocortical carcinoma. Most patients present with steroid hormone excess, for example Cushing syndrome or virilization, or abdominal mass effects, but a growing proportion of patients with adrenocortical carcinoma (currently >15%) is initially diagnosed incidentally. No general consensus on the diagnostic and therapeutic measures for adrenocortical carcinoma exists, but collaborative efforts, such as international conferences and networks, including the European Network for the Study of Adrenal Tumors (ENSAT), have substantially advanced the field. In patients with suspected adrenocortical carcinoma, a thorough endocrine and imaging work-up is recommended to guide the surgical approach aimed at complete resection of the tumor. To establish an adequate basis for treatment decisions, pathology reports include the Weiss score to assess malignancy, the resection status and the Ki67 index. As recurrence is frequent, close follow-up initially every 3 months is mandatory. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Results of a large phase III trial in advanced adrenocortical carcinoma are anticipated for 2011 and will hopefully establish a benchmark therapy. New targeted therapies, for example, IGF-1 receptor inhibitors, are under investigation and may soon improve current treatment options. Key Points Overexpression of insulin-like growth factor 2 and constitutive activation of β-catenin are key molecular alterations in adrenocortical carcinoma Detailed presurgical endocrine and imaging work-up and an expert surgeon are key prerequisites for a complete resection that offers the best chance of cure Even after radical resection, recurrence rate is high and, therefore, most patients benefit from adjuvant treatment strategies (mitotane with or without radiotherapy) Mitotane is the most effective single drug for adrenocortical carcinoma, but drug monitoring is important and management of adverse events is demanding In advanced disease not amenable to surgery, mitotane is given as monotherapy or in combination with cytotoxic chemotherapy (either etoposide combined with doxorubicin and cisplatin or streptozotocin) To facilitate progress in the treatment of adrenocortical carcinoma, patients should be enrolled in clinical trials