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- Author: Jérome Bertherat x
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Hormonal Biology Laboratory, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD), which can be sporadic or part of Carney complex and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of the tumors suggests the existence of an underlying genetic predisposition. PPNAD and Carney complex are mainly due to germline-inactivating mutations of PRKAR1A, coding for a regulatory subunit of PKA, whereas PBMAH genetic seems more complex. However, genome-wide approaches allowed the identification of a new tumor suppressor gene, ARMC5, whose germline alteration could be responsible for at least 25% of PBMAH cases. Unilateral adrenocortical tumors are more frequent, mostly adenomas. The Wnt/beta-catenin pathway can be activated in both benign and malignant tumors by CTNNB1 mutations and by ZNRF3 inactivation in adrenal cancer (ACC). Some other signaling pathways are more specific of the tumor dignity. Thus, somatic mutations of cAMP/PKA pathway genes, mainly PRKACA, coding for the catalytic alpha-subunit of PKA, are found in cortisol-secreting adenomas, whereas IGF-II overexpression and alterations of p53 signaling pathway are observed in ACC. Genome-wide approaches including transcriptome, SNP, methylome and miRome analysis have identified new genetic and epigenetic alterations and the further clustering of ACC in subgroups associated with different prognosis, allowing the development of new prognosis markers.
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Adrenocortical cancer (ACC) is a rare tumor with a poor prognosis. By contrast, benign adrenocortical tumors are frequent, underlying the importance of a correct diagnosis of malignancy of such tumors. ACC can be diagnosed by the investigation of endocrine signs of steroid excess, symptoms due to tumor growth or an adrenal incidentaloma. Hormonal investigations demonstrate in most ACC steroid oversecretion, the dominant characteristics being a co-secretion of cortisol and androgens. Imaging by CT-scan or MRI shows a large heterogeneous tumor with a low fat content. Careful pathological investigation with the assessment of the Weiss score is important for the diagnosis of malignancy. Molecular markers can also be helpful and in the future might be important for prognosis. Tumors localized to the adrenal gland (McFarlane stages 1 and 2) have a better outcome than invasive and metastatic tumors (stages 3 and 4). Tumor removal by a specialized team is crucial for treatment and should always aim at complete removal. In patients with metastatic or progressive disease, medical treatment is started with mitotane that requires a close monitoring of its blood level. Surgery is indicated when possible for local recurrence but also in some cases of metastasis. Local treatment (radiofrequency, chemoembolization, and radiation therapy) can have some indications for metastatic disease. In patients with disease progression cytotoxic chemotherapy can be used. Despite the best care, the overall prognosis of ACC is poor with a 5-year survival rate below 30% in most series. Therefore, progress in the understanding of the pathophysiology of ACC is important. Despite the rarity of ACC, significant advances have been made in the understanding of its pathogenesis the last decade. These progresses came mainly from the study of the genetics of ACC, both at the germline level in rare familial diseases, and at the somatic level by the study of molecular alterations in sporadic tumors. These advances underline the importance of genetic alterations in ACC development and point-out to various chromosomal regions (2, 11p15, 11q, 17p13) and genes (IGF-II, p53, β-catenin, ACTH receptor). This review will summarize these advances as well as the current clinical management of ACC.
Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
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Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
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Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
Institut Cochin, Inserm, Department of Endocrinology, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France
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Transcriptome analysis has been successfully used to study the gene profile expression of adrenocortical tumors (ACT) for 7 years. The various studies reported to date have produced an abundance of new information on adrenocortical cancer (ACC), underlying the validity of this approach to study the molecular genetics and pathogenesis of these tumors. The gene expression profile of ACC clearly differs from that of benign adrenocortical adenomas (ACA). Interestingly, transcriptome analysis has the ability to establish a subclassification of ACC based on the gene expression profile. In particular, it is able to identify two groups of tumors with different outcomes (i.e. good prognosis and poor prognosis). This approach has been used to develop molecular markers for ACC diagnosis and prognostication. An IGF2 cluster of genes up-regulated in ACC has been identified. Transcriptome analysis has shown that, in comparison with ACA, IGF2 is indeed the gene most overexpressed in ACC. By contrast, genes associated with steroidogenesis are down-regulated in ACC. Genes controlling the cell cycle are dysregulated in ACC, and several are dramatically overexpressed. Analysis regarding the level of expression of Wnt/β-catenin and p53 signaling has shown alterations, in keeping with the known molecular somatic genetic defects of these pathways that are observed in ACC. This review summarizes the main findings of studies reporting ACC transcriptome analysis, demonstrating its power for ACT classification, and examines the resulting progress in understanding the pathogenesis of ACC. The potential for both ACC diagnosis and the identification of new therapeutic targets will be discussed.
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Department of Genetics and Genome Sciences and Germline High Risk Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
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Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
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Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
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Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
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Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
Unité de Pharmacologie, Ecole Nationale Vétérinaire d'Alfort, Laboratoire d'Oncobiologie, Department of Pathology, Department of Endocrinology, Department of Endocrinology, Faculté de Médecine Paris-Ile de France Ouest, INSERM, Département d'Endocrinologie Métabolisme and Cancer, CNRS, Faculté de Médecine René Descartes, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
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Adrenal tumors occur more frequently in women and are the leading cause of Cushing's syndrome during pregnancy. We aimed to evaluate the potential role of sex steroids in the susceptibility of women to adrenocortical tumors. We evaluated the presence of the progesterone receptor (PR), estradiol receptors (ERs), and aromatase in 5 patients with primary pigmented nodular adrenal disease (PPNAD), 15 adrenocortical adenomas (ACAs) and adjacent normal tissues, 12 adrenocortical carcinomas (ACCs), and 3 normal adrenal glands (NA). The expression of PR and ERα was evaluated by enzyme immunoassays, real-time RT-PCR, immunohistochemistry, and cytosol-based ligand-binding assays. ERβ and aromatase levels were evaluated by real-time RT-PCR. ERα concentrations were low in NA, in adrenal tissues adjacent to ACA (51±33), in ACC (53±78), and lower in ACA (11±11 fmol/mg DNA). Conversely, PR concentrations were high in NA and adrenal tissues adjacent to ACA, at 307±216 fmol/mg DNA, and were even higher in tumors – 726±706 fmol/mg DNA in ACA and 1154±1586 fmol/mg DNA in ACC – and in isolated PPNAD nodules. Binding study results in four tumors were compatible with binding to a steroid receptor. In patients with PPNAD, a strong positive immunohistochemical signal was associated with the sole isolated nodular regions. ERβ transcript levels were very high in all samples except those for two ACCs, whereas aromatase levels were low. PR and ERβ are clearly present in normal adrenal glands and adrenal tumors. Further studies may shed light on the possible pathogenic role of these receptors in adrenal proliferation.
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Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany
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Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France
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ARMC5
is a tumor suppressor gene frequently mutated in primary bilateral macronodular adrenal hyperplasia (PBMAH), an adrenal cause of Cushing’s syndrome. The function of ARMC5 is poorly understood, aside from the fact that it regulates cell viability and adrenal steroidogenesis by mechanisms still unknown. Tumor suppressor genes play an important role in modifying intracellular redox response, which in turn regulates diverse cell signaling pathways. In this study, we demonstrated that inactivation in adrenocortical cells increased the expression of actors scavenging reactive oxygen species, such as superoxide dismutases (SOD) and peroxiredoxins (PRDX) by increasing the transcriptional regulator NRF1. Moreover, ARMC5 is involved in the NRF1 ubiquitination and in its half-life. Finally, inactivation alters adrenocortical steroidogenesis through the activation of p38 pathway and decreases cell sensitivity to ferroptosis participation to increase cell viability. Altogether, this study uncovers a function of ARMC5 as a regulator of redox homeostasis in adrenocortical cells, controlling steroidogenesis and cell survival.
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Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver, National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
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Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver, National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
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Mutations in the protein kinase A (PKA) regulatory subunit type 1A (PRKAR1A) and armadillo repeat-containing 5 (ARMC5) genes cause Cushing‘s syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral macronodular adrenocortical hyperplasia (PBMAH), respectively. Between the two genes, ARMC5 is highly polymorphic with several variants in the population, whereas PRKAR1A has very little, if any, non-pathogenic variation in its coding sequence. We tested the hypothesis that ARMC5 variants may affect the clinical presentation of PPNAD and CS among patients with PRKAR1A mutations. In this study, 91 patients with PPNAD due to PRKAR1A mutations were tested for abnormal cortisol secretion or CS and for ARMC5 sequence variants. Abnormal cortisol secretion was present in 71 of 74 patients with ARMC5 variants, whereas 11 of 17 patients negative for ARMC5 variants did not have hypercortisolemia. The presence of ARMC5 variants was a statistically strong predictor of CS among patients with PRKAR1A mutations (P < 0.001). Among patients with CS due to PPNAD, ARMC5 variants were associated with lower cortisol levels at baseline (P = 0.04) and after high dose dexamethasone administration (P = 0.02). The ARMC5 p.I170V variant increased ARMC5 protein accumulation in vitro and decreased viability of NCI-H295 cells (but not HEK 293T cells). PPNAD tissues with ARMC5 variants showed stronger ARMC5 protein expression than those that carried a normal ARMC5 sequence. Taken together, our results suggest that ARMC5 variants among patients with PPNAD due to PRKAR1A defects may play the role of a genetic modifier for the presence and severity of hypercortisolemia.
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Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Molecular pathways of malignant transformation remain poorly understood. Pheochromocytomas express various trophic peptides which may influence tumoral cell behavior. Here, we investigated the expression of trophic amidated peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM), and their receptors in benign and malignant pheochromocytomas in order to assess their potential role in chromaffin cell tumorigenesis and malignant transformation. PACAP, NPY, and AM are expressed in the majority of pheochromocytomas studied; NPY exhibiting the highest mRNA levels relative to reference genes. Although median gene expression or peptide levels were systematically lower in malignant compared to benign tumors, no statistically significant difference was found. Among all the receptors of these peptides that were analyzed, only the AM receptor RDC1 displayed a differential expression between benign and malignant pheochromocytomas. This receptor exhibited a fourfold higher expression in malignant than in benign tumors. AM and stromal cell-derived factor 1, which has also been described as a ligand for RDC1, increased the number of human pheochromocytoma cells in primary culture and exerted anti-apoptotic activity on rat pheochromocytoma PC12 cells. In addition, RDC1 gene silencing decreased the number of viable PC12 cells. This study shows the expression of several trophic peptides and their receptors in benign and malignant pheochromocytomas, and suggests that AM and its RDC1 receptor could be involved in chromaffin cell tumorigenesis through pro-survival effects. Therefore, AM and RDC1 may represent valuable targets for the treatment of malignant pheochromocytomas.
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INSERM U413, INSERM U644, Laboratory of Oncologic Genetics, Department of Endocrinology, Hypertension Unit, INSERM U567, EA4310, DC2N, IFRMP 23, University of Rouen, Mont Saint Aignan, France
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The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas. The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 (5-HT4) receptors in pheochromocytoma tissues. Tissue explants, obtained from 18 pheochromocytomas including the tumor removed from a 46-year-old female patient who experienced life-threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas (9 benign and 8 malignant) were studied. Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5-HT4 receptor ligands. In addition, total mRNAs were extracted from all the 18 tumors. Catecholamine- and granin-derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays. In addition, expression of 5-HT4 receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase-PCR. Results: Metoclopramide and the 5-HT4 receptor agonist cisapride were found to activate catecholamine- and granin-derived peptide secretions by cultured tumor cells. Metoclopramide- and cisapride-evoked catecholamine- and granin-derived peptide productions were inhibited by the 5-HT4 receptor antagonist GR 113808. 5-HT4 receptor mRNAs were detected in the patient's tumor and the series of 17 additional pheochromocytomas. This study shows that pheochromocytomas express functional 5-HT4 receptors that are responsible for the stimulatory action of metoclopramide on catecholamine- and granin-derived peptide secretion. All 5-HT4 receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma.
Department of Diabetology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Gastroenterology and Digestive Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Digestive Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Digestive Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Diabetology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Gastroenterology and Digestive Oncology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular updates changing the definition of classes. Genomic screening may provide more objective classes and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcomes (log-rank P < 0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the topmost expressed liver genes. FGA expression was associated with disease-free survival (HR = 1.13, P = 0.005) and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.
