Publications by authors named "Jérôme Bertherat"

282 Publications

Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors.

Endocr Relat Cancer 2021 Jun 1. Epub 2021 Jun 1.

G Assié, Université de Paris, INSERM, CNRS, Institut Cochin, Paris, France.

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 up-dates 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 outcome (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 top most expressed liver gene. 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.
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http://dx.doi.org/10.1530/ERC-21-0051DOI Listing
June 2021

Surgical management of insulinoma over three decades.

HPB (Oxford) 2021 Apr 27. Epub 2021 Apr 27.

Department of Digestive, Hepato-biliary and Endocrine Surgery, Cochin Hospital, APHP, 75014 Paris, France; Université de Paris, 75006 Paris, France. Electronic address:

Background: This paper reports our experience of the perioperative management of patients with sporadic, non-malignant, pancreatic insulinoma.

Methods: A retrospective monocentric cohort study was performed from January 1989 to July 2019, including all the patients who had been operated on for pancreatic insulinoma. The preoperative work-up, surgical management, and postoperative outcome were analyzed.

Results: Eighty patients underwent surgery for sporadic pancreatic insulinoma, 50 of which were female (62%), with a median age of 50 (36-70) years. Preoperatively, the tumors were localized in 76 patients (95%). Computed tomography (CT) and magnetic resonance imaging allowed exact preoperative tumor localization in 76% of the patients (64-85 and 58-88 patients, respectively), increasing to 96% when endoscopic ultrasonography was performed. Forty-one parenchyma-sparing pancreatectomies (PSP) (including enucleation, caudal pancreatectomy, and uncinate process resection) and 39 pancreatic resections were performed. The mortality rate was 6% (n = 5), with a morbidity rate of 72%, including 24 severe complications (30%) and 35 pancreatic fistulas (44%). No differences were found between formal pancreatectomy and PSP in terms of postoperative outcome procedures. The surgery was curative in all the patients.

Conclusion: CT used in combination with endoscopic ultrasonography allows accurate localization of insulinomas in almost all patients. When possible, a parenchyma-sparing pancreatectomy should be proposed as the first-line surgical strategy.
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http://dx.doi.org/10.1016/j.hpb.2021.04.013DOI Listing
April 2021

Preoperative Detection of Liver Involvement by Right-Sided Adrenocortical Carcinoma Using CT and MRI.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Department of Diagnostic and Interventional Imaging, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.

The major prognosis factor of adrenocortical carcinoma (ACC) is the completeness of surgery. The aim of our study was to identify preoperative imaging features associated with direct liver involvement (DLI) by right-sided ACC. Two radiologists, blinded to the outcome, independently reviewed preoperative CT and MRI examinations for eight signs of DLI, in patients operated for right-sided ACC and retrospectively included from November 2007 to January 2020. DLI was confirmed using surgical and histopathological findings. Kappa values were calculated. Univariable and multivariable analyses were performed by using a logistic regression model. Receiver operating characteristic (ROC) curves were built for CT and MRI. Twenty-nine patients were included. Seven patients had DLI requiring resection. At multivariable analysis, focal ACC bulge was the single independent sign associated with DLI on CT (OR: 60.00; 95% CI: 4.60-782.40; < 0.001), and ACC contour disruption was the single independent sign associated with DLI on MRI (OR: 126.00; 95% CI: 6.82-2328.21; < 0.001). Both signs were highly reproducible, with respective kappa values of 0.85 and 0.91. The areas under ROC curves of MRI and CT models were not different ( = 0.838). Focal ACC bulge on CT and ACC contour disruption on MRI are independent and highly reproducible signs, strongly associated with DLI by right-sided ACC on preoperative imaging. MRI does not improve the preoperative assessment of DLI by comparison with CT.
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http://dx.doi.org/10.3390/cancers13071603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036813PMC
March 2021

Rapid control of severe ectopic Cushing's syndrome by oral osilodrostat monotherapy.

Eur J Endocrinol 2021 May;184(5):L13-L15

Department of Endocrinology, Polyclinic of Saint Côme, Compiegne, France.

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http://dx.doi.org/10.1530/EJE-21-0147DOI Listing
May 2021

Update on primary bilateral macronodular adrenal hyperplasia (PBMAH).

Endocrine 2021 Mar 15;71(3):595-603. Epub 2021 Feb 15.

Institut Cochin, Université de Paris, Inserm U1016, CNRS UMR8104, 24 rue du Faubourg Saint-Jacques, 75014, Paris, France.

Primary bilateral macronodular adrenal hyperplasia (PBMAH), characterized by bilateral benign adrenal macronodules (>1 cm) potentially responsible for variable levels of cortisol excess, is a rare and heterogeneous disease. However, its frequency increases due to incidentally diagnosed cases on abdominal imaging carried out for reasons other than suspected adrenal disease. Mostly isolated, it can also be associated with dominantly inherited genetic conditions in rare cases. Considering the bilateral nature of adrenal involvement and the description of familial cases, the search of a genetic predisposition has led to the identification of germline heterozygous inactivating mutations of the putative tumor suppressor gene ARMC5, causing around 25% of the apparent sporadic cases. Rigorous biochemical and imaging assessment are key elements in the management of this challenging disease in terms of diagnosis. Treatment is reserved for symptomatic patients with overt or subclinical Cushing syndrome, and was historically based on bilateral adrenalectomy, which nowadays tends to be replaced by unilateral adrenalectomy or lifelong treatment with cortisol synthesis inhibitors.
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http://dx.doi.org/10.1007/s12020-021-02645-wDOI Listing
March 2021

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics.

Endocr Pathol 2021 Mar 3;32(1):102-133. Epub 2021 Feb 3.

Department of Pathology, University Health Network, Toronto, ON, Canada.

Approximately one-tenth of the general population exhibit adrenal cortical nodules, and the incidence has increased. Afflicted patients display a multifaceted symptomatology-sometimes with rather spectacular features. Given the general infrequency as well as the specific clinical, histological, and molecular considerations characterizing these lesions, adrenal cortical tumors should be investigated by endocrine pathologists in high-volume tertiary centers. Even so, to distinguish specific forms of benign adrenal cortical lesions as well as to pinpoint malignant cases with the highest risk of poor outcome is often challenging using conventional histology alone, and molecular genetics and translational biomarkers are therefore gaining increased attention as a possible discriminator in this context. In general, our understanding of adrenal cortical tumorigenesis has increased tremendously the last decade, not least due to the development of next-generation sequencing techniques. Comprehensive analyses have helped establish the link between benign aldosterone-producing adrenal cortical proliferations and ion channel mutations, as well as mutations in the protein kinase A (PKA) signaling pathway coupled to cortisol-producing adrenal cortical lesions. Moreover, molecular classifications of adrenal cortical tumors have facilitated the distinction of benign from malignant forms, as well as the prognostication of the individual patients with verified adrenal cortical carcinoma, enabling high-resolution diagnostics that is not entirely possible by histology alone. Therefore, combinations of histology, immunohistochemistry, and next-generation multi-omic analyses are all needed in an integrated fashion to properly distinguish malignancy in some cases. Despite significant progress made in the field, current clinical and pathological challenges include the preoperative distinction of non-metastatic low-grade adrenal cortical carcinoma confined to the adrenal gland, adoption of individualized therapeutic algorithms aligned with molecular and histopathologic risk stratification tools, and histological confirmation of functional adrenal cortical disease in the context of multifocal adrenal cortical proliferations. We herein review the histological, genetic, and epigenetic landscapes of benign and malignant adrenal cortical neoplasia from a modern surgical endocrine pathology perspective and highlight key mechanisms of value for diagnostic and prognostic purposes.
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http://dx.doi.org/10.1007/s12022-021-09667-0DOI Listing
March 2021

MANAGEMENT OF ENDOCRINE DISEASE: Carney complex: clinical and genetic update 20 years after the identification of the CNC1 (PRKAR1A) gene.

Eur J Endocrinol 2021 Mar;184(3):R99-R109

Université de Paris, Institut Cochin, Inserm U1016, Paris, France.

Described for the first time in 1985, Carney complex (CNC) is a rare dominantly inherited multiple neoplasia syndrome with almost full penetrance and characterized by both endocrine - primary pigmented nodular adrenocortical disease with Cushing's syndrome, acromegaly and thyroid tumors - and non-endocrine manifestations such as cardiac, cutaneous and mucosal myxomas, pigmented cutaneous lesions, psammomatous melanotic schwannoma, osteochondromyxoma and a wide range of other tumours with potential malignancy. The pathophysiology of CNC is a model of dysregulation of the cAMP/PKA signalling in human diseases. As described 20 years ago, inactivating heterozygous mutations of PRKAR1A formerly known as CNC1, encoding the regulatory subunit 1α of protein kinase A, are identified in more than 70% of the index cases, while inactivating mutations of genes encoding phosphodiesterases are found in rare and particular forms of the complex. There is at present no medical specific treatment for CNC, every confirmed or suspected CNC patient should be managed by a multi-disciplinary team according to each manifestation of the disease and offered a long-term follow-up and genetic counselling. The better knowledge that we have now of this fascinating rare disease and its genetics will help to improve patients outcome.
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http://dx.doi.org/10.1530/EJE-20-1120DOI Listing
March 2021

CRH-Receptor Molecular Imaging Reveals the Intimacy of Corticotroph Adenomas.

J Clin Endocrinol Metab 2021 Mar;106(4):e1902-e1904

Université de Paris, Institut Cochin, Inserm U1016, CNRS UMR8104, Paris, France.

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http://dx.doi.org/10.1210/clinem/dgaa883DOI Listing
March 2021

The EuRRECa Project as a Model for Data Access and Governance Policies for Rare Disease Registries That Collect Clinical Outcomes.

Int J Environ Res Public Health 2020 11 25;17(23). Epub 2020 Nov 25.

Developmental Endocrinology Research Group, Royal Hospital for Children, University of Glasgow, Glasgow G51 4TF, UK.

Rare disease (RD) registries are important platforms that facilitate communication between health care professionals, patients and other members of the multidisciplinary team. RD registries enable data sharing and promotion of research and audits, often in an international setting, with the overall aim of improving patient care. RD registries also have a fundamental role in supporting the work of clinical networks such as the European Reference Networks (ERNs) for rare diseases. With the recent expansion of RD registries, it has become even more essential to outline standards of good practice in relation to governance, infrastructure, documentation, training, audits and adopting the Findable, Accessible, Interoperable and Reusable (FAIR) data principles to maintain registries of high quality. For the purpose of this paper, we highlight vital aspects of data access and data governance policies for RD registries, using the European Registries for Rare Endocrine Conditions (EuRRECa) as an example of a project that aims to promote good standards of practice for improving the quality of utilization of RD registries.
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http://dx.doi.org/10.3390/ijerph17238743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727867PMC
November 2020

Screening of a Large Cohort of Asymptomatic SDHx Mutation Carriers in Routine Practice.

J Clin Endocrinol Metab 2021 Mar;106(3):e1301-e1315

Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.

Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers that would benefit from screening protocols.

Objective: To define the tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers.

Design And Setting: Retrospective multicentric study in 6 referral centers.

Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least 1 imaging work-up were enrolled.

Results: Initial work-up, including anatomical (98% of subjects [97-100% according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from 1 to 9 subsequent follow-up assessments (mean: 1.9 per patient), with a median follow-up time of 5 (1-13) years. Anatomical (86% [49-100 %]) and/or functional imaging (36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 paraganglioma [PGL], including 45 head and neck PGL, 2 pheochromocytoma [PCC], 1 gastrointestinal stromal tumor [GIST]), were detected in 50 patients (22 [13%] SDHB, 1 [3.2%] SDHC, and 27 [57%] SDHD), with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up.

Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers, with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutation carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data.
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http://dx.doi.org/10.1210/clinem/dgaa888DOI Listing
March 2021

HOX genes promote cell proliferation and are potential therapeutic targets in adrenocortical tumours.

Br J Cancer 2021 02 20;124(4):805-816. Epub 2020 Nov 20.

Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, UK.

Background: Understanding the pathways that drive adrenocortical carcinoma (ACC) is essential to the development of more effective therapies. This study investigates the role of the transcription factor HOXB9 and other HOX factors in ACC and its treatment.

Methods: We used transgenic mouse models to determine the role of Hoxb9 in adrenal tumour development. Patient transcriptomic data was analysed for the expression of HOX genes and their association with disease. Drug response studies on various adrenocortical models were done to establish novel therapeutic options.

Results: Our human ACC dataset analyses showed high expression of HOXB9, and other HOX factors, are associated with poorer prognosis. Transgenic overexpression of Hoxb9 in the adrenal cortex of mice with activated Ctnnb1 led to larger adrenal tumours. This phenotype was preferentially observed in male mice and was characterised by more proliferating cells and an increase in the expression of cell cycle genes, including Ccne1. Adrenal tumour cells were found to be dependent on HOX function for survival and were sensitive to a specific peptide inhibitor.

Conclusions: These studies show Hoxb9 can promote adrenal tumour progression in a sex-dependent manner and have identified HOX factors as potential drug targets, leading to novel therapeutic approaches in ACC.
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http://dx.doi.org/10.1038/s41416-020-01166-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884796PMC
February 2021

Choroidal imaging in patients with Cushing syndrome.

Acta Ophthalmol 2020 Nov 16. Epub 2020 Nov 16.

Department of Ophthalmology, OphtalmoPôle, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, AP-HP, Université Paris 5, Sorbonne Paris Cité, Paris, France.

Aims: Glucocorticoid intake is a well-established risk factor for central serous chorioretinopathy that belongs to the pachychoroid spectrum disease (PSD). The study aimed to assess the prevalence of PSD and analyse the choroidal phenotype in patients with Cushing syndrome.

Methods: A cross-sectional study was performed in Ophtalmopôle hôpital Cochin, Paris, France, with a systematic evaluation of hospitalized patients with Cushing syndrome, between November 2017 and July 2018. 56 eyes from 28 Cushing syndrome patients and 56 eyes of 28 age and gender-matched, and close spherical equivalent healthy participants were included. All patients underwent a complete ophthalmic examination including Enhanced-Depth Imaging (EDI)-Optical Coherence Tomography (OCT). Measures of subfoveal, 1000 µm nasal and 1000 µm temporal choroidal thicknesses were realized, and the presence of choroidal pachyvessels was evaluated. Hormonal tests evaluated the corticotropic axis.

Results: The number of eyes with PSD was significantly higher in Cushing syndrome patients as compared to controls (21.4% versus 3.6%, p = 0.004). In Cushing patients' eyes, 17.9% had a pachychoroid pigment epitheliopathy (PPE) and 3.6% had a polypoidal choroidal vasculopathy. Pachyvessels were more common in Cushing syndrome patients than in healthy subjects (71.4% versus 42.9%, p = 0.002). Mean subfoveal choroidal thickness was 331 ± 110 µm in Cushing patients, with no statistical difference between the two groups. There was no correlation between choroidal thickness and urinary and salivary cortisol levels.

Conclusion: Patients with Cushing syndrome have a higher prevalence of PDS. An ophthalmologic specialized follow-up of these patients with EDI-OCT could detect chorioretinal abnormalities and adapt the surveillance of these patients.
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http://dx.doi.org/10.1111/aos.14664DOI Listing
November 2020

Genomic classification of benign adrenocortical lesions.

Endocr Relat Cancer 2021 Jan;28(1):79-95

Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France.

Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological insights. Benign adrenocortical tumors (n = 146) were analyzed by transcriptome, methylome, miRNome, chromosomal alterations and mutational status, using expression arrays, methylation arrays, miRNA sequencing, SNP arrays, and exome or targeted next-generation sequencing respectively. Pathological and hormonal data were collected for all tumors. Pangenomic analysis identifies four distinct molecular categories: (1) tumors responsible for overt Cushing, gathering distinct tumor types, sharing a common cAMP/PKA pathway activation by distinct mechanisms; (2) adenomas with mild autonomous cortisol excess and non-functioning adenomas, associated with beta-catenin mutations; (3) primary macronodular hyperplasia with ARMC5 mutations, showing an ovarian expression signature; (4) aldosterone-producing adrenocortical adenomas, apart from other benign tumors. Epigenetic alterations and steroidogenesis seem associated, including CpG island hypomethylation in tumors with no or mild cortisol secretion, miRNA patterns defining specific molecular groups, and direct regulation of steroidogenic enzyme expression by methylation. Chromosomal alterations and somatic mutations are subclonal, found in less than 2/3 of cells. New pathophysiological insights, including distinct molecular signatures supporting the difference between mild autonomous cortisol excess and overt Cushing, ARMC5 implication into the adreno-gonadal differentiation faith, and the subclonal nature of driver alterations in benign tumors, will orient future research. This first genomic classification provides a large amount of data as a starting point.
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http://dx.doi.org/10.1530/ERC-20-0128DOI Listing
January 2021

PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A.

Endocr Relat Cancer 2020 11;27(11):647-656

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA.

Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.
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http://dx.doi.org/10.1530/ERC-20-0309DOI Listing
November 2020

Letter to the Editor from Berthon: "Cardiac Myxoma Caused by Fumarate Hydratase Gene Deletion in Patient With Cortisol-Secreting Adrenocortical Adenoma".

J Clin Endocrinol Metab 2020 11;105(11)

Section on Endocrinology & Genetics, The Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland.

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http://dx.doi.org/10.1210/clinem/dgaa530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899563PMC
November 2020

Molecular Basis of Primary Aldosteronism and Adrenal Cushing Syndrome.

J Endocr Soc 2020 Sep 29;4(9):bvaa075. Epub 2020 Jun 29.

Reference Center for Rare Adrenal Diseases, Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France.

This review reports the main molecular alterations leading to development of benign cortisol- and/or aldosterone-secreting adrenal tumors. Causes of adrenal Cushing syndrome can be divided in 2 groups: multiple bilateral tumors or adenomas secreting cortisol. Bilateral causes are mainly primary pigmented nodular adrenocortical disease, most of the time due to germline-inactivating mutations, and primary bilateral macronodular adrenal hyperplasia that can be caused in some rare syndromic cases by germline-inactivating mutations of , , and and of in isolated forms. somatic-activating mutations are the main alterations in unilateral cortisol-producing adenomas. In primary hyperaldosteronism (PA), familial forms were identified in 1% to 5% of cases: familial hyperaldosteronism type I (FH-I) due to a chimeric hybrid gene, FH-II due to germline mutations, FH-III due to germline mutations, FH-IV due to germline mutations and PA, and seizures and neurological abnormalities syndrome due to germline mutations. Several somatic mutations have been found in aldosterone-producing adenomas in , , , , and genes. In addition to these genetic alterations, genome-wide approaches identified several new alterations in transcriptome, methylome, and miRnome studies, highlighting new pathways involved in steroid dysregulation.
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http://dx.doi.org/10.1210/jendso/bvaa075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412855PMC
September 2020

Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma.

Endocr Connect 2020 Jul;9(7):705-714

Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.

Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n = 26), chromosome alteration profiles were determined using SNP arrays (n = 14) and methylation profiles were determined using four-gene bisulfite pyrosequencing (n = 12).

Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients, respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were 'Noisy' (numerous and anarchic alterations) in 8/14 and 'Chromosomal' (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).

Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable and might be more robust for the prognostic assessment.
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http://dx.doi.org/10.1530/EC-20-0228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424337PMC
July 2020

F-fluorocholine PET/CT in MEN1 Patients with Primary Hyperparathyroidism.

World J Surg 2020 Nov 17;44(11):3761-3769. Epub 2020 Jul 17.

Université de Paris, Paris, France.

Background: Primary hyperparathyroidism (HPT1) is the most frequent endocrinopathy in multiple endocrine neoplasia type 1 (MEN1). Its surgical management is challenging. We aimed to describe and compare the imaging findings of parathyroid ultrasound (US), sestaMIBI scintigraphy (sestaMIBI), and F-fluorocholine (FCH) PET/CT in a series of MEN1 patients with HPT1.

Methods: Retrospective analysis of a cohort of MEN1 patients with HPT1 assessed by parathyroid US, sestaMIBI scintigraphy and SPECT/CT, and FCH-PET/CT for potential surgery between 2015 and 2019.

Results: Twenty-two patients with a confirmed diagnosis of MEN1 who presented with HPT1 and were assessed by the 3 imaging modalities were included. After imaging workups, 11 patients were operated on for the first time, 4 underwent a redo surgery, and 7 did not undergo an operation. The overall patient-based positivity rate of imaging was 91% (20 of 22) for parathyroid US and 96% (21 of 22) for both sestaMIBI and FCH-PET/CT. The 3 imaging modalities demonstrated negative findings in 1/22 patient who did not undergo surgery. Overall, 3 pathologic glands were not detected by any imaging technique. SestaMIBI and FCH-PET/CT both resulted in the same 3 false-positive results in ectopic areas with a significant uptake on two thymic carcinoid tumors and one inflammatory lymph node. FCH-PET/CT provided more surgically relevant data than sestaMIBI in 4/11 patients with initial surgery and in 1/4 patient who underwent redo surgery.

Conclusions: Compared to sestaMIBI scintigraphy, FCH-PET/CT provides additional information regarding the number of pathologic parathyroid glands and their localization in MEN1 patients with HPT1.
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http://dx.doi.org/10.1007/s00268-020-05695-9DOI Listing
November 2020

ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing's syndrome.

Endocr Relat Cancer 2020 09;27(9):509-517

Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA.

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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http://dx.doi.org/10.1530/ERC-20-0273DOI Listing
September 2020

Efficacy and safety of dopamine agonists in patients treated with antipsychotics and presenting a macroprolactinoma.

Eur J Endocrinol 2020 Aug;183(2):221-231

Assistance Publique Hôpitaux de Paris, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse HYPO, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Context: In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge.

Objective: Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics.

Design: This was a multicenter (France and Belgium) retrospective study.

Patients: Eighteen patients treated with antipsychotics were included.

Results: Under DA, median PRL levels decreased from 1247 (117-81 132) to 42 (4-573) ng/mL (P = 0.008), from 3850 (449-38 000) to 141 (60-6000) ng/mL (P = 0.037) and from 1664 (94-9400) to 1215 (48-5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0-57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions.

Conclusions: Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics.
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http://dx.doi.org/10.1530/EJE-20-0125DOI Listing
August 2020

Adrenalectomy during pregnancy: A 15-year experience at a tertiary referral center.

Surgery 2020 Aug 17;168(2):335-339. Epub 2020 May 17.

Department of Digestive, Hepato-biliary and Endocrine Surgery, Referral Center for Rare Adrenal Diseases, Cochin Hospital, APHP, Paris, France; Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité, France; INSERM Unité 1016, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, Paris, France.

Background: Adrenal lesions diagnosed during pregnancy remain rare, and their management is challenging because of maternal physiologic modifications, restricted imaging investigations, and contraindications to several treatments. Surgical issues of adrenalectomy during pregnancy and consequences on perinatal outcomes are poorly described. We therefore aimed to report maternal and fetal outcomes after adrenalectomy during pregnancy.

Methods: All pregnant women who underwent adrenalectomy over a 15-year inclusion period were identified from a prospectively maintained database. Surgical management and maternal and fetal outcomes were reviewed.

Results: From January 2003 to July 2018, a total of 12 women underwent adrenalectomy at a median gestation of 20 weeks. Of these women, 11 had hyper-secreting lesions, including 8 with cortisol oversecretion, and 11 had benign lesions, including cortisol-secreting adenoma (n = 5), pheochromocytoma (n = 2), primary pigmented, nodular adrenal disease (n = 1), severe Cushing's disease (n = 2), and hematoma (n = 1). A total of 3 patients with severe Cushing's disease (n = 2) and primary pigmented, nodular adrenal disease (n = 1) required bilateral adrenalectomy. One patient presented with a malignant adrenal Ewing sarcoma. Adrenalectomy during pregnancy was performed by the lateral laparoscopic transabdominal laparoscopic route in 9 patients. Postoperative morbidity occurred in 3 women. Maternal mortality was nil, but preterm birth occurred in 7 cases and intrauterine growth retardation was observed in 3 cases. Finally, among the 12 women, 10 had a child in good health.

Conclusion: During pregnancy, a lateral laparoscopic transabdominal approach is a feasible procedure. Maternal outcome is acceptable but fetal outcome is determined by the underlying disease, with a worse outcome when the adrenalectomy is indicated for malignant lesions or Cushing's syndrome.
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http://dx.doi.org/10.1016/j.surg.2020.03.019DOI Listing
August 2020

Mass spectrometry-based steroid profiling in primary bilateral macronodular adrenocortical hyperplasia.

Endocr Relat Cancer 2020 07;27(7):403-413

Section on Endocrinology and Genetics, TheEunice Kennedy ShriverInstitute of Child Health and Human Development National Institutes of Health, Bethesda, Maryland, USA.

Biochemical characterization of primary bilateral macronodular adrenocortical hyperplasia (PBMAH) by distinct plasma steroid profiles and its putative correlation to disease has not been previously studied. LC-MS/MS-based steroid profiling of 16 plasma steroids was applied to 36 subjects (22 females, 14 males) with PBMAH, 19 subjects (16 females, 3 males) with other forms of adrenal Cushing's syndrome (ACS), and an age and sex-matched control group. Germline ARMC5 sequencing was performed in all PBMAH cases. Compared to controls, PBMAH showed increased plasma 11-deoxycortisol, corticosterone, 11-deoxycorticosterone, 18-hydroxycortisol, and aldosterone, but lower progesterone, DHEA, and DHEA-S with distinct differences in subjects with and without pathogenic variants in ARMC5. Steroids that showed isolated differences included cortisol and 18-oxocortisol with higher (P < 0.05) concentrations in ACS than in controls and aldosterone with higher concentrations in PBMAH when compared to controls. Larger differences in PBMAH than with ACS were most clear for corticosterone, but there were also trends in this direction for 18-hydroxycortisol and aldosterone. Logistic regression analysis indicated four steroids - DHEA, 11-deoxycortisol, 18-oxocortisol, and corticosterone - with the most power for distinguishing the groups. Discriminant analyses with step-wise variable selection indicated correct classification of 95.2% of all subjects of the four groups using a panel of nine steroids; correct classification of subjects with and without germline variants in ARMC5 was achieved in 91.7% of subjects with PBMAH. Subjects with PBMAH show distinctive plasma steroid profiles that may offer a supplementary single-test alternative for screening purposes.
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http://dx.doi.org/10.1530/ERC-20-0102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354003PMC
July 2020

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors.

Cancers (Basel) 2020 Feb 22;12(2). Epub 2020 Feb 22.

Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.

Phosphodiesterases (PDEs) form a superfamily of enzymes that catalyze the hydrolysis of cyclic nucleotides adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) to their inactive 5' monophosphates. cAMP plays a critical role as a second messenger in endocrine tissues, and activation of cAMP signaling has been reported in endocrine tumors. Germline variants in PDEs have been associated with benign cortisol-secreting adrenocortical adenomas and testicular germ cell cancer but not adrenocortical carcinoma. We performed whole genome sequencing (WGS) and whole exome sequencing (WES) of paired blood and tumor samples from 37 pediatric adrenocortical tumors (ACTs). Germline inactivating variants in PDEs were observed in 9 of 37 (24%) patients. Tumor DNA analysis revealed loss of heterozygosity, with maintenance of the mutated allele in all cases. Our results suggest that germline variants in PDEs and other regulators of the cAMP-signaling pathway may contribute to pediatric adrenocortical tumorigenesis, perhaps by cooperating with germline hypomorphic mutant alleles and uniparental disomy of chromosome 11p15 (Beckwith-Wiedemann syndrome).
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http://dx.doi.org/10.3390/cancers12020506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072638PMC
February 2020

Update of Genetic and Molecular Causes of Adrenocortical Hyperplasias Causing Cushing Syndrome.

Horm Metab Res 2020 Aug 25;52(8):598-606. Epub 2020 Feb 25.

Cochin Institute, Inserm U1016, CNRS UMR8104, Paris, France.

Bilateral hyperplasias of the adrenal cortex are rare causes of chronic endogenous hypercortisolemia also called Cushing syndrome. These hyperplasias have been classified in two categories based on the adrenal nodule size: the micronodular types include Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and isolated Micronodular Adrenal Disease (iMAD) and the macronodular also named Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH). This review discusses the genetic and molecular causes of these different forms of hyperplasia that involve mutations and dysregulation of various regulators of the cAMP/protein kinase A (PKA) pathway. PKA signaling is the main pathway controlling cortisol secretion in adrenocortical cells under ACTH stimulation. Although mutations of the regulatory subunit R1α of PKA (PRKAR1A) is the main cause of familial and sporadic PPNAD, inactivation of two cAMP-binding phosphodiesterases (PDE11A and PDE8B) are associated with iMAD even if they are also found in PPNAD and PBMAH cases. Interestingly, PBMAH that is observed in multiple familial syndrome such as APC, menin, fumarate hydratase genes, has initially been associated with the aberrant expression of G-protein coupled receptors (GPCR) leading to an activation of cAMP/PKA pathway. However, more recently, the discovery of germline mutations in Armadillo repeat containing protein 5 (ARMC5) gene in 25-50% of PBMAH patients highlights its importance in the development of PBMAH. The potential relationship between mutations and aberrant GPCR expression is discussed as well as the potential other causes of PBMAH.
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http://dx.doi.org/10.1055/a-1061-7349DOI Listing
August 2020

Cullin 3 targets the tumor suppressor gene ARMC5 for ubiquitination and degradation.

Endocr Relat Cancer 2020 04;27(4):221-230

Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France.

ARMC5 (Armadillo repeat containing 5 gene) was identified as a new tumor suppressor gene responsible for hereditary adrenocortical tumors and meningiomas. ARMC5 is ubiquitously expressed and encodes a protein which contains a N-terminal Armadillo repeat domain and a C-terminal BTB (Bric-a-Brac, Tramtrack and Broad-complex) domain, both docking platforms for numerous proteins. At present, expression regulation and mechanisms of action of ARMC5 are almost unknown. In this study, we showed that ARMC5 interacts with CUL3 requiring its BTB domain. This interaction leads to ARMC5 ubiquitination and further degradation by the proteasome. ARMC5 alters cell cycle (G1/S phases and cyclin E accumulation) and this effect is blocked by CUL3. Moreover, missense mutants in the BTB domain of ARMC5, identified in patients with multiple adrenocortical tumors, are neither able to interact and be degraded by CUL3/proteasome nor alter cell cycle. These data show a new mechanism of regulation of the ARMC5 protein and open new perspectives in the understanding of its tumor suppressor activity.
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http://dx.doi.org/10.1530/ERC-19-0502DOI Listing
April 2020

Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up.

J Clin Endocrinol Metab 2020 03;105(3)

INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris.

Introduction: Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far.

Methods: This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation.

Results: The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype.

Conclusion: This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.
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http://dx.doi.org/10.1210/clinem/dgaa002DOI Listing
March 2020

Pangenomic Classification of Pituitary Neuroendocrine Tumors.

Cancer Cell 2020 01 26;37(1):123-134.e5. Epub 2019 Dec 26.

INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes-Université de Paris, 75006 Paris, France; Department of Endocrinology, Center for Rare Adrenal Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France. Electronic address:

Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.
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http://dx.doi.org/10.1016/j.ccell.2019.11.002DOI Listing
January 2020

Surgical management of pancreatic neuroendocrine tumors: an introduction.

Expert Rev Anticancer Ther 2019 12 17;19(12):1089-1100. Epub 2019 Dec 17.

Department of Digestive, Hepato-biliary and Endocrine Surgery, Cochin Hospital, APHP, Paris, France.

: Neuroendocrine tumors of the pancreas (pNETs) represent only 1% to 2% of all pancreatic neoplasms. These tumors can be classified as functional or nonfunctional tumors; as sporadic or from a genetic origin; as neuroendocrine neoplasms or carcinoma. Over the last decade, diagnosis of pNETs has increased significantly mainly due to the widespread use of cross-sectional imaging. Those tumors are usually associated with a good prognosis. Surgery, the only curative option for those patients, should always be discussed, ideally in a multidisciplinary team setting.: We discuss ), the preoperative management of pNETs and the importance of accurate diagnosis, localization, grading and staging with computed tomography, magnetic resonance imaging, endoscopic ultrasound, and nuclear medicine imaging; ), surgical indications and ), the surgical approach (standard pancreatectomy pancreatic-sparing surgery).: The treatment option of all patients presenting with pNETs should be discussed in a multidisciplinary team setting with surgeon's experienced in both pancreatic surgery and neuroendocrine tumor management. A complete preoperative imaging assessment - morphological and functional - must be performed. Surgery is usually recommended for functional pNETs, nonfunctional pNETs >2 cm (nf-pNETs) or for symptomatic nf-pNETs.
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http://dx.doi.org/10.1080/14737140.2019.1703677DOI Listing
December 2019

Transcriptome Analysis of lncRNAs in Pheochromocytomas and Paragangliomas.

J Clin Endocrinol Metab 2020 03;105(3)

Paris University, PARCC, INSERM, Equipe labellisée par la Ligue contre le cancer, Paris, France.

Context: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors explained by germline or somatic mutations in about 70% of cases. Patients with SDHB mutations are at high risk of developing metastatic disease, yet no reliable tumor biomarkers are available to predict tumor aggressiveness.

Objective: We aimed at identifying long noncoding RNAs (lncRNAs) specific for PPGL molecular groups and metastatic progression.

Design And Methods: To analyze the expression of lncRNAs, we used a mining approach of transcriptome data from a well-characterized series of 187 tumor tissues. Clustering consensus analysis was performed to determine a lncRNA-based classification, and informative transcripts were validated in an independent series of 51 PPGLs. The expression of metastasis-related lncRNAs was confirmed by RT-qPCR. Receiver operating characteristic (ROC) curve analysis was used to estimate the predictive accuracy of potential markers.

Main Outcome Measure: Univariate/multivariate and metastasis-free survival (MFS) analyses were carried out for the assessment of risk factors and clinical outcomes.

Results: Four lncRNA-based subtypes strongly correlated with mRNA expression clusters (chi-square P-values from 1.38 × 10-32 to 1.07 × 10-67). We identified one putative lncRNA (GenBank: BC063866) that accurately discriminates metastatic from benign tumors in patients with SDHx mutations (area under the curve 0.95; P = 4.59 × 10-05). Moreover, this transcript appeared as an independent risk factor associated with poor clinical outcome of SDHx carriers (log-rank test P = 2.29 × 10-05).

Conclusion: Our findings extend the spectrum of transcriptional dysregulations in PPGL to lncRNAs and provide a novel biomarker that could be useful to identify potentially metastatic tumors in patients carrying SDHx mutations.
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http://dx.doi.org/10.1210/clinem/dgz168DOI Listing
March 2020