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Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany
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Department of Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Digestive and Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Department of Digestive and Endocrine Surgery, 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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Department of Endocrinology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Institute of Metabolism and System Research, University of Birmingham, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Department of Endocrinology, 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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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.
Inserm U1016-CNRS UMR8104, Paris, France
Hormonology Department, Cochin Hospital, Paris, France
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Inserm U1016-CNRS UMR8104, Paris, France
Radiology Department, Cochin Hospital, Paris, France
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Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
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Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
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Hormonology Department, Cochin Hospital, Paris, France
INSERM, Physiopathologie et Pharmacotoxicologie Placentaire Humaine : Microbiote Pré & Post natal, Paris, France
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Inserm U1016-CNRS UMR8104, Paris, France
Diabetology Department, Cochin Hospital, Paris, France
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Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
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Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
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Hormonology Department, Cochin Hospital, Paris, France
INSERM, Physiopathologie et Pharmacotoxicologie Placentaire Humaine : Microbiote Pré & Post natal, Paris, France
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UR 7537 BioSTM, Paris, France
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Inserm U1016-CNRS UMR8104, Paris, France
Reference Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Paris, France
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Objective
Large response of steroid precursors, including 17-hydroxyprogesterone, to adrenocorticotropic hormone (ACTH) has been described in adrenocortical tumors, suggesting the existence of intra-tumoral enzymatic deficiencies. This study aimed to compare steroidogenesis enzymes activity in unilateral and bilateral benign tumors using serum steroid profiling in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) in the basal state and after ACTH 1-24 stimulation.
Design and methods
A serum profile of seven consecutive adrenal steroids was determined in LC-MS/MS in the basal state (T0) and after ACTH 1-24 stimulation (T60) in 35 patients with bilateral adrenocortical tumors (BL), 38 patients with unilateral tumors (UL) and 37 control subjects (CT). Response amplitude of each individual steroid was evaluated by T60/T0 ratio, whereas enzymatic activity was assessed by the downstream/upstream steroid ratio. Adrenal volume was quantified by a semi-automatic segmentation method.
Results
For the seven steroids assayed, the amplitude of response to ACTH was higher in BL than in UL and in CT. The difference between BL and UL persisted even after matching patients on adrenal volume. On glucocorticoids pathway, enzymatic activity of CYP11B1 was significantly decreased in BL (78.3 (43.1-199.4)) in comparison to both UL (122.7 (13.8-228.4), P = 0.0002) and CT (186.8 (42.1-1236.3), P < 0.0001). On mineralocorticoids and androgens pathways, the enzymatic activity of CYP11B2 and CYP17A1-17,20 lyase was also lower in BL than UL and CT.
Conclusions
Decreased activity of distal steroidogenesis enzymes CYP11B1, CYP11B2 and CYP17A1-17,20 lyase, responsible for an explosive response to ACTH of upstream precursors in bilateral tumors, limits the synthesis of bioactive steroids, in particular cortisol, despite the increase in adrenal mass.
Significance statement
Activity of distal steroidogenesis enzymes (CYP11B1, CYP11B2 and CYP17A1 on glucocorticoids, mineralocorticoids and androgens pathways, respectively) is decreased in adrenocortical benign tumors. This decrease is more pronounced in bilateral lesions and seems to depend more on the nature of the lesion than on the increase in adrenal volume. It is responsible for the explosive response to ACTH of steroid precursors located upstream of these enzymes. It probably allows bioactive steroids, particularly cortisol, to stay in the normal range for a long time despite the increase in adrenal mass.
Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, INSERM, UMRS1138, Paris, France
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Université Paris-Saclay, Inserm U1185, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et Diabète de l’Enfant, Centre de Référence des Maladies Rares du Calcium et du Phosphore et Filière de Santé Maladies Rares OSCAR, Hôpital Bicêtre Paris Saclay, Le Kremlin-Bicêtre, France
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Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Assistance Publique-Hôpitaux de Paris, Institut Necker-Enfants Malades, INSERM U1151 – CNRS UMR 8253, Paris, France
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Association Francophone de Chirurgie Endocrinienne (AFCE), France
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Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Biochimie et Génétique Moléculaires, Paris, France
INSERM, U1169, Université Paris Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France
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INSERM, U1418, CIC-EC, Hôpital Européen Georges Pompidou, Paris, France
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Centre de Référence des Maladies Rares du Calcium et du Phosphore Filière de Santé Maladies Rares OSCAR, Paris, France
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, INSERM, UMRS1138, Paris, France
CNRS, ERL8228, Paris, France
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Context
Recent guidelines have provided recommendations for the care of patients with chronic hypoparathyroidism. Very little is known about actual physicians’ practices or their adherence to such guidelines.
Objective
To describe the physicians’ practice patterns and their compliance with international guidelines.
Design
The cohort studies included were Épi-Hypo (118 physicians and 107 patients, from September 2016 to December 2019) and ePatients (110 patients, November 2019).
Methods
Internet-based cohorts involving all settings at a nationwide level (France). Participants were (i) physicians treating patients with chronic hypoparathyroidism and patients with chronic hypoparathyroidism either participating in the (ii) Épi-Hypo study (Épi-Hypo 2019 patients), or (iii) Hypoparathyroidism France, the national representative association (ePatients).
Results
The physicians’ specialties were mainly endocrinology (61%), nephrology (28%), family medicine (2.5%), pediatrics (2.5%), rheumatology (2%), or miscellaneous (4%) and 45% were practicing in public universities. The median number of pharmaceutical drug classes prescribed was three per patient. The combination of active vitamin D and calcium salt was given to 59 and 58% of ePatients and Épi-Hypo 2019 patients, respectively. Eighty-five percent of ePatients and 87% of physicians reported monitoring plasma calcium concentrations at a steady state at least twice a year. In 32 and 26% of cases, respectively, ePatients and physicians reported being fully in accordance with international guidelines that recommend targeting symptoms, plasma calcium and phosphate values, and urine calcium excretion.
Conclusions
The care of patients with chronic hypoparathyroidism involves physicians with very different practices, so guidelines should include and target other specialists as well as endocrinologists. Full adherence to the guidelines is low in France.
