ECE2023 Oral Communications Oral Communications 7: Pituitary and Neuroendocrinology 2 (6 abstracts)
Lysine demethylase KDM1A and ectopic expression of GIP-receptor in somatotropinomas of patients with paradoxical response to oral glucose
Fanny Chasseloup 1,2 , Lucie Tosca 3 , Daniela Regazzo 4 , Alexis Proust 5 , Mirella Hage 1 , Emmanuelle Kuhn 6 , Christel Jublanc 7 , Karima Mokhtari 8 , Sylvie Salenave 1,2 , Stephan Gaillard 6 , Fabrice Parker 9 , Anne-Laure Boch 6 , Gerard Tachdjian 3 , Philippe Chanson 1,2 , Jerome Bouligand 5 , Gianluca Occhi 4,10 & Peter Kamenicky 1,2
1Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes; 2Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et Maladies de la Reproduction, Le Kremlin Bicêtre, France; 3Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital Antoine Béclère, Service d’Histologie, Embryologie et Cytogénétique, Clamart, France; 4Endocrinology Unit, Department of Medicine, Hospital-University of Padua, Padua, Italy; 5Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Génétique Moléculaire et d’Hormonologie, Le Kremlin Bicêtre, Le Kremlin Bicêtre, France; 6Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Service de Neurochirurgie, Paris, France; 7Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Service d’Endocrinologie, Paris, France; 8Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Service d’Anatomopathologie, Paris, France; 9Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Neurochirurgie, Le Kremlin Bicêtre, France; 10University of Padova, Department of Biology, Padova, Italy
Introduction: Paradoxical increase of GH following oral glucose load has been described in ~30% of patients with acromegaly and has been related to the ectopic expression of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in somatotropinomas. Recently, we identified germline pathogenic variants of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome. Patients also displayed a deletion of chromosome 1p, including the KDM1A locus in their adrenal tissues, resulting in complete loss of KDM1A expression. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism. The aim of our study was to search for genetic abnormalities of KDM1A in somatotroph pituitary adenomas.
Methods: We collected somatotropinoma specimens from acromegalic patients followed in two tertiary endocrine centers in France and one in Italy. Somatic DNA was studied by targeted exome NGS and array-CGH. GIPR and KDM1A expression was quantified in the tumors using digital droplet PCR.
Results: We included 186 patients: 108 patients (70.6 %) had a classic pathological GH response after oral glucose load, whereas 45 patients (29.4%) displayed a paradoxical rise of GH concentrations. Patients with a paradoxical response displayed higher IGF-1 levels (360 ± 111.8% above ULN vs 309.8 ± 107.3 %, P=0.0130) and less invasive and smaller tumors (14.5 ± 5.58 mm vs 18.5 ± 8.73 m, P=0.0066). We did not identify any KDM1A pathogenic variants amongst the 146 somatotropinomas analyzed by targeted-NGS. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 26 tumors. This 1p deletion was more frequently, but not exclusively, found in patients with paradoxical GH response compared to those with classic GH response. This somatic deletion of one KMD1A allele was associated with a lower KDM1A expression (P=4.5e-5) and a higher GIPR expression (P=0.0005).
Discussion: Unlike in GIP-dependent PBMAH, we did not identify KDM1A genetic variants in a large cohort of acromegalic patients, independently of their GH response pattern to oral glucose loading. We identified recurrent 1p deletion in some tumors and pituitary adenomas with a loss of one KDM1A copy due to chromosome 1p deletion harbored higher levels of GIPR transcripts than adenomas diploid for the KDM1A locus. If KDM1A haploinsufficiency leads to partial transcriptional derepression at the GIPR locus and a paradoxical rise of GH after glucose load warrants further investigations.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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