Lysine demethylase KDM1A and ectopic expression of GIP-receptor in somatotroph adenomas

F. Chasseloup*^a (Dr), L. Tosca^b (Dr), A. Proust^c (Mr), E. Kuhn^d (Dr), D. Regazzo^e (Dr), M. Hage^f (Dr), C. Jublanc^g (Dr), S. Salenave^h (Dr), S. Gaillard^d (Dr), F. Parkerⁱ (Prof), AL. Boch^d (Prof), J. Bouligand^j (Dr), P. Chanson^h (Prof), G. Occhi^e (Prof), P. Kamenicky^h (Prof)

^a Université Paris Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin Bicêtre Cedex, FRANCE ; ^b Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital Antoine Béclère, Service d'Histologie, Embryologie et Cytogénétique, Clamart, FRANCE ; ^c Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Génétique Moléculaire et d’Hormonologie, Le Kremlin Bicêtre, FRANCE ; ^d Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Service de Neurochirurgie, Paris, FRANCE ; ^e Endocrinology Unit, Department of Medicine, DIMED, Hospital-University of Padova, Padua, ITALY ; ^f Université Paris Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin Bicêtre, FRANCE ; ^g Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Service d'Endocrinologie, Paris, FRANCE ; ^h Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Le Kremlin Bicêtre, FRANCE ; ⁱ Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Neurochirurgie, Le Kremlin Bicêtre, FRANCE ; ^j Université Paris Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service de Génétique Moléculaire et d’Hormonologie, Le Kremlin Bicêtre, FRANCE

* fanny.chasseloup@u-psud.fr

Introduction: Paradoxical increase of GH after oral glucose load has been described in around 10-30% of patients with acromegaly and is related to the ectopic pituitary expression of GIP-receptor. We identified that Primary bilateral macronodular adrenal hyperplasia (PBMAH) with (GIP)-dependent Cushing’s syndrome and ectopic adrenal expression of GIP receptor (GIPR) is caused by germline pathogenic variant and loss of heterozygosity of KDM1A. The ectopic expression of GIPR in both tissues suggests a common molecular mechanism, therefore, we aimed to identify the implication of KDM1A in the ectopic GIPR expression in somatotropinomas.

Patients/Methods: We collected somatotropinoma specimens from acromegalic patients followed at two expert endocrine centers in France. Somatic DNA was studied by targeted exome NGS and arrayCGH. GIPR expression was quantified in the tumors using RT-qPCR. Samples collected from an Italian expert center will be analyzed.

Results: Somatotropinoma samples from 72 patients with acromegaly were studied. 50 more specimens are being collected. GIP-receptor expression in the 18 (25%) somatotropinomas from patients with a paradoxical rise of GH was more elevated than in the 54 (75%) specimens from patients without paradoxical rise of GH (p<0.0001). None of the somatotropinomas harbored KDM1A pathogenic variants, but 21 patients displayed a recurrent loss of the KDM1A locus. These specimens hemizygous for KDM1A displayed an increased GIPR expression (p<0.0001).

Discussion: We did not identify somatic KDM1A mutations in somatotropinomas expressing GIPR ectopically, however, the recurrent chromosome loss of the locus of KDM1A in some somatotropinomas suggests that KDM1A haploinsufficiency may contribute to GIPR expression in those tumors by partial derepressing transcription of targeted genes including GIPR.

The author has declared no conflict of interest.