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KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas.
Chasseloup, Fanny; Regazzo, Daniela; Tosca, Lucie; Proust, Alexis; Kuhn, Emmanuelle; Hage, Mirella; Jublanc, Christel; Mokhtari, Karima; Dalle Nogare, Mattia; Avallone, Serena; Ceccato, Filippo; Tachdjian, Gerard; Salenave, Sylvie; Young, Jacques; Gaillard, Stephan; Parker, Fabrice; Boch, Anne-Laure; Chanson, Philippe; Bouligand, Jerome; Occhi, Gianluca; Kamenický, Peter.
Affiliation
  • Chasseloup F; Inserm, Université Paris-Saclay, Physiologie et Physiopathologie Endocriniennes, AP-HP, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94270 Le Kremlin-Bicêtre, France.
  • Regazzo D; Department of Medicine, Endocrinology Unit, University of Padova, 35128 Padova, Italy.
  • Tosca L; AP-HP, Hôpital Antoine Béclère, Université Paris-Saclay, Service d'Histologie, Embryologie et Cytogénomique, 92140 Clamart, France.
  • Proust A; AP-HP, Hôpital Bicêtre, Service de Génétique Moléculaire et d'Hormonologie, 94270 Le Kremlin Bicêtre, France.
  • Kuhn E; AP-HP, Hôpital Pitié-Salpêtrière, Service de Neurochirurgie, 75013 Paris, France.
  • Hage M; AP-HP, Hôpital Pitié-Salpêtrière, Unité Hypophyse, 75013 Paris, France.
  • Jublanc C; Inserm, Université Paris-Saclay, Physiologie et Physiopathologie Endocriniennes, AP-HP, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94270 Le Kremlin-Bicêtre, France.
  • Mokhtari K; AP-HP, Hôpital Pitié-Salpêtrière, Unité Hypophyse, 75013 Paris, France.
  • Dalle Nogare M; AP-HP, Institut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neuropathologie, Onconeurothèque, 75013 Paris, France.
  • Avallone S; Department of Biology, University of Padova, 35128 Padova, Italy.
  • Ceccato F; Department of Medicine, Endocrinology Unit, University of Padova, 35128 Padova, Italy.
  • Tachdjian G; Department of Medicine, Endocrinology Unit, University of Padova, 35128 Padova, Italy.
  • Salenave S; Endocrine Disease Unit, University-Hospital of Padova, 35128 Padova, Italy.
  • Young J; AP-HP, Hôpital Antoine Béclère, Université Paris-Saclay, Service d'Histologie, Embryologie et Cytogénomique, 92140 Clamart, France.
  • Gaillard S; Inserm, Université Paris-Saclay, Physiologie et Physiopathologie Endocriniennes, AP-HP, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94270 Le Kremlin-Bicêtre, France.
  • Parker F; Inserm, Université Paris-Saclay, Physiologie et Physiopathologie Endocriniennes, AP-HP, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94270 Le Kremlin-Bicêtre, France.
  • Boch AL; AP-HP, Hôpital Pitié-Salpêtrière, Service de Neurochirurgie, 75013 Paris, France.
  • Chanson P; AP-HP, Hôpital Bicêtre, Service de Neurochirurgie, 94270 Le Kremlin-Bicêtre, France.
  • Bouligand J; AP-HP, Hôpital Pitié-Salpêtrière, Service de Neurochirurgie, 75013 Paris, France.
  • Occhi G; Inserm, Université Paris-Saclay, Physiologie et Physiopathologie Endocriniennes, AP-HP, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94270 Le Kremlin-Bicêtre, France.
  • Kamenický P; AP-HP, Hôpital Antoine Béclère, Université Paris-Saclay, Service d'Histologie, Embryologie et Cytogénomique, 92140 Clamart, France.
Eur J Endocrinol ; 190(2): 173-181, 2024 Feb 01.
Article in En | MEDLINE | ID: mdl-38330165
ABSTRACT
IMPORTANCE A paradoxical increase of growth hormone (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 and somatic loss of heterozygosity of lysine demethylase 1A (KDM1A) in patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. The ectopic expression of GIPR in both adrenal and pituitary lesions suggests a common molecular mechanism.

OBJECTIVE:

We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas. SETTINGS We conducted a cohort study at university hospitals in France and in Italy. We collected pituitary adenoma specimens from acromegalic patients who had undergone pituitary surgery. We performed targeted exome sequencing (gene panel analysis) and array-comparative genomic hybridization on somatic DNA derived from adenomas and performed droplet digital PCR on adenoma samples to quantify KDM1A and GIPR expressions.

RESULTS:

One hundred and forty-six patients with sporadic acromegaly were studied; 72.6% presented unsuppressed classical GH response, whereas 27.4% displayed a paradoxical rise in GH after oral glucose load. We did not identify any pathogenic variant in the KDM1A gene in the adenomas of these patients. However, we identified a recurrent 1p deletion encompassing the KDM1A locus in 29 adenomas and observed a higher prevalence of paradoxical GH rise (P = .0166), lower KDM1A expression (4.47 ± 2.49 vs 8.56 ± 5.62, P < .0001), and higher GIPR expression (1.09 ± 0.92 vs 0.43 ± 0.51, P = .0012) in adenomas from patients with KDM1A haploinsufficiency compared with those with 2 KDM1A copies. CONCLUSIONS AND RELEVANCE Unlike in GIP-dependent primary bilateral macronodular adrenal hyperplasia, KDM1A genetic variations are not the cause of GIPR expression in somatotroph pituitary adenomas. Recurrent KDM1A haploinsufficiency, more frequently observed in GIPR-expressing adenomas, could be responsible for decreased KDM1A function resulting in transcriptional derepression on the GIPR locus.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pituitary Neoplasms / Acromegaly / Adenoma / Human Growth Hormone / Growth Hormone-Secreting Pituitary Adenoma / Somatotrophs Type of study: Observational_studies / Risk_factors_studies Limits: Humans Language: En Journal: Eur J Endocrinol Journal subject: ENDOCRINOLOGIA Year: 2024 Document type: Article Affiliation country: France Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pituitary Neoplasms / Acromegaly / Adenoma / Human Growth Hormone / Growth Hormone-Secreting Pituitary Adenoma / Somatotrophs Type of study: Observational_studies / Risk_factors_studies Limits: Humans Language: En Journal: Eur J Endocrinol Journal subject: ENDOCRINOLOGIA Year: 2024 Document type: Article Affiliation country: France Country of publication: United kingdom