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.
Department of Medicine, Endocrinology Unit, University of Padova, 35128 Padova, Italy.
Eur J Endocrinol. 2024 Feb 1;190(2):173-181. doi: 10.1093/ejendo/lvae013.
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.
We aimed to analyze KDM1A gene sequence and KDM1A and GIPR expressions in somatotroph pituitary adenomas.
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.
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.
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.
在约 30%的肢端肥大症患者中，口服葡萄糖负荷后生长激素 (GH) 呈反常性增加，这与生长抑素瘤中葡萄糖依赖性胰岛素释放肽 (GIP) 受体 (GIPR) 的异位表达有关。最近，我们在伴有库欣综合征的 GIP 依赖性双侧大结节性肾上腺增生的患者中发现了赖氨酸去甲基酶 1A (KDM1A) 的种系致病性变异和体细胞杂合性丢失。GIPR 在肾上腺和垂体病变中的异位表达提示存在共同的分子机制。
我们旨在分析 GH 依赖性垂体生长激素腺瘤中 KDM1A 基因序列和 KDM1A 和 GIPR 的表达。
我们在法国和意大利的大学医院进行了一项队列研究。我们收集了接受垂体手术的肢端肥大症患者的垂体腺瘤标本。我们对来源于腺瘤的体细胞 DNA 进行了靶向外显子组测序（基因panel 分析）和 array-comparative genomic hybridization，并对腺瘤样本进行了数字 PCR 定量，以检测 KDM1A 和 GIPR 的表达。
研究了 146 例散发性肢端肥大症患者；72.6%表现为未被抑制的经典 GH 反应，而 27.4%在口服葡萄糖负荷后 GH 呈反常性升高。我们未在这些患者的腺瘤中发现 KDM1A 基因的致病性变异。然而，我们在 29 例腺瘤中发现了一个包含 KDM1A 基因座的 1p 缺失，并且观察到更多的 GH 反常性升高（P=.0166），KDM1A 表达降低（4.47±2.49 与 8.56±5.62，P＜.0001），GIPR 表达升高（1.09±0.92 与 0.43±0.51，P=.0012）在 KDM1A 杂合不足的腺瘤中，与 KDM1A 有 2 个拷贝的患者相比。
与 GIP 依赖性双侧大结节性肾上腺增生不同，KDM1A 基因变异不是 GH 依赖性垂体生长激素腺瘤中 GIPR 表达的原因。在 GIPR 表达的腺瘤中更频繁观察到的复发性 KDM1A 杂合不足，可能导致 KDM1A 功能降低，从而导致 GIPR 基因座的转录去抑制。
