Inserm U1185, Le Kremlin Bicêtre, France.
Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
JCI Insight. 2017 Sep 21;2(18). doi: 10.1172/jci.insight.92184.
GIP-dependent Cushing's syndrome is caused by ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in cortisol-producing adrenal adenomas or in bilateral macronodular adrenal hyperplasias. Molecular mechanisms leading to ectopic GIPR expression in adrenal tissue are not known. Here we performed molecular analyses on adrenocortical adenomas and bilateral macronodular adrenal hyperplasias obtained from 14 patients with GIP-dependent adrenal Cushing's syndrome and one patient with GIP-dependent aldosteronism. GIPR expression in all adenoma and hyperplasia samples occurred through transcriptional activation of a single allele of the GIPR gene. While no abnormality was detected in proximal GIPR promoter methylation, we identified somatic duplications in chromosome region 19q13.32 containing the GIPR locus in the adrenocortical lesions derived from 3 patients. In 2 adenoma samples, the duplicated 19q13.32 region was rearranged with other chromosome regions, whereas a single tissue sample with hyperplasia had a 19q duplication only. We demonstrated that juxtaposition with cis-acting regulatory sequences such as glucocorticoid response elements in the newly identified genomic environment drives abnormal expression of the translocated GIPR allele in adenoma cells. Altogether, our results provide insight into the molecular pathogenesis of GIP-dependent Cushing's syndrome, occurring through monoallelic transcriptional activation of GIPR driven in some adrenal lesions by structural variations.
GIP 依赖性库欣综合征是由葡萄糖依赖性胰岛素释放多肽受体（GIPR）在产生皮质醇的肾上腺腺瘤或双侧大结节性肾上腺增生中的异位表达引起的。导致肾上腺组织中异位 GIPR 表达的分子机制尚不清楚。在这里，我们对来自 14 名 GIP 依赖性肾上腺库欣综合征患者和 1 名 GIP 依赖性醛固酮增多症患者的肾上腺腺瘤和双侧大结节性肾上腺增生进行了分子分析。所有腺瘤和增生样本中的 GIPR 表达都是通过 GIPR 基因的单个等位基因的转录激活发生的。虽然近端 GIPR 启动子甲基化没有异常，但我们在 3 名患者的肾上腺皮质病变中发现了包含 GIPR 基因座的 19q13.32 染色体区域的体细胞重复。在 2 个腺瘤样本中，重复的 19q13.32 区域与其他染色体区域重排，而仅有一个组织增生样本存在 19q 重复。我们证明，在新鉴定的基因组环境中与顺式作用调节序列（如糖皮质激素反应元件）并列，驱动了腺瘤细胞中转录异位 GIPR 等位基因的异常表达。总之，我们的研究结果为 GIP 依赖性库欣综合征的分子发病机制提供了新的见解，其发生是由于一些肾上腺病变中 GIPR 的单等位基因转录激活，而这种激活是由结构变异驱动的。
