Aix Marseille Univ, INSERM, APHM, MMG, UMR1251, Marmara Institute, La Conception, Hospital Laboratory of Molecular Biology, 13385 Marseille, France.
Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, 94270 Le Kremlin-Bicêtre, Île-de-France, France.
Int J Mol Sci. 2021 Jul 15;22(14):7570. doi: 10.3390/ijms22147570.
Forty percent of somatotroph tumors harbor recurrent activating mutations, historically called the oncogene. In -negative somatotroph tumors, expression itself is highly variable; those with overexpression most resemble phenotypically those carrying the oncogene. is monoallelically expressed in the normal pituitary due to methylation-based imprinting. We hypothesize that changes in imprinting of -negative tumors affect expression levels and tumorigenesis. We characterized the locus in two independent somatotroph tumor cohorts: one of 23 tumors previously published (PMID: 31883967) and classified by pan-genomic analysis, and a second with 82 tumors. Multi-omics analysis of the first cohort identified a significant difference between -negative and -positive tumors in the methylation index at the known differentially methylated region (DMR) of the A/B transcript promoter, which was confirmed in the larger series of 82 tumors. allelic expression was analyzed using a polymorphic Fok1 cleavage site in 32 heterozygous -negative tumors. expression was significantly reduced in the 14 tumors with relaxed imprinting and biallelic expression, compared to 18 tumors with monoallelic expression. Tumors with relaxed imprinting showed significantly lower and expression levels. Altered A/B DMR methylation was found exclusively in -negative somatotroph tumors. 43% of -negative tumors showed imprinting relaxation, which correlated with lower , and expression, indicating lower sensitivity to somatostatin analogues and potentially aggressive behavior.
40%的生长激素细胞瘤含有复发性激活突变，历史上称为致癌基因。在无 - 阴性生长激素细胞瘤中，表达本身高度可变；那些过度表达的最类似于携带致癌基因的那些表型。由于基于甲基化的印迹，在正常垂体中， 是单等位基因表达的。我们假设 - 阴性肿瘤印迹的变化会影响 表达水平和肿瘤发生。我们在两个独立的生长激素细胞瘤队列中描述了 基因座：一个是以前发表的 23 个肿瘤（PMID：31883967），并通过泛基因组分析进行了分类，另一个是 82 个肿瘤。第一组的多组学分析在已知的 A/B 转录启动子差异甲基化区域（DMR）的甲基化指数上，在 - 阴性和 - 阳性肿瘤之间发现了显著差异，在 82 个较大系列的肿瘤中得到了证实。在 32 个杂合性 - 阴性肿瘤中使用多态性 Fok1 切割位点分析了 等位基因表达。与 18 个单等位基因表达的肿瘤相比，在 14 个放松印迹和双等位基因表达的肿瘤中， 表达显著降低。放松 印迹的肿瘤显示出明显较低的 和 表达水平。仅在 - 阴性生长激素细胞瘤中发现了改变的 A/B DMR 甲基化。43%的 - 阴性肿瘤表现出印迹松弛，这与较低的 、 和 表达相关，表明对生长抑素类似物的敏感性降低，可能具有侵袭性行为。
