Chiloiro Sabrina, Costanza Flavia, Scaglione Giovanni Luca, Russo Filippo, Nardelli Carmela, Giampietro Antonella, Mattogno Pier Paolo, Lauretti Liverana, Rindi Guido, De Marinis Laura, Gessi Marco, Bianchi Antonio, Doglietto Francesco, Capoluongo Ettore Domenico, Pontecorvi Alfredo
Department of Medical and Surgical Translational Sciences, Catholic University of the Sacred Heart, 00168, Rome, Italy.
Pituitary Unit, Department of Endocrinology, Diabetology and Internal Medicine, Fondazione Policlinico Universitario Agostino Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00168, Rome, Italy.
Pituitary. 2025 May 26;28(3):63. doi: 10.1007/s11102-025-01537-w.
The tumor microenvironment (TME) may provide a useful framework for understanding the heterogeneous behavior of growth hormone (GH) secreting pituitary adenomas. Although the interest in TME in somatotropinomas has increased exponentially over the last few decades, there is limited elucidation of its mechanisms, particularly in relation to genes expression involved in its regulation.
A retrospective, observational, single-center study was conducted on 85 subjects: 46 patients diagnosed with acromegaly and 39 controls. After DNA extraction, clinical exome sequencing was performed and genomic alterations were detected, classified, and filtered using a dedicated bioinformatics pipeline.
5759 unique genetic variants were found in patients with acromegaly. 33 patients (72%) showed the presence of at least one pathogenic variant in at least one of the following genes: FANCD2, SPTA1, TYRO3, and ZNF335. The enrichment pathway analysis of mutated genes was performed and showed that these genes were included in the same genetic pathway called "regulation of lymphocyte activation" (GO:0051249). Inflammatory infiltrate was analyzed in histological samples in 26 patients. A significantly higher number of CD68 + macrophages (P-value = 0.008), a lower number of CD8 + T lymphocytes (P-value = 0.037) and a higher CD68 + macrophages/ CD8 + T-lymphocytes ratio (P-value = 0.004) were observed in patients with pathogenic variants of genes of "regulation of lymphocyte activation" pathway.
This study provides new insights into the genetic basis of the TME in somatotropinomas and suggests that genetics may influence immune cells infiltration in acromegaly.
肿瘤微环境（TME）可能为理解分泌生长激素（GH）的垂体腺瘤的异质性行为提供一个有用的框架。尽管在过去几十年中，对生长激素瘤中TME的关注呈指数级增长，但其机制的阐明仍然有限，特别是与参与其调节的基因表达相关的机制。
对85名受试者进行了一项回顾性、观察性、单中心研究：46名被诊断为肢端肥大症的患者和39名对照。在提取DNA后，进行临床外显子组测序，并使用专用的生物信息学管道检测、分类和筛选基因组改变。
在肢端肥大症患者中发现了5759个独特的基因变异。33名患者（72%）在以下至少一个基因中显示存在至少一个致病变异：FANCD2、SPTA1、TYRO3和ZNF335。对突变基因进行了富集途径分析，结果表明这些基因包含在一个名为“淋巴细胞活化调节”（GO:0051249）的相同遗传途径中。对26名患者的组织学样本进行了炎症浸润分析。在“淋巴细胞活化调节”途径基因具有致病变异的患者中，观察到CD68 +巨噬细胞数量显著增加（P值 = 0.008），CD8 + T淋巴细胞数量减少（P值 = 0.037），以及CD68 +巨噬细胞/CD8 + T淋巴细胞比值升高（P值 = 0.004）。
本研究为生长激素瘤中TME的遗传基础提供了新的见解，并表明遗传学可能影响肢端肥大症中免疫细胞的浸润。
