Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy.
Unit of Endocrinology, University Hospital 'G. Martino', Messina, Italy.
J Endocrinol Invest. 2019 Jul;42(7):825-831. doi: 10.1007/s40618-018-0988-8. Epub 2018 Nov 28.
Biomarkers of clinical and therapeutic outcome in acromegaly are needed. Polymorphisms or epigenetic changes of detoxification genes, such as those coding for the aryl hydrocarbon receptor (AHR) and the glutathione-S-transferase-P1 (GSTP1), could have a role in GH secreting pituitary tumors' pathophysiology and clinical expression. In this study, we assessed the contribution of GSTP1 gene promoter methylation status, per se or in combination with the occurrence of the AHR gene rs2066853 variant, on clinical features and response to somatostatin analogs (SSA) treatment in acromegaly patients.
This is an observational, retrospective study, carried out in the Endocrine Unit of an Italian University Hospital. We enrolled 77 wild-type AIP gene acromegaly patients, who have been screened for germline AHR rs2066853 variant and GSTP1 gene promoter methylation. Clinical and biochemical parameters were compared after patients' stratification according to GSTP1 methylation status and the presence of AHR rs2066853. We also evaluated the response to SSA treatment in 71 cases.
17 patients carried the AHR rs2066853 variant and 26 had methylated GSTP1 (GSTP1-methyl) gene promoter. GSTP1-methyl patients showed a higher prevalence of diabetes mellitus (p = 0.01), colonic polyps (p = 0.05), and were more resistant to SSA (p = 0.02) as compared to GSTP1 unmethylated patients (GSTP1-unmethyl). Patients GSTP1-unmethyl and AHR wild-type were the most sensitive to SSA treatment, while those with both GSTP1-methyl and AHR rs2066853 variant were all resistant to SSA (p = 0.01).
In acromegaly, GSTP1 gene methylation associates with resistance to SSA treatment, especially in patients carrying also the AHR rs2066853 variant, and with increased prevalence of colonic polyps and diabetes mellitus.
需要寻找与肢端肥大症临床和治疗结果相关的生物标志物。解毒基因（如编码芳香烃受体（AHR）和谷胱甘肽-S-转移酶-P1（GSTP1）的基因）的多态性或表观遗传变化可能在 GH 分泌性垂体肿瘤的发病机制和临床表型中发挥作用。在这项研究中，我们评估了 GSTP1 基因启动子甲基化状态本身或与 AHR 基因 rs2066853 变异的发生相结合，对肢端肥大症患者的临床特征和生长抑素类似物（SSA）治疗反应的影响。
这是一项在意大利大学医院内分泌科进行的观察性、回顾性研究。我们招募了 77 例野生型 AIP 基因肢端肥大症患者，对其进行了种系 AHR rs2066853 变异和 GSTP1 基因启动子甲基化筛查。根据 GSTP1 甲基化状态和 AHR rs2066853 的存在对患者进行分层后，比较临床和生化参数。我们还评估了 71 例患者对 SSA 治疗的反应。
17 例患者携带 AHR rs2066853 变异，26 例患者 GSTP1（GSTP1-methyl）基因启动子甲基化。与 GSTP1 未甲基化患者（GSTP1-unmethyl）相比，GSTP1-methyl 患者更易发生糖尿病（p=0.01）、结肠息肉（p=0.05），并且对 SSA 的耐药性更高（p=0.02）。GSTP1-unmethyl 和 AHR 野生型患者对 SSA 治疗最敏感，而同时携带 GSTP1-methyl 和 AHR rs2066853 变异的患者对 SSA 均耐药（p=0.01）。
在肢端肥大症中，GSTP1 基因甲基化与 SSA 治疗耐药相关，尤其是在同时携带 AHR rs2066853 变异的患者中，并且与结肠息肉和糖尿病的发生率增加相关。
