Cannavo S, Ferrau F, Ragonese M, Romeo P D, Torre M L, Puglisi S, De Menis E, Arnaldi G, Salpietro C, Cotta O R, Albani A, Ruggeri R M, Trimarchi F
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
Clin Endocrinol (Oxf). 2014 Aug;81(2):249-53. doi: 10.1111/cen.12424. Epub 2014 Mar 17.
Aryl hydrocarbon receptor (AHR) pathway has a key role in cellular detoxification mechanisms and seems implicated in tumorigenesis. Moreover, polymorphisms and mutations of AHR gene have been associated with several human and animal tumours. Although AHR has been found differently expressed in pituitary adenomas, AHR gene mutation status has never been investigated in acromegalic patients.
In this study, we evaluated patients with apparently sporadic GH-secreting pituitary adenoma for AHR gene variants.
Seventy patients with sporadic GH-secreting pituitary adenoma (M = 27, age 59.1 ± 1.6 years) and 157 sex- and age-matched controls were enrolled in the study. In all patients and controls, the exons 1, 2, 3, 5 and 10 of AHR gene were evaluated for nucleotide variants by sequencing analysis.
The rs2066853 polymorphism was identified in the exon 10 of 18/70 acromegalic patients and 9/157 healthy subjects (25.7 vs. 5.7%, χ(2) = 18.98 P < 0.0001), in homozygosis in one patient and in heterozygosis in the other 17 and in the 9 healthy subjects. Moreover, a heterozygous rs4986826 variant in exon 10 was identified in a patient with heterozygous rs2066853 polymorphism, and in the patient with homozygous rs2066853 variant. This second polymorphism was not detected in the control group. Patients with rs2066853 polymorphism showed increased IGF-1 ULN (P < 0.05) and prevalence of cavernous sinus invasion (P = 0.05), thyroid (P = 0.02), bladder (P = 0.0001) or lymphohematopoietic (P < 0.05) tumours.
AHR gene rs2066853 polymorphism is significantly more frequent in acromegalic patients than in healthy subjects and is associated with increased disease aggressivity. Moreover, the rs4986826 variant was detected in few patients with rs2066853 polymorphism, but its role is to be cleared.
芳烃受体（AHR）通路在细胞解毒机制中起关键作用，似乎与肿瘤发生有关。此外，AHR基因的多态性和突变与多种人类和动物肿瘤相关。尽管已发现AHR在垂体腺瘤中的表达存在差异，但从未在肢端肥大症患者中研究过AHR基因突变状态。
在本研究中，我们评估了明显散发的生长激素分泌型垂体腺瘤患者的AHR基因变异情况。
70例散发的生长激素分泌型垂体腺瘤患者（男性27例，年龄59.1±1.6岁）和157例年龄及性别匹配的对照者纳入研究。对所有患者和对照者，通过测序分析评估AHR基因的外显子1、2、3、5和10的核苷酸变异。
在18/70例肢端肥大症患者的外显子10中鉴定出rs2066853多态性，9/157例健康受试者中也有该多态性（25.7%对5.7%，χ² = 18.98，P < 0.0001），1例患者为纯合子，17例患者及9例健康受试者为杂合子。此外，在1例rs2066853多态性杂合子患者和1例rs2066853纯合子患者中鉴定出外显子10中的杂合rs4986826变异。对照组未检测到第二种多态性。rs2066853多态性患者的胰岛素样生长因子-1（IGF-1）高于正常上限（P < 0.05），海绵窦侵袭发生率（P = 0.05）、甲状腺（P = 0.02）、膀胱（P = 0.0001）或淋巴造血系统（P < 0.05）肿瘤发生率增加。
AHR基因rs2066853多态性在肢端肥大症患者中显著高于健康受试者，且与疾病侵袭性增加相关。此外，在少数rs2066853多态性患者中检测到rs4986826变异，但其作用尚待明确。
