Mendoza Victoria, Sosa Ernesto, Espinosa-de-Los-Monteros Ana Laura, Salcedo Mauricio, Guinto Gerardo, Cheng Sonia, Sandoval Carolina, Mercado Moises
Endocrinology Service, Experimental Endocrinology Unit, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Aristòteles 68, Colonia Polanco 11560, México City, México.
Growth Horm IGF Res. 2005 Feb;15(1):28-32. doi: 10.1016/j.ghir.2004.10.001. Epub 2004 Dec 10.
The frequency of activating mutations of the GSPalpha gene as the etiology of GH-secreting pituitary adenomas has been the subject of important ethnogenetic variability. Whereas up to 40% of Caucasian patients with acromegaly have tumors which harbor these somatic mutations, their prevalence among Asian populations is much lower. The correlation between the presence of these mutations and the clinical and biological behavior of these tumors has also been a matter of controversy. In the present study, we investigated the prevalence of GSPalpha mutations in GH-secreting tumors obtained from a genetically homogenous population of Mexican patients with acromegaly. We also sought to establish whether or not the presence of these mutations correlates in any way with the clinical or biochemical characteristics of the disease.
Fifty eight GH-secreting pituitary adenomas were examined for the presence of point mutations in either codon 201 or 227 of the GSPalpha gene, using PCR and direct sequencing of DNA extracted from either fresh or paraffin-embedded tissues. Patients were prospectively followed clinically and biochemically for up to nine years after pituitary surgery.
Heterozygous point mutations in exon 8 (codon 201) were found in 11 patients (19%), and no molecular alterations were evident in exon 9. The frequency and severity of the different clinical features of acromegaly did not differ between patients with and without GSPalpha mutations. Patients with and without mutations had pre-operative GH and IGF-I elevations of similar magnitude, and although microadenomas appeared to be more frequent among patients with GSPalpha mutations, this did not reach statistical significance. Upon short-term follow-up, biochemical cure (normal age- and gender-adjusted IGF-I and post-glucose GH below 1 ng/mL) was similarly achieved in both groups. After 3-9 years of post-operative follow up however, a significantly greater proportion of patients with the mutation achieved a "safe" basal GH value (100% vs 33%, p=0.001) as well a lower nadir post-glucose GH (0.53+/-0.5 vs 2.9+/-6.2 ng/mL, p=0.04) although the rate of IGF-1 normalization did not differ between the 2 groups.
Our results show that the prevalence of GSPalpha mutations in Mexican patients with acromegaly is intermediate between that found in Asian and Caucasian populations. In this well-defined genetic population the presence of codon 201 mutations appeared to be associated with a greater probability of achieving a "safe" GH value upon long-term follow-up.
作为生长激素分泌型垂体腺瘤病因的GSPalpha基因激活突变频率存在重要的种族遗传变异性。高达40%的白种人肢端肥大症患者的肿瘤存在这些体细胞突变，而它们在亚洲人群中的患病率要低得多。这些突变的存在与这些肿瘤的临床和生物学行为之间的相关性也一直存在争议。在本研究中，我们调查了从墨西哥肢端肥大症患者这一基因同质群体中获取的生长激素分泌型肿瘤中GSPalpha突变的患病率。我们还试图确定这些突变的存在是否与该疾病的临床或生化特征存在任何关联。
使用聚合酶链反应（PCR）和对从新鲜或石蜡包埋组织中提取的DNA进行直接测序，对58例生长激素分泌型垂体腺瘤检测GSPalpha基因第201或227密码子是否存在点突变。垂体手术后对患者进行长达9年的临床和生化随访。
在11例患者（19%）中发现外显子8（第201密码子）存在杂合点突变，外显子9未发现明显分子改变。肢端肥大症不同临床特征的频率和严重程度在有和没有GSPalpha突变的患者之间没有差异。有和没有突变的患者术前生长激素和胰岛素样生长因子-I升高幅度相似，虽然微腺瘤在有GSPalpha突变的患者中似乎更常见，但未达到统计学意义。短期随访时，两组均同样实现了生化治愈（年龄和性别校正后的胰岛素样生长因子-I正常且葡萄糖负荷后生长激素低于1 ng/mL）。然而，术后3 - 9年随访时，有突变的患者中达到“安全”基础生长激素值的比例显著更高（100%对33%，p = 0.001），葡萄糖负荷后生长激素最低点也更低（0.53±0.5对2.9±6.2 ng/mL，p = 0.04），尽管两组间胰岛素样生长因子-1正常化率没有差异。
我们的结果表明，墨西哥肢端肥大症患者中GSPalpha突变的患病率介于亚洲和白种人群体之间。在这个明确界定的基因群体中，第201密码子突变的存在似乎与长期随访时达到“安全”生长激素值的可能性更大相关。
