MON-436 Clinical Phenotypes of GNAS Gene Mutations in Acromegalic Patients

Abstract

Introduction Acromegaly is mostly caused by growth hormone (GH) hypersecretion. Guanine nucleotide-binding protein, α stimulating (GNAS) gene have been reported to be associated with GH secreting pituitary adenoma. Approximately 40% of patients with acromegaly have GNAS mutation. In this study, we investigated the prevalence of GNAS mutation in Korean acromegalic patients and assessed whether mutation status correlated with the biochemical or clinical characteristics. Method We studied acromegalic patients who underwent surgery between from July 2005 to January 2007 in Severance Hospital. Tumor genomic DNA was extracted using QIAamp DNA FFPE Tissue Kit from paraffin blocks of surgically resected tissue. GNAS gene analysis was performed with amplications of regions containing hotspot 2 sites of activating somatic mutations in codons 201 and 227. We evaluated the age, gender, GH, IGF-1 levels and immunohistochemical staining results of tumor. Biochemical remission of acromegaly was defined as a normal serum IGF-1 level or nadir GH after oral glucose tolerance test (OGTT) was less than 1ng/ml. Biochemical characteristics had been followed up at least 10 years. Result We analyzed 126 patients. GNAS mutations were present in 75 of the 126 acromegalic pateints (59.5%). Among the GNAS mutant patient, 61 subjects (81%) had mutation in codon 201. Patients with and without GNAS mutations were similar in age distribution and Hardy classification. The mutation negative group was 76.5% female and the mutation positive group was 48.0% female (p=0.006). GNAS mutant group had higher prevalence of overall GH expression in immunohistochemical staining (98.7% vs. 92.2%, p = 0.015). GNAS mutant patients are associated with higher IGF-1 level preoperatively (791.3 vs. 697.0ng/ml, p=0.045). Immediate postoperative basal GH (0.9 vs. 1.0ng/ml, p = 0.191) and nadir GH (0.3 vs. 0.6ng/ml, p=0.012) in OGTT was lower in GNAS mutant patients. Surgical remission rates were significantly higher in GNAS mutant patients, evaluated both at immediately and at 6 months after operation (70.7% vs. 54.9%, p=0.011; 85.3% vs. 82.4%, p=0.007, respectively). Conclusion In conclusion, GNAS mutation was more frequently found in Korean acromegalic patients. GNAS mutation positive tumors tended to have higher preoperative IGF-1 level, surgical remission rate and lower immediate postoperative nadir GH on OGTT. Identifying the GNAS mutation would be helpful in predicting patient’s clinical features and prognosis.