GSTP1 gene methylation and AHR rs2066853 variant predict resistance to first generation somatostatin analogs in patients with acromegaly

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 GSTP1gene promoter methylation status, per se or in combination with the occurrence of the AHRgene 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 AIPgene acromegaly patients, who have been screened for germline AHRrs2066853 variant and GSTP1gene promoter methylation. Clinical and biochemical parameters were compared after patients’ stratification according to GSTP1methylation status and the presence of AHRrs2066853. We also evaluated the response to SSA treatment in 71 cases. 17 patients carried the AHRrs2066853 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 GSTP1unmethylated patients (GSTP1-unmethyl). Patients GSTP1-unmethyl and AHRwild-type were the most sensitive to SSA treatment, while those with both GSTP1-methyl and AHRrs2066853 variant were all resistant to SSA (p= 0.01). In acromegaly, GSTP1gene methylation associates with resistance to SSA treatment, especially in patients carrying also the AHRrs2066853 variant, and with increased prevalence of colonic polyps and diabetes mellitus.