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

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Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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.

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Funding

This study has been supported by a grant of the Ministry of Education, University and Research (PRIN 2015, Prot. 2015ZHKFTA) and of the Ministry of Health (Progetto Ordinario Ricerca Finalizzata RF-2013-02356201) of the Italian Government.

Author information

Authors and Affiliations

  1. Department of Human Pathology of Adulthood and Childhood, University of Messina, Messina, Italy

    F. Ferraù, P. D. Romeo, M. Ragonese, C. Salpietro & S. Cannavò

  2. Unit of Endocrinology, University Hospital ‘G. Martino’, Messina, Italy

    S. Puglisi, F. Spagnolo & S. Cannavò

  3. Department of Biomedical Sciences, Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy

    R. Ientile, M. Currò, G. Visalli & I. A. M. Picerno

  4. Department of Economics, University of Messina, Messina, Italy

    A. Alibrandi

Authors
  1. F. Ferraù
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Correspondence to F. Ferraù.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Ferraù, F., Romeo, P.D., Puglisi, S. et al. GSTP1 gene methylation and AHR rs2066853 variant predict resistance to first generation somatostatin analogs in patients with acromegaly. J Endocrinol Invest 42, 825–831 (2019). https://doi.org/10.1007/s40618-018-0988-8

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