Methylation of somatostatin receptor 2 gene in neuroendocrine tumours as a predictor of tumour response to peptide receptor radionuclide therapy
Aims
Somatostatin receptors are a fundamental target for treating neuroendocrine tumours (NETs) with ‘cold’ or ‘hot’ somatostatin analogues. Metastatic NETs progressing after medical therapy can receive peptide receptor radionuclide therapy (PRRT) on the precondition that patients exhibit positive radiotracer uptake using 68Gallium-DOTA0-Tyr3-octreotate positron emission tomography / computed tomography imaging. However, the confirmation of somatostatin receptor 2 (SSTR2) as evidenced by the positive imaging fails to translate into treatment efficacy for PRRT pursuing the same pathway. Moreover, there is a lack of predictors of response to this highly expensive treatment. Studies have established that positive radiotracer uptake is associated with better treatment outcomes. The aim of this study was to ascertain the relationship between promoter methylation in the SSTR2 gene with SSTR2 expression and tumour response to PRRT.
Methods
Methylation analysis of the upstream promoter region of the SSTR2 gene was conducted on 27 samples from patients with advanced NETs and treated with PRRT from 2008 to 2016. Tissue microarray blocks were constructed and sections were immunostained for SSTR2 using the UMB-1 antibody.
Results
Twenty-seven cases were identified: 51% male, mean age 55 years ±13.4. One-hundred per cent presented with metastatic disease. Thirty-three percent of cases were from small bowel primary NET. Five samples were lost due to inadequate quality. Median methylation of the SSTR2 promoter in patient samples was 12.38%, significantly higher than controls (5.21%, p=0.006). A significant difference in SSTR2 promoter methylation was observed in patients who respond to PRRT in contrast to non-responders (12.17% vs 15.18%, p=0.047).
Conclusion
A hypermethylated state of the SSTR2 gene promoter region may be associated with reduced response to PRRT. Future studies should ascertain a suitable cut-off for methylation status that could stratify patients for those that may have increased likelihood in responding to PRRT. Epigenetic drugs should be explored for potential utility in selectively modifying the silenced epigenetic state of the SSTR2 promoter.
Conflict of interest statement
None declared.
- © Royal College of Physicians 2019. All rights reserved.
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