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Updated: Mar 7, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing
Samuel Backman1, Olov Norlén1, Barbro Eriksson2
1Department of Surgical, Uppsala University, Uppsala, Sweden.
Abstract:
Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.
Patients And Methods:
Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.
Results:
Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.
Conclusion:
Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.
Insights
This study investigated mutations in pancreatic neuroendocrine tumors (NETs) treated with everolimus. No MTOR pathway mutations were found, but pathogenic variants in MEN1 and DAXX genes were identified, suggesting further research is needed.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Mechanistic target of rapamycin (MTOR) pathway mutations are common in human cancers, including up to 15% of pancreatic neuroendocrine tumors (NETs).
- Everolimus, an MTOR inhibitor, shows efficacy in treating pancreatic NETs, leading to disease stabilization in many patients, though objective tumor responses are less common.
- Genomic alterations activating the MTOR pathway are hypothesized to predict sensitivity to everolimus therapy.
Purpose of the Study:
- To investigate the genetic landscape of pancreatic neuroendocrine tumors (NETs) treated with everolimus.
- To identify potential genomic markers associated with treatment response to everolimus in pancreatic NETs.
- To assess the feasibility and diagnostic yield of targeted next-generation sequencing (NGS) for genetic characterization of pancreatic NETs.
Main Methods:
- Retrospective analysis of six patients with NETs treated with everolimus, who had available tumor tissue.
- Targeted next-generation sequencing (NGS) was employed to analyze 22 genes implicated in the MTOR pathway or gastroenteropancreatic NET tumorigenesis.
- Radiological responses were assessed using Response Evaluation Criteria in Solid Tumors (RECIST).
Main Results:
- Of the six patients, one achieved a partial response, and four had stable disease.
- Targeted NGS analysis revealed a total of 494 genetic variants, with four identified as pathogenic.
- All validated pathogenic variants were exclusively found in the menin 1 (MEN1) and death domain associated protein (DAXX) genes; no mutations were detected in MTOR pathway-related genes.
Conclusions:
- Targeted NGS is a viable and effective method for the genetic characterization of pancreatic NETs, offering a high diagnostic yield.
- The study did not find mutations in MTOR pathway genes in the analyzed pancreatic NETs.
- Further research is warranted to explore the potential association between specific genetic mutations in NETs and their response to everolimus treatment.
