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Updated: Jan 27, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
ONCOGENE PANEL SEQUENCING ANALYSIS IDENTIFIES CANDIDATE ACTIONABLE GENES IN ADVANCED WELL-DIFFERENTIATED
Abstract:
Objective: To report the rate of candidate actionable somatic mutations in patients with locally advanced and metastatic gastro-enteropancreatic (GEP) neuroendocrine tumors (NET) and of other genetic alterations that may be associated with tumorigenesis. Methods: A phase II mutation targeted therapy trial was conducted in patients with advanced well-differentiated G1/G2 GEP-NET. Mutations found in the mTOR pathway-associated genes led to treatment with the mTOR inhibitor everolimus, and were defined as actionable. Tumor deoxyribonucleic acid (DNA) from GEP-NET were sequenced and compared with germline DNA, using the OncoVAR-NET assay, designed for hybrid capture sequencing of 500 tumor suppressor genes and oncogenes. Somatic variants were called and copy-number (CN) variant analysis was performed. Results: Thirty patients (14 small-intestine, 8 pancreatic, 3 unknown primary NET, and 5 of other primary sites) harbored 37 lesions (4 patients had DNA of multiple lesions sequenced). Only 2 patients with sporadic NET (n = 26) had an actionable mutation leading to treatment with everolimus. Driver somatic mutations were detected in 18 of 30 patients (21/37 lesions sequenced). In the remaining samples without a driver mutation, CN alterations were found in 11/16 tumors (10/12 patients), including CN loss of chromosome (Chr) 18 (P<.05), CN gain of Chr 5, and loss of Chr 13. CN losses in Chr 18 were more common in patients without driver mutations detected. Pronounced genetic heterogeneity was detected in patients with multiple lesions sequenced. Conclusion: Genome-wide DNA sequencing may identify candidate actionable genes and lead to the identification of novel target genes for advanced well-differentiated GEP-NET. Abbreviations: Chr = chromosome; CN = copy number; DNA = deoxyribonucleic acid; FDA = Food and Drug Administration; GEP = gastro-enteropancreatic; MEN-1 = multiple endocrine neoplasia syndrome type 1; mTOR = mammalian target of rapamycin; NET = neuroendocrine tumor; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumors; SINET = small-intestine neuroendocrine tumor.
Insights
Somatic mutations in gastro-enteropancreatic neuroendocrine tumors (GEP-NET) are rare, but copy number alterations are common. Genome-wide DNA sequencing can identify potential therapeutic targets for advanced GEP-NET.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Gastro-enteropancreatic neuroendocrine tumors (GEP-NET) are a heterogeneous group of neoplasms.
- Identifying actionable mutations is crucial for targeted therapy in advanced GEP-NET.
- Understanding the genetic landscape of GEP-NET can reveal novel therapeutic targets.
Purpose of the Study:
- To determine the frequency of actionable somatic mutations in advanced GEP-NET.
- To identify other genetic alterations associated with GEP-NET tumorigenesis.
- To explore the potential of genome-wide DNA sequencing for discovering new therapeutic targets.
Main Methods:
- A phase II trial involving patients with advanced, well-differentiated GEP-NET (G1/G2).
- Sequencing of tumor deoxyribonucleic acid (DNA) using the OncoVAR-NET assay for 500 genes.
- Analysis of somatic variants and copy-number (CN) alterations compared to germline DNA.
Main Results:
- Only 2 out of 26 sporadic NET patients had actionable mutations targeting the mTOR pathway.
- Driver somatic mutations were found in 18 of 30 patients (21/37 lesions).
- Copy number alterations, particularly loss of chromosome 18, were observed in 10/12 patients lacking driver mutations.
Conclusions:
- Actionable somatic mutations are infrequent in advanced GEP-NET.
- Copy number alterations are prevalent and may represent alternative therapeutic targets.
- Genome-wide DNA sequencing is a valuable tool for identifying novel therapeutic targets in GEP-NET.
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