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Updated: Jan 18, 2026
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Circulating Tumor DNA Profiling Identifies Actionable Mutations as Prognostic Markers in Advanced Neuroendocrine
Na Zhou1, Guofeng Zhao2, Yang Gao3
1Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Introduction: Neuroendocrine tumors (NETs) are a rare and heterogeneous group of neoplasms with both clinical and genetic diversity. The clinical applicability of molecular profiling using liquid biopsy for identifying actionable drug targets and prognostic indicators in patients with advanced NETs remains unclear.
Methods:
In this study, we utilized a custom-made 37 genes panel of circulating tumor DNA (ctDNA) based on next-generation sequencing in 47 patients with advanced NETs.
Results:
A total of 223 non-synonymous mutations were identified, with the highest frequencies found in TSC2, JAG2, NOTCH3, KMT2C, and SETD2. NETs originating from the stomach exhibited the highest average mutation frequency, while paragangliomas had the lowest. TERT mutations were associated with significantly higher hazard ratios for both progression-free survival (PFS) and overall survival (OS). Higher blood tumor mutational burden (bTMB) was linked to poor prognosis in octreotide LAR-treated patients and correlated with higher Ki-67 levels and alterations in the TM, mTOR, and Notch pathways. Treatment responders had higher bTMB, chromatin remodeling signaling mutation burden, and maximum somatic allele frequency (MSAF). Patients with high MSAF demonstrated better PFS, whereas those with low MSAF had better OS. A strong positive correlation was observed between MSAF levels and mutational burden. Co-occurring mutations in the TM, mTOR, and NOTCH pathways suggested future therapeutic strategies.
Conclusions:
We constructed an overview of mutations in 37 genes, linking ctDNA to survival in advanced NETs. TERT mutations, bTMB, and MSAF predict PFS or OS. Co-occurring TM, mTOR, and NOTCH pathway alterations highlight ctDNA's potential in guiding precision medicine.
.Insights
Liquid biopsy using circulating tumor DNA (ctDNA) reveals key mutations in advanced neuroendocrine tumors (NETs). Specific mutations and blood tumor mutational burden (bTMB) can predict patient survival and guide precision medicine strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Neuroendocrine tumors (NETs) are rare and diverse neoplasms.
- The role of molecular profiling via liquid biopsy in advanced NETs is not well-defined.
Purpose of the Study:
- To investigate the clinical utility of circulating tumor DNA (ctDNA) analysis in advanced NETs.
- To identify actionable drug targets and prognostic indicators using a 37-gene panel.
Main Methods:
- Employed next-generation sequencing on a custom 37-gene panel of ctDNA.
- Analyzed samples from 47 patients with advanced NETs.
Main Results:
- Identified 223 mutations, with TSC2, JAG2, NOTCH3, KMT2C, and SETD2 being most frequent.
- TERT mutations and higher blood tumor mutational burden (bTMB) correlated with poorer progression-free survival (PFS) and overall survival (OS).
- Treatment responders showed higher bTMB and maximum somatic allele frequency (MSAF); TM, mTOR, and Notch pathway alterations suggest therapeutic avenues.
Conclusions:
- ctDNA analysis provides a comprehensive mutation profile for advanced NETs.
- TERT mutations, bTMB, and MSAF are significant predictors of PFS and OS.
- Identifying co-occurring pathway alterations (TM, mTOR, Notch) demonstrates ctDNA's potential for guiding precision oncology in NETs.
