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Updated: Jul 29, 2025
Heterogeneity Mapping of Protein Expression in Tumors using Quantitative Immunofluorescence
Published on: October 25, 2011
Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases
Yiying Guo1, Chao Tian2, Zixuan Cheng2
1Department of Integrative Oncology, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Introduction:
Treatment response to the standard therapy is low for metastatic pancreatic neuroendocrine tumors (PanNETs) mainly due to the tumor heterogeneity. We investigated the heterogeneity between primary PanNETs and metastases to improve the precise treatment.
Methods:
The genomic and transcriptomic data of PanNETs were retrieved from the Genomics, Evidence, Neoplasia, Information, Exchange (GENIE), and Gene Expression Omnibus (GEO) database, respectively. Potential prognostic effects of gene mutations enriched in metastases were investigated. Gene set enrichment analysis was performed to investigate the functional difference. Oncology Knowledge Base was interrogated for identifying the targetable gene alterations.
Results:
Twenty-one genes had significantly higher mutation rates in metastases which included TP53 (10.3% vs. 16.9%, p = 0.035) and KRAS (3.7% vs. 9.1%, p = 0.016). Signaling pathways related to cell proliferation and metabolism were enriched in metastases, whereas epithelial-mesenchymal transition (EMT) and TGF-β signaling were enriched in primaries. Gene mutations were highly enriched in metastases that had significant unfavorable prognostic effects included mutation of TP53 (p < 0.001), KRAS (p = 0.001), ATM (p = 0.032), KMT2D (p = 0.001), RB1 (p < 0.001), and FAT1 (p < 0.001). Targetable alterations enriched in metastases included mutation of TSC2 (15.5%), ARID1A (9.7%), KRAS (9.1%), PTEN (8.7%), ATM (6.4%), amplification of EGFR (6.0%), MET (5.5%), CDK4 (5.5%), MDM2 (5.0%), and deletion of SMARCB1 (5.0%).
Conclusion:
Metastases exhibited a certain extent of genomic and transcriptomic diversity from primary PanNETs. TP53 and KRAS mutation in primary samples might associate with metastasis and contribute to a poorer prognosis. A high fraction of novel targetable alterations enriched in metastases deserves to be validated in advanced PanNETs.
Insights
Metastatic pancreatic neuroendocrine tumors (PanNETs) show genomic differences from primary tumors. Mutations in TP53 and KRAS in primary PanNETs may predict metastasis and poorer outcomes, highlighting potential new therapeutic targets.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Metastatic pancreatic neuroendocrine tumors (PanNETs) have limited treatment response due to tumor heterogeneity.
- Understanding genomic and transcriptomic differences between primary and metastatic PanNETs is crucial for improving treatment strategies.
Purpose of the Study:
- To investigate the genomic and transcriptomic heterogeneity between primary and metastatic PanNETs.
- To identify potential prognostic markers and targetable alterations in metastatic PanNETs.
Main Methods:
- Genomic and transcriptomic data from PanNETs were analyzed using the GENIE and GEO databases.
- Gene set enrichment analysis was performed to identify functional differences.
- Oncology Knowledge Base was used to identify targetable gene alterations.
Main Results:
- Metastases showed significantly higher mutation rates in genes including TP53 and KRAS compared to primary tumors.
- Signaling pathways related to cell proliferation and metabolism were enriched in metastases, while EMT and TGF-β signaling were enriched in primaries.
- TP53, KRAS, ATM, KMT2D, RB1, and FAT1 mutations in metastases were associated with unfavorable prognoses. Targetable alterations like TSC2, ARID1A, KRAS, and PTEN mutations were enriched in metastases.
Conclusions:
- Metastatic PanNETs display genomic and transcriptomic diversity compared to primary tumors.
- TP53 and KRAS mutations in primary PanNETs may be linked to metastasis and poorer prognosis.
- Novel targetable alterations enriched in metastases warrant further validation for advanced PanNET treatment.
