Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases

Yiying Guo; Chao Tian; Zixuan Cheng; Ruao Chen; Yuanliang Li; Fei Su; Yanfen Shi; Huangying Tan

doi:10.1159/000530968

Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases

Neuroendocrinology. 2023;113(9):943-956. doi: 10.1159/000530968. Epub 2023 May 12.

Authors

Yiying Guo¹, Chao Tian², Zixuan Cheng², Ruao Chen², Yuanliang Li^{3

4}, Fei Su³, Yanfen Shi⁵, Huangying Tan^{1

2

3}

Affiliations

¹ Department of Integrative Oncology, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
² Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing University of Chinese Medicine, Beijing, China.
³ Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China.
⁴ Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
⁵ Department of Pathology, China-Japan Friendship Hospital, Beijing, China.

Abstract

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.

Keywords: Genetics; Metastasis; Molecular heterogeneity; Pancreatic neuroendocrine tumors; Targeted therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Mutation
Neuroendocrine Tumors* / pathology
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / pathology
Proto-Oncogene Proteins p21(ras) / genetics
Signal Transduction

Substances

Proto-Oncogene Proteins p21(ras)

Grants and funding

This work was funded by the National Key Research and Development Program of China (grant number 2019YFB1309704).