Genomic and Transcriptomic Landscapes of MEN1-Wild-Type Low-Grade Metastatic Pancreatic NETs Uncover Key Oncogenic Drivers and Targetable Pathways
Recommended Citation
Uddin MH, Mahdi Z, Muqbil I, Herring BR, Rose B, Khan HY, Li Y, Aboukameel A, Bannoura SF, Jimenez H, Johansen AM, Al-Hallak MN, Azar I, Mohamed A, Hadid T, Vaishampayan N, Shi Y, Wan Y, Ong V, Dyson G, Beydoun R, Tobon M, Beal EW, Chen H, Shields AF, Philip PA, Beebe-Dimmer J, Mohammad RM, Pasche BC, El-Rayes BF, Azmi AS. Genomic and Transcriptomic Landscapes of MEN1-Wild-Type Low-Grade Metastatic Pancreatic NETs Uncover Key Oncogenic Drivers and Targetable Pathways. Int J Biol Sci. 2026;22(14):7908-7927.
Document Type
Article
Publication Date
9-3-2026
Publication Title
Int J Biol Sci
Keywords
Pancreatic Neoplasms, Humans, Transcriptome, Neuroendocrine Tumors, Genomics, Mutation, Gene Expression Regulation, Neoplastic, Signal Transduction
Abstract
Sporadic pancreatic neuroendocrine tumors (pNETs) with wild-type MEN1 represent a major yet largely ignored subset whose biology and metastatic potential remain poorly understood. Because metastasis can occur despite low histologic grade and modest mutational burden, we hypothesized that metastatic competence in MEN1-wild-type pNETs reflects quantitative reinforcement of shared oncogenic pathways rather than distinct mutational processes. We profiled 75 primary WHO G1/G2 pNETs by whole-exome and RNA sequencing, including 25% with lymph node and/or liver metastasis, and integrated genomic and transcriptomic data to connect pathway lesions with expression state. Metastatic tumors showed a slight increase in mutation frequency but conserved base-substitution spectra relative to non-metastatic cases, and adverse clinicopathologic features were enriched in Grade 2 disease. Aggregating alterations to pathways revealed broad convergence on canonical networks, with transcriptomic analyses demonstrating cohort-wide enrichment of Calcium, WNT, and KRAS/PI3K-AKT programs in metastasis. Intersection of significantly mutated genes with differentially expressed genes identified a focused 29-gene overlap, including RYR1 and ZNF273, that marks these convergent axes and distinguishes metastatic from non-metastatic tumors. Gene set enrichment confirmed preferential activation of Calcium, WNT, and PI3K-AKT signaling in metastatic tumors, consistent with a network-intensity model of progression. Finally, upstream-regulator analysis (iPathwayGuide) and gene-centric perturbation mapping (Gene2Drug) nominated candidate targeted and repurposable agents predicted to reverse the metastatic expression phenotype and flagged drugs unlikely to provide benefit, yielding a prioritized, testable therapeutic shortlist which includes fasudil and spaglumic acid. Convergent, domain-specific mutational patterns in highly mutated genes such as ZNF273 and CLCA1 define a molecular signature that could stratify metastatic risk in low-grade pNETs. Functional validation identified ZNF273 and RYR1 as candidate effectors of metastatic fitness in MEN1-wild-type pNETs, as siRNA-mediated silencing reduced cell viability, clonogenicity, spheroid growth, and migration in BON1 and QGP1 models. Predicted compounds showed in vitro activity, with doxorubicin exhibiting the strongest cytotoxic effect, supporting a therapeutically tractable KRAB-ZNF/calcium signaling axis in metastatic pNETs. Collectively, our data reframe metastasis in MEN1-wild-type low-grade pNETs as a property of pathway state rather than mutation quantity and provide a translational blueprint for biomarker-guided therapy development focused on Calcium, WNT, and KRAS/PI3K hubs.
Medical Subject Headings
Pancreatic Neoplasms; Humans; Transcriptome; Neuroendocrine Tumors; Genomics; Mutation; Gene Expression Regulation, Neoplastic; Signal Transduction
PubMed ID
42807949
Volume
22
Issue
14
First Page
7908
Last Page
7927
