ArticleModern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc2025
Recurrent BEND2 Fusion Genes Identified by Whole Transcriptome Sequencing of Nonfunctional Pancreatic Neuroendocrine Tumors Correlate With Poor Patient Prognosis.
Article in Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- EWSR1::BEND2 gene fusions characterize a majority of ACTH-producing neuroendocrine neoplasms of the pancreas: A follow-up study and brief review of the recent literature.Virchows Archiv : an international journal of pathology · 2026Article
- Multi-omic profiles of neuroendocrine neoplasms of the pancreas: an integrated landscape.Molecular cancer · 2026Review
- A novel BEND2 monoclonal antibody enables highly specific immunohistochemical diagnosis of BEND2-fusion astroblastomas.Acta neuropathologica · 2026Article
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56 authors.
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Abstract
Pancreatic neuroendocrine tumors (PanNETs) exhibit heterogeneous clinical behavior, and a growing number of nonfunctional PanNETs (NF-PanNETs) have been discovered incidentally. Although chromatin remodeling and telomere maintenance gene alterations, such as ATRX and DAXX mutations, are well established in the metastatic progression of PanNETs, many tumors lack known driver mutations. To identify additional prognostic biomarkers and alternative oncogenic mechanisms in primary NF-PanNETs, we employed whole transcriptome sequencing on 73 nonsyndromic NF-PanNETs with extended clinical follow-up (>4 years). Findings were validated via immunohistochemistry in an independent multi-institutional cohort of 539 PanNETs. Clinicopathologic correlation and survival analyses assessed the prognostic significance of identified biomarkers. Transcriptomic profiling identified 6 distinct clusters, with cluster 6 (C6) demonstrating aggressive features, including high World Health Organization grade and distant metastases. Gene ontology pathway analysis of C6 tumors revealed upregulation of protein homeostasis, immune regulation, insulin metabolic activity, and telomere maintenance via telomerase activation. Recurrent fusion genes involving the chromatin remodeling gene, BEND2 (CHD7::BEND2 and EWSR1::BEND2), were detected in 7% (5/73) of NF-PanNETs, exclusively in C6 and independent of ATRX/DAXX status. Orthogonal validation showed BEND2 expression in 3% (16/539) of PanNETs, all harboring BEND2 fusion genes by whole transcriptome sequencing. Patients with BEND2-positive tumors had significantly shorter disease-free survival (P < .001) and disease-specific survival (P < .001). Furthermore, multivariate analysis confirmed BEND2 as an independent negative prognostic factor for disease-free survival (P < .001) and disease-specific survival (P = .001). Overall, ATRX, DAXX, and BEND2 alterations were present in 62% of metastatic NF-PanNETs. This study identifies recurrent BEND2 fusion genes as a novel oncogenic mechanism in aggressive NF-PanNETs and establishes BEND2 expression as an independent prognostic biomarker, emphasizing the importance of chromatin remodeling and telomere maintenance in the metastatic progression of NF-PanNETs.
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