Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2025
Recurrent BEND2 Fusion Genes Identified by Whole Transcriptome Sequencing of Nonfunctional Pancreatic Neuroendocrine Tumors Correlate With Poor Patient Prognosis.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Wood-Trageser Michelle A, Nichols C Tolson, Hutchings Danielle A, Bell Diana, Wald Abigail I, Smith Katelyn, Hong Seung-Mo, Luchini Claudio, Brosens Lodewijk A A, Verschuur Anna Vera D, Bevere Michele, Lawlor Rita T, Scarpa Aldo, Keating Shannon, Tucker James, O'Sullivan Roderick J, Liu Ta-Chiang, McGrath Kevin, Fasanella Kenneth, Brand Randall E, Lennon Anne Marie, Das Rohit, Singh Harkirat, Slivka Adam, Mahmood Sultan, Hosmer Amy E, Khalid Asif, Romutis Stephanie L, Zureikat Amer H, Zeh Herbert J, Hogg Melissa E, Lee Kenneth K, Paniccia Alessandro, Nunns Geoffrey, Ongchin Melanie, Park Walter G, Polanco Patricio M, He Jin, Simeone Diane M, Ferrone Cristina R, Hsu Dennis, Zhang Janie, Gorantla Vikram, Rhee John, Hruban Ralph H, Singhi Anju H, Singhi Sara A, Wang Candice K, Shaker Nuha, Bubar Robert, Grupillo Maria, Lai Yi-Tak, Nikiforova Marina N, Heaphy Christopher M, Waters Kevin M, Singhi Aatur D
Аннотация
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.