Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors
| Autor: | Kevin McGrath, Allan Tsung, Adam Slivka, Kristi L. Cressman, Kenneth K. Lee, Aatur D. Singhi, Amer H. Zureikat, Kimberly Fuhrer, Justin L. Roncaioli, Nathan Bahary, Ta-Chiang Liu, Randall E. Brand, Roderick J. O’Sullivan, Melissa E. Hogg, J. Wallis Marsh, Herbert J. Zeh, Dengfeng Cao |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult Male Cancer Research X-linked Nuclear Protein Disease Neuroendocrine tumors Biology Disease-Free Survival Article 03 medical and health sciences 0302 clinical medicine Death-associated protein 6 Exome Sequencing medicine Carcinoma Humans Neoplasm Metastasis Exome sequencing ATRX In Situ Hybridization Fluorescence Adaptor Proteins Signal Transducing Aged Aged 80 and over Cancer Nuclear Proteins Telomere Homeostasis Middle Aged Telomere medicine.disease Carcinoma Neuroendocrine Gene Expression Regulation Neoplastic Pancreatic Neoplasms 030104 developmental biology Oncology 030220 oncology & carcinogenesis Lymphatic Metastasis Cancer research Immunohistochemistry Female Co-Repressor Proteins Molecular Chaperones |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 23(2) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: Pancreatic neuroendocrine tumors (PanNET) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs. Experimental Design: Telomere-specific FISH and DAXX/ATRX IHC was performed on a multi-institutional cohort of 321 patients with resected PanNET and 191 distant metastases from 52 patients. These results were correlated with clinicopathologic features, including disease-free survival (DFS) and disease-specific survival (DSS). Results: The prevalence of ALT and DAXX/ATRX loss in resected PanNETs was 31% and 26%, respectively, and associated with larger tumor size, higher WHO grade, lymph node metastasis, and distant metastasis (P < 0.001). The 5-year DFS and 10-year DSS of patients with ALT-positive and DAXX/ATRX-negative PanNETs were 40% and 50%, respectively, as compared with 96% and 89%, respectively, for wild-type PanNETs. Among distant metastases, ALT and DAXX/ATRX loss was 67% and 52%, respectively, and only occurred in the setting of an ALT-positive and DAXX/ATRX-negative primary PanNET. By multivariate analysis, both ALT and DAXX/ATRX loss were negative, independent prognostic factors for DFS. Conclusions: ALT and DAXX/ATRX loss in PanNETs was associated with shorter DFS and DSS and likely plays a significant role in driving metastatic disease. Clin Cancer Res; 23(2); 600–9. ©2016 AACR. |
| Databáze: | OpenAIRE |
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