期刊
CLINICAL CANCER RESEARCH
卷 23, 期 6, 页码 1598-1606出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-1147
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资金
- Asan Institute for Life Sciences [2015-554]
- National Research Foundation of Korea [NRF- 2016R1A2B4009381]
- NCI [R01CA172380]
Purpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET). Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors. Results: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, Rho < 0.001). ALT also strongly correlated with lymphovascular (Rho < 0.001) and perineural invasion (Rho = 0.001) and the presence of lymph node (Rho < 0.001) and distant metastases (Rho = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83-6.27; Rho < 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT- positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08-0.68; Rho = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (Rho < 0.001), aggressive clinical behavior, and reduced recurrencefree survival (Rho < 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (Rho = 0.003). Conclusions: Both primary ALT-positive and ATRX/DAXX negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrencefree survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease. (C) 2016 AACR.
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