Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival

Abstract

<b>Purpose:</b> 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).<b>Experimental Design:</b> 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.<b>Results:</b> 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, <i>P</i> < 0.001). ALT also strongly correlated with lymphovascular (<i>P</i> < 0.001) and perineural invasion (<i>P</i> = 0.001) and the presence of lymph node (<i>P</i> < 0.001) and distant metastases (<i>P</i> = 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; <i>P</i> < 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; <i>P</i> = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (<i>P</i> < 0.001), aggressive clinical behavior, and reduced recurrence-free survival (<i>P</i> < 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (<i>P</i> = 0.003).<b>Conclusions:</b> Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free 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. <i>Clin Cancer Res; 23(6); 1598-606. ©2016 AACR</i>.