Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors Is Associated with Aggressive Clinical Behavior and Poor Survival.
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,P< 0.001). ALT also strongly correlated with lymphovascular (P< 0.001) and perineural invasion (P= 0.001) and the presence of lymph node (P< 0.001) and distant metastases (P= 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;P< 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;P= 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (P< 0.001), aggressive clinical behavior, and reduced recurrence-free survival (P< 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (P= 0.003).Conclusions: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.Clin Cancer Res; 23(6); 1598-606. ©2016 AACR.
Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.
Joo Young
JY
Kim
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Jacqueline A
JA
Brosnan-Cashman
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Soyeon
S
An
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Sung Joo
SJ
Kim
Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Ki-Byung
KB
Song
Asan Institute for Life Science, Asan Medical Center, Seoul, Korea.
Min-Sun
MS
Kim
Asan Institute for Life Science, Asan Medical Center, Seoul, Korea.
Mi-Ju
MJ
Kim
Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Dae Wook
DW
Hwang
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Alan K
AK
Meeker
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Eunsil
E
Yu
Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Asan Institute for Life Science, Asan Medical Center, Seoul, Korea.
Song Cheol
SC
Kim
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Ralph H
RH
Hruban
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland. smhong28@gmail.com cheaphy@jhmi.edu.
Christopher M
CM
Heaphy
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. smhong28@gmail.com cheaphy@jhmi.edu.|Asan Institute for Life Science, Asan Medical Center, Seoul, Korea.
Seung-Mo
SM
Hong
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D056970:Co-Repressor Proteins; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D059505:Telomere Homeostasis / Q000235:genetics*; D000075924:X-linked Nuclear Protein / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
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