Alternative lengthening of telomeres and loss of DAXX/ATRX expression predicts metastatic disease and poor survival in patients with pancreatic neuroendocrine tumors

Aatur D. Singhi, Ta Chiang Liu, Justin L. Roncaioli, Dengfeng Cao, Herbert J. Zeh, Amer H. Zureikat, Allan Tsung, J. Wallis Marsh, Kenneth K. Lee, Melissa E. Hogg, Nathan Bahary, Randall E. Brand, Kevin M. Mcgrath, Adam Slivka, Kristi L. Cressman, Kimberly Fuhrer, Roderick J. O'Sullivan

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

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 diseasespecific 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, higherWHOgrade, 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 were40%and 50%, respectively, as compared with96%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/ATRXnegative 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.

Original languageEnglish (US)
Pages (from-to)600-609
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number2
DOIs
StatePublished - Jan 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Singhi, A. D., Liu, T. C., Roncaioli, J. L., Cao, D., Zeh, H. J., Zureikat, A. H., Tsung, A., Marsh, J. W., Lee, K. K., Hogg, M. E., Bahary, N., Brand, R. E., Mcgrath, K. M., Slivka, A., Cressman, K. L., Fuhrer, K., & O'Sullivan, R. J. (2017). Alternative lengthening of telomeres and loss of DAXX/ATRX expression predicts metastatic disease and poor survival in patients with pancreatic neuroendocrine tumors. Clinical Cancer Research, 23(2), 600-609. https://doi.org/10.1158/1078-0432.CCR-16-1113