Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors.

Autor:	Singhi AD; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. singhiad@upmc.edu., Liu TC; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Roncaioli JL; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania., Cao D; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Zeh HJ; Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Zureikat AH; Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Tsung A; Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Marsh JW; Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Lee KK; Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Hogg ME; Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Bahary N; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Brand RE; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., McGrath KM; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Slivka A; Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Cressman KL; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Fuhrer K; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., O'Sullivan RJ; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Jan 15; Vol. 23 (2), pp. 600-609. Date of Electronic Publication: 2016 Jul 12.
DOI:	10.1158/1078-0432.CCR-16-1113
Abstrakt:	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. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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