Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases. Issue 3 (March 2020)

• Record Type: Journal Article
• Authors: Pea, Antonio; Yu, Jun; Marchionni, Luigi; Noe, Michael; Luchini, Claudio; Pulvirenti, Alessandra; de Wilde, Roeland F.; Brosens, Lodewijk A.; Rezaee, Neda; Javed, Ammar; Chianchiano, Peter; Gobbo, Stefano; Regi, Paolo; Salvia, Roberto; Bassi, Claudio; He, Jin; Weiss, Matthew J.; Cameron, John L.; Offerhaus, G. Johan A.; Hruban, Ralph H.; Lawlor, Rita T.; Scarpa, Aldo; Heaphy, Christopher M.; Wood, Laura D.; Wolfgang, Christopher L.
• Is Part Of: Annals of surgery. Volume 271:Issue 3(2020)
• Publication Date: 2020-03
• Subjects: ALT -- genetic subgroups -- liver metastases -- pancreatic neuroendocrine tumors (PanNETs); Surgery -- Periodicals; 617.005
• DOI: 10.1097/SLA.0000000000003022
• Languages: English
• ISSNs: 0003-4932

Abstract

Abstract : Objective: The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. Background: Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. Methods: A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation. Results: In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121–1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458–14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093–11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss. Conclusions: We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs. Abstract : Supplemental Digital Content is available in the text