TY - JOUR
T1 - Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups with Differing Risks of Liver Metastases
AU - Pea, Antonio
AU - Yu, Jun
AU - Marchionni, Luigi
AU - Noe, Michael
AU - Luchini, Claudio
AU - Pulvirenti, Alessandra
AU - De Wilde, Roeland F.
AU - Brosens, Lodewijk A.
AU - Rezaee, Neda
AU - Javed, Ammar
AU - Chianchiano, Peter
AU - Gobbo, Stefano
AU - Regi, Paolo
AU - Salvia, Roberto
AU - Bassi, Claudio
AU - He, Jin
AU - Weiss, Matthew J.
AU - Cameron, John L.
AU - Offerhaus, G. Johan A.
AU - Hruban, Ralph H.
AU - Lawlor, Rita T.
AU - Scarpa, Aldo
AU - Heaphy, Christopher M.
AU - Wood, Laura D.
AU - Wolfgang, Christopher L.
N1 - Funding Information:
This study was supported by the ‘‘Department of Surgery Pancreatic Tumor Research Fund—PI: C.L.W.’’ Part of the study was supported by the NIH grant P30CA006973, NIH/NCI P50 CA62924; NIH/NIDDK K08 DK107781; Sol Goldman Pancreatic Cancer Research Center; Buffone Family Gastrointestinal Cancer Research Fund; Kaya Tuncer Career Development Award in Gastrointestinal Cancer Prevention; AGA-Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer; Sidney Kimmel Foundation for Cancer Research Kimmel Scholar Award; AACR-Incyte Corporation Career Development Award for Pancreatic Cancer Research; Rolfe Pancreatic Cancer Foundation; Joseph C Monastra Foundation; The Gerald O Mann Charitable Foundation (Harriet and Allan Wulfstat, Trustees); Sigma Beta Sorority; the Neuroendocrine Tumor Research Foundation, the Margie & Robert E. Petersen and by the 2016 Basic/Translational Science Investigator Award to C. Heaphy from the North American Neuroendocrine Tumor Society; Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute, CUP_J33G13000210001); Associazione Italiana Ricerca Cancro (grant 12182); FP7 European Community Grant Cam-Pac (n: 602783); Italian Cancer Genome Project—Ministry of University (FIRB RBAP10AHJB). M.N. and L.A.B. were supported by the Dutch Digestive Foundation (CDG 14-02).
Publisher Copyright:
© 2020 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2020/3/1
Y1 - 2020/3/1
N2 - 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 (<3cm), 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.
AB - 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 (<3cm), 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.
KW - ALT
KW - genetic subgroups
KW - liver metastases
KW - pancreatic neuroendocrine tumors (PanNETs)
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U2 - 10.1097/SLA.0000000000003022
DO - 10.1097/SLA.0000000000003022
M3 - Article
C2 - 30339629
AN - SCOPUS:85079891962
VL - 271
SP - 566
EP - 573
JO - Annals of Surgery
JF - Annals of Surgery
SN - 0003-4932
IS - 3
ER -