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.
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.
Authors: Aldo Scarpa; David K Chang; Katia Nones; Vincenzo Corbo; Ann-Marie Patch; Peter Bailey; Rita T Lawlor; Amber L Johns; David K Miller; Andrea Mafficini; Borislav Rusev; Maria Scardoni; Davide Antonello; Stefano Barbi; Katarzyna O Sikora; Sara Cingarlini; Caterina Vicentini; Skye McKay; Michael C J Quinn; Timothy J C Bruxner; Angelika N Christ; Ivon Harliwong; Senel Idrisoglu; Suzanne McLean; Craig Nourse; Ehsan Nourbakhsh; Peter J Wilson; Matthew J Anderson; J Lynn Fink; Felicity Newell; Nick Waddell; Oliver Holmes; Stephen H Kazakoff; Conrad Leonard; Scott Wood; Qinying Xu; Shivashankar Hiriyur Nagaraj; Eliana Amato; Irene Dalai; Samantha Bersani; Ivana Cataldo; Angelo P Dei Tos; Paola Capelli; Maria Vittoria Davì; Luca Landoni; Anna Malpaga; Marco Miotto; Vicki L J Whitehall; Barbara A Leggett; Janelle L Harris; Jonathan Harris; Marc D Jones; Jeremy Humphris; Lorraine A Chantrill; Venessa Chin; Adnan M Nagrial; Marina Pajic; Christopher J Scarlett; Andreia Pinho; Ilse Rooman; Christopher Toon; Jianmin Wu; Mark Pinese; Mark Cowley; Andrew Barbour; Amanda Mawson; Emily S Humphrey; Emily K Colvin; Angela Chou; Jessica A Lovell; Nigel B Jamieson; Fraser Duthie; Marie-Claude Gingras; William E Fisher; Rebecca A Dagg; Loretta M S Lau; Michael Lee; Hilda A Pickett; Roger R Reddel; Jaswinder S Samra; James G Kench; Neil D Merrett; Krishna Epari; Nam Q Nguyen; Nikolajs Zeps; Massimo Falconi; Michele Simbolo; Giovanni Butturini; George Van Buren; Stefano Partelli; Matteo Fassan; Kum Kum Khanna; Anthony J Gill; David A Wheeler; Richard A Gibbs; Elizabeth A Musgrove; Claudio Bassi; Giampaolo Tortora; Paolo Pederzoli; John V Pearson; Nicola Waddell; Andrew V Biankin; Sean M Grimmond Journal: Nature Date: 2017-02-15 Impact factor: 49.962
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