TY - JOUR
T1 - Non-functional pancreatic neuroendocrine tumours
T2 - ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size
AU - Hackeng, Wenzel M.
AU - Brosens, Lodewijk A.A.
AU - Kim, Joo Young
AU - O'Sullivan, Roderick
AU - Sung, You Na
AU - Liu, Ta Chiang
AU - Cao, Dengfeng
AU - Heayn, Michelle
AU - Brosnan-Cashman, Jacqueline
AU - An, Soyeon
AU - Morsink, Folkert H.M.
AU - Heidsma, Charlotte M.
AU - Valk, Gerlof D.
AU - Vriens, Menno R.
AU - Nieveen Van Dijkum, Els
AU - Offerhaus, G. Johan A.
AU - Dreijerink, Koen M.A.
AU - Zeh, Herbert
AU - Zureikat, Amer H.
AU - Hogg, Melissa
AU - Lee, Kenneth
AU - Geller, David
AU - Marsh, J. Wallis
AU - Paniccia, Alessandro
AU - Ongchin, Melanie
AU - Pingpank, James F.
AU - Bahary, Nathan
AU - Aijazi, Muaz
AU - Brand, Randall
AU - Chennat, Jennifer
AU - Das, Rohit
AU - Fasanella, Kenneth E.
AU - Khalid, Asif
AU - McGrath, Kevin
AU - Sarkaria, Savreet
AU - Singh, Harkirat
AU - Slivka, Adam
AU - Nalesnik, Michael
AU - Han, Xiaoli
AU - Nikiforova, Marina N.
AU - Lawlor, Rita Teresa
AU - Mafficini, Andrea
AU - Rusev, Boris
AU - Corbo, Vincenzo
AU - Luchini, Claudio
AU - Bersani, Samantha
AU - Pea, Antonio
AU - Cingarlini, Sara
AU - Landoni, Luca
AU - Salvia, Roberto
AU - Milione, Massimo
AU - Milella, Michele
AU - Scarpa, Aldo
AU - Hong, Seung Mo
AU - Heaphy, Christopher M.
AU - Singhi, Aatur D.
N1 - Funding Information:
This study was supported in part by grants from the Dutch Digestive Foundation/Maag Lever Darm Stichting (CDG 14-020) (to WMH and LAAB); Associazione Italiana Ricerca Cancro (AIRC 5 - 1000 n. 12 182 and Start up n. 18718), European Community ERANET PMTR-pNET (cod. D18TR5, B46C17000260001), Italian Ministry of Health (FIMPCUP_J38D19000690001), Fondazione Cariverona: Oncology Biobank Project (prot. 203885/2017) (to A. Scarpa); NRF-2016R1A2B4009381 from the National Research Foundation of Korea (to S-MH); the Basic/Translational Science Investigator Award from the North American Neuroendocrine Tumor Society supported by the Neuroendocrine Tumor Research Foundation (to CH); National Institute of Health (NIH/NCI 1R01CA263622), National Pancreas Foundation, Sky Foundation, and the Pittsburgh Liver Research Center at the University of Pittsburgh (NIH/NIDDK P30DK120531) (to ADS).
Funding Information:
Funding This study was supported in part by grants from the Dutch Digestive Foundation/Maag Lever Darm Stichting (CDG 14–020) (to WMH and LAAB); Associazione Italiana Ricerca Cancro (AIRC 5×1000 n. 12 182 and Start up n. 18718), European Community ERANET PMTR-pNET (cod. D18TR5, B46C17000260001), Italian Ministry of Health (FIMPCUP_J38D19000690001), Fondazione Cariverona: Oncology Biobank Project (prot. 203885/2017) (to A. Scarpa); NRF-2016R1A2B4009381 from the National Research Foundation of Korea (to S-MH); the Basic/Translational Science Investigator Award from the North American Neuroendocrine Tumor Society supported by the Neuroendocrine Tumor Research Foundation (to CH); National Institute of Health (NIH/NCI 1R01CA263622), National Pancreas Foundation, Sky Foundation, and the Pittsburgh Liver Research Center at the University of Pittsburgh (NIH/NIDDK P30DK120531) (to ADS).
Publisher Copyright:
©
PY - 2022/5/1
Y1 - 2022/5/1
N2 - Objective Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. Design An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). Results ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). Conclusions ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
AB - Objective Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. Design An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). Results ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). Conclusions ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
KW - neuroendocrine tumors
KW - pancreatic endocrine tumour
KW - pancreatic islet cell
KW - pancreatic pathology
KW - pancreatic surgery
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U2 - 10.1136/gutjnl-2020-322595
DO - 10.1136/gutjnl-2020-322595
M3 - Article
C2 - 33849943
AN - SCOPUS:85104459455
SN - 0017-5749
VL - 71
SP - 961
EP - 973
JO - Gut
JF - Gut
IS - 5
ER -