Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size

Wenzel M Hackeng; Lodewijk A A Brosens; Joo Young Kim; Roderick O'Sullivan; You-Na Sung; Ta-Chiang Liu; Dengfeng Cao; Michelle Heayn; Jacqueline Brosnan-Cashman; Soyeon An; Folkert H M Morsink; Charlotte M Heidsma; Gerlof D Valk; Menno R Vriens; Els Nieveen van Dijkum; G Johan A Offerhaus; Koen M A Dreijerink; Herbert Zeh; Amer H Zureikat; Melissa Hogg; Kenneth Lee; David Geller; J Wallis Marsh; Alessandro Paniccia; Melanie Ongchin; James F Pingpank; Nathan Bahary; Muaz Aijazi; Randall Brand; Jennifer Chennat; Rohit Das; Kenneth E Fasanella; Asif Khalid; Kevin McGrath; Savreet Sarkaria; Harkirat Singh; Adam Slivka; Michael Nalesnik; Xiaoli Han; Marina N Nikiforova; Rita Teresa Lawlor; Andrea Mafficini; Boris Rusev; Vincenzo Corbo; Claudio Luchini; Samantha Bersani; Antonio Pea; Sara Cingarlini; Luca Landoni; Roberto Salvia; Massimo Milione; Michele Milella; Aldo Scarpa; Seung-Mo Hong; Christopher M Heaphy; Aatur D Singhi

doi:10.1136/gutjnl-2020-322595

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size

Wenzel M Hackeng
, Lodewijk A A Brosens
, Joo Young Kim
, Roderick O'Sullivan
, You-Na Sung
, Ta-Chiang Liu
, Dengfeng Cao
, Michelle Heayn
, Jacqueline Brosnan-Cashman
, Soyeon An
, Folkert H M Morsink
, Charlotte M Heidsma
, Gerlof D Valk
, Menno R Vriens
, Els Nieveen van Dijkum
, G Johan A Offerhaus
, Koen M A Dreijerink
, Herbert Zeh
, Amer H Zureikat
, Melissa Hogg

Kenneth Lee, David Geller, J Wallis Marsh, Alessandro Paniccia, Melanie Ongchin, James F Pingpank, Nathan Bahary, Muaz Aijazi, Randall Brand, Jennifer Chennat, Rohit Das, Kenneth E Fasanella, Asif Khalid, Kevin McGrath, Savreet Sarkaria, Harkirat Singh, Adam Slivka, Michael Nalesnik, Xiaoli Han, Marina N Nikiforova, Rita Teresa Lawlor, Andrea Mafficini, Boris Rusev, Vincenzo Corbo, Claudio Luchini, Samantha Bersani, Antonio Pea, Sara Cingarlini, Luca Landoni, Roberto Salvia, Massimo Milione, Michele Milella, Aldo Scarpa, Seung-Mo Hong, Christopher M Heaphy, Aatur D Singhi

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Abstract

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.

Original language	English
Pages (from-to)	961-973
Number of pages	13
Journal	Gut
Volume	71
Issue number	5
Early online date	13 Apr 2021
DOIs	https://doi.org/10.1136/gutjnl-2020-322595
Publication status	Published - May 2022

Keywords

neuroendocrine tumors
pancreatic endocrine tumour
pancreatic islet cell
pancreatic pathology
pancreatic surgery

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10.1136/gutjnl-2020-322595Licence: CC BY-NC

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Hackeng, W. M., Brosens, L. A. A., Kim, J. Y., O'Sullivan, R., Sung, Y.-N., Liu, T.-C., Cao, D., Heayn, M., Brosnan-Cashman, J., An, S., Morsink, F. H. M., Heidsma, C. M., Valk, G. D., Vriens, M. R., Nieveen van Dijkum, E., Offerhaus, G. J. A., Dreijerink, K. M. A., Zeh, H., Zureikat, A. H., ... Singhi, A. D. (2022). Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size. Gut, 71(5), 961-973. https://doi.org/10.1136/gutjnl-2020-322595

@article{2540a7b99b3d4d80a1713dd097e3824f,

title = "Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size",

abstract = "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.",

keywords = "neuroendocrine tumors, pancreatic endocrine tumour, pancreatic islet cell, pancreatic pathology, pancreatic surgery",

author = "Hackeng, \{Wenzel M\} and Brosens, \{Lodewijk A A\} and Kim, \{Joo Young\} and Roderick O'Sullivan and You-Na Sung and Ta-Chiang Liu and Dengfeng Cao and Michelle Heayn and Jacqueline Brosnan-Cashman and Soyeon An and Morsink, \{Folkert H M\} and Heidsma, \{Charlotte M\} and Valk, \{Gerlof D\} and Vriens, \{Menno R\} and \{Nieveen van Dijkum\}, Els and Offerhaus, \{G Johan A\} and Dreijerink, \{Koen M A\} and Herbert Zeh and Zureikat, \{Amer H\} and Melissa Hogg and Kenneth Lee and David Geller and Marsh, \{J Wallis\} and Alessandro Paniccia and Melanie Ongchin and Pingpank, \{James F\} and Nathan Bahary and Muaz Aijazi and Randall Brand and Jennifer Chennat and Rohit Das and Fasanella, \{Kenneth E\} and Asif Khalid and Kevin McGrath and Savreet Sarkaria and Harkirat Singh and Adam Slivka and Michael Nalesnik and Xiaoli Han and Nikiforova, \{Marina N\} and Lawlor, \{Rita Teresa\} and Andrea Mafficini and Boris Rusev and Vincenzo Corbo and Claudio Luchini and Samantha Bersani and Antonio Pea and Sara Cingarlini and Luca Landoni and Roberto Salvia and Massimo Milione and Michele Milella and Aldo Scarpa and Seung-Mo Hong and Heaphy, \{Christopher M\} and Singhi, \{Aatur D\}",

note = "Publisher Copyright: {\textcopyright} ",

year = "2022",

month = may,

doi = "10.1136/gutjnl-2020-322595",

language = "English",

volume = "71",

pages = "961--973",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "5",

}

Hackeng, WM, Brosens, LAA, Kim, JY, O'Sullivan, R, Sung, Y-N, Liu, T-C, Cao, D, Heayn, M, Brosnan-Cashman, J, An, S, Morsink, FHM, Heidsma, CM, Valk, GD , Vriens, MR, Nieveen van Dijkum, E, Offerhaus, GJA, Dreijerink, KMA, Zeh, H, Zureikat, AH, Hogg, M, Lee, K, Geller, D, Marsh, JW, Paniccia, A, Ongchin, M, Pingpank, JF, Bahary, N, Aijazi, M, Brand, R, Chennat, J, Das, R, Fasanella, KE, Khalid, A, McGrath, K, Sarkaria, S, Singh, H, Slivka, A, Nalesnik, M, Han, X, Nikiforova, MN, Lawlor, RT, Mafficini, A, Rusev, B, Corbo, V, Luchini, C, Bersani, S, Pea, A, Cingarlini, S, Landoni, L, Salvia, R, Milione, M, Milella, M, Scarpa, A, Hong, S-M, Heaphy, CM & Singhi, AD 2022, 'Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size', Gut, vol. 71, no. 5, pp. 961-973. https://doi.org/10.1136/gutjnl-2020-322595

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size. / Hackeng, Wenzel M; Brosens, Lodewijk A A; Kim, Joo Young et al.
In: Gut, Vol. 71, No. 5, 05.2022, p. 961-973.

Research output: Contribution to journal › Article › Academic › peer-review

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

PY - 2022/5

Y1 - 2022/5

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

UR - https://www.scopus.com/pages/publications/85104459455

U2 - 10.1136/gutjnl-2020-322595

DO - 10.1136/gutjnl-2020-322595

M3 - Article

C2 - 33849943

SN - 0017-5749

VL - 71

SP - 961

EP - 973

JO - Gut

JF - Gut

IS - 5

ER -

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size

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