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

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...

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Detalles Bibliográficos
Autores principales: Hackeng, Wenzel M, Brosens, Lodewijk A A, Kim, Joo Young, O'Sullivan, Roderick, Sung, You-Na, Liu, Ta-Chiang, Cao, Dengfeng, Heayn, Michelle, Brosnan-Cashman, Jacqueline, An, Soyeon, Morsink, Folkert H M, Heidsma, Charlotte M, Valk, Gerlof D, Vriens, Menno R, Nieveen van Dijkum, Els, Offerhaus, G Johan A, Dreijerink, Koen M A, Zeh, Herbert, Zureikat, Amer H, Hogg, Melissa, Lee, Kenneth, Geller, David, Marsh, J Wallis, Paniccia, Alessandro, Ongchin, Melanie, Pingpank, James F, Bahary, Nathan, Aijazi, Muaz, Brand, Randall, Chennat, Jennifer, Das, Rohit, Fasanella, Kenneth E, Khalid, Asif, McGrath, Kevin, Sarkaria, Savreet, Singh, Harkirat, Slivka, Adam, Nalesnik, Michael, Han, Xiaoli, Nikiforova, Marina N, Lawlor, Rita Teresa, Mafficini, Andrea, Rusev, Boris, Corbo, Vincenzo, Luchini, Claudio, Bersani, Samantha, Pea, Antonio, Cingarlini, Sara, Landoni, Luca, Salvia, Roberto, Milione, Massimo, Milella, Michele, Scarpa, Aldo, Hong, Seung-Mo, Heaphy, Christopher M, Singhi, Aatur D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Pancreas
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511349/
https://www.ncbi.nlm.nih.gov/pubmed/33849943
http://dx.doi.org/10.1136/gutjnl-2020-322595
Descripción
Sumario: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.

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