The evolutionary history of metastatic pancreatic neuroendocrine tumours reveals a therapy driven route to high-grade transformation.
alkylating chemotherapy
heterogeneity
metastasis
mismatch repair
multi‐omics
neuroendocrine tumours
pancreas
tumour evolution
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
03 Oct 2024
03 Oct 2024
Historique:
revised:
08
08
2024
received:
13
02
2024
accepted:
09
08
2024
medline:
3
10
2024
pubmed:
3
10
2024
entrez:
3
10
2024
Statut:
aheadofprint
Résumé
Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high-grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high-grade disease. We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post-alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with MEN1 inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high-grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden >50 (50%). In comparison, among the eight patients who did not show high-grade progression, 0 had a tumour mutational burden >50 (0%; odds ratio 'infinite', 95% confidence interval 1.8 to 'infinite', p = 0.02). Our findings contribute to broaden the understanding of metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Cancerfonden
Organisme : European Neuroendocrine Tumor Society
Organisme : Vetenskapsrådet
Organisme : Åke Wiberg Stiftelse
Organisme : Knut and Alice Wallenberg Foundation
Organisme : Intramural Research Program of the National Institutes of Health
Organisme : Swedish Research Council
Organisme : Eunice Kennedy Shriver National Institute of Child Health and Human Development
Organisme : American Association for Cancer Research
Organisme : Lions Cancerforskningsfond Uppsala
Organisme : Söderbergs stiftelser
Informations de copyright
© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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