DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms

Neuroendocrine neoplasms (NEN) are thought to originate from diffuse neuroendocrine networks and therefore most frequently arise in the gastrointestinal tract and lungs. The liver is a frequent site of metastasis of NEN but also the existence of primary hepatic NEN has been proposed. Due to the impact on disease management, it is urgently required to discriminate the origin of hepatic NEN metastases and to identify clinically relevant subgroups. Using a comprehensive set of NEN (N = 212) from two independent cohorts, we show that the DNA methylation profiles of NEN of distinct anatomical localizations differ significantly and primary tumor-metastasis pairs cluster together, enabling the identification of the tumor origin. Furthermore, the subgroup of hepatic NEN without clinically detectable primary tumor, thus classified as primary hepatic NEN, does not form a distinct cluster by DNA methylation analysis but colocalizes with various subgroups of extrahepatic NEN. Organ-specific subtyping of NEN delineates a foregut-like epigenetic profile for hepatic NEN with unknown primary. We propose a classifier with high prediction accuracy for each of the different organ sites. In conclusion, our results demonstrate that DNA methylation profiling enables precise prediction of NEN origin and suggests that a substantial proportion of presumed primary hepatic NEN may in fact represent misclassified secondary hepatic NEN of unknown primary.

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Publication Details

Journal
Nature Communications
Published
2025-10-27
DOI
https://doi.org/10.1038/s41467-025-65227-8
Citations
2
Primary Topic
Neuroendocrine Tumor Research Advances
Type
article
Field-Weighted Citation Impact
2.71
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article

DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms

De‐Hua Chang, Louis de Mestier, Petr V. Nazarov, Thomas Albrecht et al.
2 citations
Nature Communications
Neuroendocrine Tumor Research Advances
2.71
article

DNA methylation patterns facilitate tracing the origin of neuroendocrine neoplasms

De‐Hua Chang, Louis de Mestier, Petr V. Nazarov, Thomas Albrecht, Stéphanie Roessler, Benjamin Goeppert, Daniel Schrimpf, Junfang Ji, Alexander Brobeil, Leonidas Apostolidis, Aurel Perren, Andreas von Deimling, Réka Tóth, Jérôme Cros, Alphonse Charbel, E. W. Bohn, Yue Zhang, Stephan Singer, Monika Vogel, Danial Tabbakh
article en
2 citations

Abstract

Neuroendocrine neoplasms (NEN) are thought to originate from diffuse neuroendocrine networks and therefore most frequently arise in the gastrointestinal tract and lungs. The liver is a frequent site of metastasis of NEN but also the existence of primary hepatic NEN has been proposed. Due to the impact on disease management, it is urgently required to discriminate the origin of hepatic NEN metastases and to identify clinically relevant subgroups. Using a comprehensive set of NEN (N = 212) from two independent cohorts, we show that the DNA methylation profiles of NEN of distinct anatomical localizations differ significantly and primary tumor-metastasis pairs cluster together, enabling the identification of the tumor origin. Furthermore, the subgroup of hepatic NEN without clinically detectable primary tumor, thus classified as primary hepatic NEN, does not form a distinct cluster by DNA methylation analysis but colocalizes with various subgroups of extrahepatic NEN. Organ-specific subtyping of NEN delineates a foregut-like epigenetic profile for hepatic NEN with unknown primary. We propose a classifier with high prediction accuracy for each of the different organ sites. In conclusion, our results demonstrate that DNA methylation profiling enables precise prediction of NEN origin and suggests that a substantial proportion of presumed primary hepatic NEN may in fact represent misclassified secondary hepatic NEN of unknown primary.

Nature CommunicationsVol. 16(1)
University of Bern (CH), Inserm (FR), German Cancer Research Center (DE), Université Paris Cité (FR), Heidelberg University (DE), Hôpital Beaujon (FR), University Hospital Heidelberg (DE), Robert Bosch Hospital (DE), Assistance Publique – Hôpitaux de Paris (FR), Luxembourg Institute of Health (LU), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), Luzerner Kantonsspital (CH), Klinikum Ludwigsburg (DE), Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE), Zhejiang University (CN), University of Tübingen (DE)
Openalex Percentile: Top 8%
Neuroendocrine Tumor Research Advances
2.71
DOIOpen Access PDFOpenAlex
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