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DNA methylation classifier to diagnose pancreatic ductal adenocarcinoma metastases from different anatomical sites

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Title: DNA methylation classifier to diagnose pancreatic ductal adenocarcinoma metastases from different anatomical sites
Authors: Teodor G. Calina, Eilís Perez, Elena Grafenhorst, Jamal Benhamida, Simon Schallenberg, Adrian Popescu, Ines Koch, Tobias Janik, BaoQing Chen, Jana Ihlow, Stephanie Roessler, Benjamin Goeppert, Bruno Sinn, Marcus Bahra, George A. Calin, Eliane T. Taube, Uwe Pelzer, Christopher C. M. Neumann, David Horst, Erik Knutsen, David Capper, Mihnea P. Dragomir
Source: Clin Epigenetics
Clinical Epigenetics, Vol 16, Iss 1, Pp 1-17 (2024)
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Male, 0301 basic medicine, DNA Methylation/genetics [MeSH], Cholangiocarcinoma/diagnosis [MeSH], Aged [MeSH], Pancreatic Neoplasms/pathology [MeSH], Diagnosis, Differential [MeSH], Male [MeSH], Pancreatic Neoplasms/diagnosis [MeSH], Breast Neoplasms/diagnosis [MeSH], DNA methylation, Liver Neoplasms/genetics [MeSH], Breast Neoplasms/pathology [MeSH], Female [MeSH], Pancreatic Neoplasms/genetics [MeSH], Liver Neoplasms/diagnosis [MeSH], Humans [MeSH], Bile Duct Neoplasms/diagnosis [MeSH], Breast Neoplasms/genetics [MeSH], Bile Duct Neoplasms/pathology [MeSH], Middle Aged [MeSH], Carcinoma, Pancreatic Ductal/genetics [MeSH], Cancer of unknown primary, Carcinoma, Pancreatic Ductal/pathology [MeSH], Cholangiocarcinoma/pathology [MeSH], Liver Neoplasms/secondary [MeSH], Epigenetics, Molecular diagnosis, Research, Biomarkers, Tumor/genetics [MeSH], Neoplasm Metastasis/genetics [MeSH], Pancreatic ductal adenocarcinoma, Cholangiocarcinoma/genetics [MeSH], Bile Duct Neoplasms/genetics [MeSH], Breast Neoplasms, QH426-470, Cholangiocarcinoma, Diagnosis, Differential, 03 medical and health sciences, Genetics, Biomarkers, Tumor, Humans, Neoplasm Metastasis, Aged, 0303 health sciences, Liver Neoplasms, DNA Methylation, Middle Aged, Pancreatic Neoplasms, Bile Duct Neoplasms, Medicine, Female, Carcinoma, Pancreatic Ductal
Description: Background We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites. Methods For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain. Results The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition. Conclusions The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid.
Document Type: Article
Other literature type
Language: English
ISSN: 1868-7083
DOI: 10.1186/s13148-024-01768-x
Access URL: https://pubmed.ncbi.nlm.nih.gov/39523345
https://doaj.org/article/6d749e8836f14bb88e912de9ad31cd5f
https://repository.publisso.de/resource/frl:6523952
Rights: CC BY
Accession Number: edsair.doi.dedup.....8e87a00f14f465bc1a44f32d9bd36bc4
Database: OpenAIRE
Description
Abstract:Background We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites. Methods For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain. Results The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition. Conclusions The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid.
ISSN:18687083
DOI:10.1186/s13148-024-01768-x