Faculty, Staff and Student Publications

Publication Date

11-10-2024

Journal

Clinical Epigenetics

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.

Keywords

Humans, DNA Methylation, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Female, Male, Cholangiocarcinoma, Liver Neoplasms, Middle Aged, Aged, Diagnosis, Differential, Neoplasm Metastasis, Bile Duct Neoplasms, Biomarkers, Tumor, Breast Neoplasms, Pancreatic ductal adenocarcinoma, DNA methylation, Molecular diagnosis, Cancer of unknown primary, Epigenetics

DOI

10.1186/s13148-024-01768-x

PMID

39523345

PMCID

PMC11550539

PubMedCentral® Posted Date

11-10-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

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