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

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252130 | GEO | 2024/11/20

REPOSITORIES: GEO

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Project description:Background: With the incidence of papillary thyroid carcinoma rising worldwide, the decision about lobectomy versus total thyroidectomy will become relevant for an increasing number of patients. There exists no reliable biomarker for metastatic potential or tendency of recurrence that could assist in the risk stratification of patients. Objective: To develop a gene expression classifier for metastatic potential by measuring RNA expression in the primary tumor at the time of cancer surgery. Further, to investigate the ability of the gene expression classifier to identify metastatic and recurrent cases. Method: Genome-wide expression analyses. The development cohort consisted of freshly frozen tissues from 38 patients collected between the years 1986 and 2009. Validation was performed on a consecutive cohort of formalin fixated paraffin embedded surgical tissue specimens from 183 patients treated at Odense and Aarhus University Hospitals. Results: A 17 gene classifier (ADAMTS1, ANTXR1, C7, CXCL12, EBF1, FBLN2, FOSL2, GGT5, GPR124, JAM3, LRIG1, NDRG1, PRRX1, ROBO1, SORL1, TCF4, and ZEB1) was identified based on the expression values of these genes in the groups with and without metastasis in the development cohort. The 17 gene classifier for regional and/or distant metastasis identified was tested against the clinical status in the validation cohort. Sensitivity was 51.6% (95% CI 41.2%-61.8) and specificity 61.6 % (95% CI 50.5%-71.9%). Further, the Kaplan-Meyer method was used to estimate whether the classifier was useful as a prognostic marker for recurrences. Log-rank testing failed to identify any significance (p=0.32). Conclusion: A 17 gene classifier for metastatic potential was developed, and the results showed a clear biological difference between groups. However, through validation, the prognostic significance of this classifier could not be shown in identifying metastatic cases or in the ability of dichotomizing patients according to risk of recurrence after primary treatment. 38 patients with papillary thyroid carcinoma from a consecutive cohort of patients, no replicates

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

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