Faculty Collaboration Database

EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers. Clin Cancer Res 2021 Nov 15;27(22):6135-6144

Date

09/02/2021

Pubmed ID

34465601

Pubmed Central ID

PMC8595812

DOI

10.1158/1078-0432.CCR-21-1982

Scopus ID

2-s2.0-85119931744 (requires institutional sign-in at Scopus site)   74 Citations

Abstract

PURPOSE: DNA methylation alterations have emerged as front-runners in cell-free DNA (cfDNA) biomarker development. However, much effort to date has focused on single cancers. In this context, gastrointestinal (GI) cancers constitute the second leading cause of cancer-related deaths worldwide; yet there is no blood-based assay for the early detection and population screening of GI cancers.

EXPERIMENTAL DESIGN: Herein, we performed a genome-wide DNA methylation analysis of multiple GI cancers to develop a pan-GI diagnostic assay. By analyzing DNA methylation data from 1,781 tumor and adjacent normal tissues, we first identified differentially methylated regions (DMR) between individual GI cancers and adjacent normal, as well as across GI cancers. We next prioritized a list of 67,832 tissue DMRs by incorporating all significant DMRs across various GI cancers to design a custom, targeted bisulfite sequencing platform. We subsequently validated these tissue-specific DMRs in 300 cfDNA specimens and applied machine learning algorithms to develop three distinct categories of DMR panels RESULTS: We identified three distinct DMR panels: (i) cancer-specific biomarker panels with AUC values of 0.98 (colorectal cancer), 0.98 (hepatocellular carcinoma), 0.94 (esophageal squamous cell carcinoma), 0.90 (gastric cancer), 0.90 (esophageal adenocarcinoma), and 0.85 (pancreatic ductal adenocarcinoma); (ii) a pan-GI panel that detected all GI cancers with an AUC of 0.88; and (iii) a multi-cancer (tissue of origin) prediction panel, EpiPanGI Dx, with a prediction accuracy of 0.85-0.95 for most GI cancers.

CONCLUSIONS: Using a novel biomarker discovery approach, we provide the first evidence for a cfDNA methylation assay that offers robust diagnostic accuracy for GI cancers.

Author List

Kandimalla R, Xu J, Link A, Matsuyama T, Yamamura K, Parker MI, Uetake H, Balaguer F, Borazanci E, Tsai S, Evans D, Meltzer SJ, Baba H, Brand R, Von Hoff D, Li W, Goel A

Author

Douglas B. Evans MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Area Under Curve
Biomarkers, Tumor
Cell-Free Nucleic Acids
DNA Methylation
Early Detection of Cancer
Epigenesis, Genetic
Epigenomics
Gastrointestinal Neoplasms
Gene Expression Profiling
Humans
ROC Curve