Ajay Goel, Ph.D. of the City of Hope speaks about the AACR 2020 Abstract 1084: EpiPanGI-Dx: A cell-free DNA methylation fingerprint for the early detection of gastrointestinal cancers.
Summary
Purpose: DNA methylation alterations have emerged as front-runners in biomarker development in view of high cancer specificity, especially as cell-free DNA (cf-DNA) biomarkers for early cancer detection. Much effort to date, however, has concentrated on the development of cancer type-specific biomarkers, but the prospect of developing a pan-cancer diagnostic assay has not been explored. In this sense, gastrointestinal ( GI) cancers, including colorectal (CRC), esophageal squamous cell and adenocarcinoma (ESCC and EAC), gastric (GC), liver (HCC) and pancreatic ductal adenocarcinoma (PDAC) are the world’s second leading cause of cancer-related deaths; but, early detection and population screening of GI cancers is not done through blood. A genome-wide DNA methylation study for multiple GI cancers was carried out here, followed by the creation of a new biomarker panel for cf-DNA methylation for early detection of GI cancers (EpiPanGI Dx).
Experimental design: We first identified the differentially methylated regions (DMRs) between individual GI cancers and adjacent normal tissues, as well as across all GI cancers by analyzing the DNA methylation data from the 1940 tumor and adjacent normal tissues from TCGA and GSE72872 datasets. Next, we prioritized a list of DMRs covering a genomic area of 25.6 Mb by integrating all known DMRs across various GI cancers to build a custom SeqCap Epi, a targeted bisulfite sequencing platform that is optimized for the study of plasma-derived low-abundance cf-DNA. Using this method, we sequenced 300 plasma specimens from all GI cancers with a 40X coverage, as well as age-matched stable controls. Lastly, we defined special DMR panels for the detection of different GI cancers using machine learning algorithms.
Results: In all the comparisons across all GI cancers, methylation profiling results from different GI tissues contributed to the detection of 67,832 DMRs with a modified p<0.001 and a delta beta value of 0.2. Subsequent analysis of these tissue-specific DMRs in 300 cf-DNA specimens using our custom SeqCap panel resulted in the development of three distinct categories of DMR panels: 1) Cancer-specific biomarker panels with AUC values of 0.98 (CRC), 0.94 (ESCC), 0.90 (EAC), 0.90 (GC), 0.98 (HCC), and 0.85 (PDAC); 2) A pan-GI biomarker panel which detected all GI cancers with an AUC of 0.90; and 3) A multi-cancer prediction When qualified and tested in the cf-DNA cohorts, all three groups of DMR panels achieved excellent diagnostic precision with AUC values ranging from 0.74-0.98, including for each of the early-stage GI cancers.
Conclusions: Using a novel approach to biomarker discovery, we provide first evidence for cell-free biomarkers of DNA methylation that provide robust diagnostic precision for the identification of specific types of cancer and demonstrate their possible clinical use as an early detection panel for all gastrointestinal cancers.
Citation Format: Raju Kandimalla, Jianfeng Xu, Alexander Link, Takatoshi Matsuyama, Kensuke Yamamura, Iqbal Parker, Hiroyuki Uetake, Eva Hernández-Illan, Juanjo Lozano, Erkut Borazanci, Susan Tsai, Douglas Evans, Stephen J. Meltzer, Hideo Baba, Randall Brand, Daniel Von Hoff, Francesc Balaguer, Wei Li, Ajay Goel. EpiPanGI-Dx: A cell-free DNA methylation fingerprint for early detection of [abstract] gastrointestinal cancers. In: Proceedings of the American Association for Cancer Research Annual Meeting 2020; Apr 27-28 and Jun 22-24, 2020. AACR; Cancer Res 2020;80(16 Suppl): Abstract nr 1084. Philadelphia (PA).
https://cancerres.aacrjournals.org/content/80/16_Supplement/1084