Dataset Information

EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers.

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.

SUBMITTER: Kandimalla R

PROVIDER: S-EPMC8595812 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers.

Kandimalla Raju R Xu Jianfeng J Link Alexander A Matsuyama Takatoshi T Yamamura Kensuke K Parker M Iqbal MI Uetake Hiroyuki H Balaguer Francesc F Borazanci Erkut E Tsai Susan S Evans Douglas D Meltzer Stephen J SJ Baba Hideo H Brand Randall R Von Hoff Daniel D Li Wei W Goel Ajay A

Clinical cancer research : an official journal of the American Association for Cancer Research 20210831 22

<h4>Purpose</h4>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.<h4>Experimental design</h4>Herein, we performed a genome-wide DNA methylation analysis of multiple GI ...[more]

PMID: 34465601

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Project description:BackgroundLung cancer remains the leading cause of cancer mortality worldwide. Early detection of lung cancer helps improve treatment and survival. Numerous aberrant DNA methylations have been reported in early-stage lung cancer. Here, we sought to identify novel DNA methylation biomarkers that could potentially be used for noninvasive early diagnosis of lung cancers.MethodsThis prospective-specimen collection and retrospective-blinded-evaluation trial enrolled a total of 317 participants (198 tissues and 119 plasmas) comprising healthy controls, patients with lung cancer and benign disease between January 2020 and December 2021. Tissue and plasma samples were subjected to targeted bisulfite sequencing with a lung cancer specific panel targeting 9,307 differential methylation regions (DMRs). DMRs associated with lung cancer were identified by comparing the methylation profiles of tissue samples from patients with lung cancer and benign disease. Markers were selected with minimum redundancy and maximum relevance algorithm. A prediction model for lung cancer diagnosis was built through logistic regression algorithm and validated independently in tissue samples. Furthermore, the performance of this developed model was evaluated in a set of plasma cell-free DNA (cfDNA) samples.ResultsWe identified 7 DMRs corresponding to 7 differentially methylated genes (DMGs) including HOXB4, HOXA7, HOXD8, ITGA4, ZNF808, PTGER4, and B3GNTL1 that were highly associated with lung cancer by comparing the methylation profiles of lung cancer and benign nodule tissue. Based on the 7-DMR biomarker panel, we developed a new diagnostic model in tissue samples, termed "7-DMR model", to distinguish lung cancers from benign diseases, achieving AUCs of 0.97 (95%CI: 0.93-1.00)/0.96 (0.92-1.00), sensitivities of 0.89 (0.82-0.95)/0.92 (0.86-0.98), specificities of 0.94 (0.89-0.99)/1.00 (1.00-1.00), and accuracies of 0.90 (0.84-0.96)/0.94 (0.89-0.99) in the discovery cohort (n = 96) and the independent validation cohort (n = 81), respectively. Furthermore, the 7-DMR model was applied to noninvasive discrimination of lung cancers and non-lung cancers including benign lung diseases and healthy controls in an independent validation cohort of plasma samples (n = 106), yielding an AUC of 0.94 (0.86-1.00), sensitivity of 0.81 (0.73-0.88), specificity of 0.98 (0.95-1.00), and accuracy of 0.93 (0.89-0.98).ConclusionThe 7 novel DMRs could be promising methylation biomarkers that merits further development as a noninvasive test for early detection of lung cancer.

Dataset Information

EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers.

Purpose

Experimental design

Conclusions

Publications

EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers.

Similar Datasets

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