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The IMPRESS assay is developed for eight lethal cancer types using 1,791 CpG sites, analyzed across blood, tumor, and normal samples, and validated with ddPCR. A classifier using 358 CpG targets achieves sensitivity 0.95 and specificity 0.91, supporting liquid biopsy potential.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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British)[ British](www.nature.com/bjc British) Journal of Cancer  \nARTICLE OPEN   \nMolecular Diagnostics  \nIMPRESS: Improved methylation profiling using restriction enzymes and smMIP sequencing, combined with a new biomarker panel, creating a multi-cancer detection assay  \nJanah Vandenhoeck 1,2,6, Isabelle Neefs 1,2,6, Thomas Vanpoucke1,2,6, Joe Ibrahim 1,2, Arvid Suls 1, Dieter Peeters3, Anne Schepers1, Alexander Hoischen4,5, Erik Fransen1, Marc Peeters2, Guy Van Camp1,2,7 and Ken Op de Beeck1,2,7 ✉  \n© The Author(s) 2024  \nBACKGROUND: Despite the worldwide progress in cancer diagnostics, more sensitive diagnostic biomarkers are needed. The methylome has been extensively investigated in the last decades, but a low-cost, bisulfite-free detection method for multiplex analysis is still lacking.  \nMETHODS: We developed a methylation detection technique called IMPRESS, which combines methylation-sensitive restriction enzymes and single-molecule Molecular Inversion Probes. We used this technique for the development of a multi-cancer detection assay for eight of the most lethal cancer types worldwide. We selected 1791 CpG sites that can distinguish tumor from normal tissue based on DNA methylation. These sites were analysed with IMPRESS in 35 blood, 111 tumor and 114 normal samples. Finally, a classifier model was built.  \nRESULTS: We present the successful development of IMPRESS and validated it with ddPCR. The final classifier model discriminating tumor from normal samples was built with 358 CpG target sites and reached a sensitivity of 0.95 and a specificity of 0.91 . Moreover, we provide data that highlight IMPRESS’s potential for liquid biopsies.  \nCONCLUSIONS: We successfully created an innovative DNA methylation detection technique. By combining this method with anew multi-cancer biomarker panel, we developed a sensitive and specific multi-cancer assay, with potential use in liquid biopsies.  \nBritish Journal of Cancer (2024) 131:1224–1236; [https://doi.org/10.1038/s41416-024-02809-1](https://doi.org/10.1038/s41416-024-02809-1)  \nINTRODUCTION  \nCancer remains one of the most lethal diseases worldwide. Breast, lung, colorectal, and prostate cancer are amongst the most common cancers, with each over 1.4 million cases per year [1] . Diagnosis typically occurs in an advanced disease stage due to the lack of clear symptoms and the absence of effective screening programs for most cancer types [2] . This is reflected in the percentages of late-stage diagnoses, for example, 68% and 59% in lung and colorectal cancer respectively [3] . Clearly, there is anunfulfilled need for effective diagnostic biomarkers.  \nAn interesting biomarker candidate for cancer detection is DNA methylation. Genome wide epigenetic reprogramming of tumors occurs early in carcinogenesis. Methylation patterns of many tumor types are widely dysregulated compared to those of healthy cells, but the tumor type specific patterns are very distinctive [4–6] . Many studies have investigated the potential of the methylome in recent years but, to date, there are only a few  \nsuccessful methylation biomarkers for cancer in a clinical setting. Our research group has already shown the promise of methylationas a diagnostic biomarker [6] . We demonstrated the capability to discriminate 14 different cancer types from normal tissue and from each other using methylation biomarkers in silico, with high sensitivity and specificity.  \nIt is important to detect biomarkers in a sensitive and specific manner. Currently, bisulfite sequencing is still considered the gold standard for DNA methylation analysis. However, bisulfite is a harsh chemical that degrades DNA, limiting the sensitivity of downstream applications [7] . Alternative bisulfite-free techniques, such as affinity-based methods (e.g. MeDIP-seq, Methyl Cap), are shown to have a lower accuracy compared to bisulfite sequencing [8] . Other bisulfite-free methods include restriction enzymes, which can eithe","cbCaisgJMvXDSEAb","https://ap.wps.com/l/cbCaisgJMvXDSEAb","pdf",1697444,"English","# Background\n# Methods\n## IMPRESS assay design and target selection\n## Sample analysis and classifier building\n# Results\n## ddPCR validation\n## Performance metrics and liquid biopsy potential\n# Conclusions\n# Introduction\n## Need for sensitive diagnostic biomarkers\n## Limitations of bisulfite and alternatives","[{\"question\":\"What problem does IMPRESS address in cancer diagnostics?\",\"answer\":\"It targets the need for more sensitive diagnostic biomarkers while providing a low-cost, bisulfite-free method for multiplex methylation analysis.\"},{\"question\":\"How does IMPRESS detect DNA methylation?\",\"answer\":\"IMPRESS combines methylation-sensitive restriction enzymes with single-molecule molecular inversion probes (smMIP) to assay methylation across selected CpG sites.\"},{\"question\":\"What performance did the final classifier achieve?\",\"answer\":\"The classifier distinguishing tumor from normal samples used 358 CpG target sites and reached sensitivity 0.95 and specificity 0.91, validated with ddPCR.\"}]","IMPRESS: Improved methylation profiling using restriction enzymes and smMIP sequencing, combined with a new biomarker panel, creating a multi-cancer detection assay | PDF",1789982290,33]