MetDecode: methylation-based deconvolution of cell-free DNA for non-invasive multi-cancer typing

Cell-free DNA (cfDNA) mediated early cancer detection is based on detecting alterations in the cfDNA components. However, the underlying pathology can usually not be readily identified. We built a reference atlas based on the methylome of multiple cancer and blood-cell types and developed MetDecode, an epigenetic signature-based deconvolution algorithm. MetDecode accurately estimates the tumour proportion in in-silico mixtures and identifies the tissue of origin in 81.25% cfDNA samples from cancer patients. This method will complement cancer screening programs and guide clinical follow-up. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Research Foundation-Flanders (FWO-Vlaanderen; 1S74420N to ST; 1SB2721N to AP, 12Y5623N to DR), Agentschap Innoveren en Ondernemen (VLAIO; Flanders Innovation and Entrepreneurship grant HBC.2018.2108 to TJ), Stichting tegen Kanker (STK grant 2018-134 to JRV and FA), Kom op tegen Kanker (KotK grant 2018/11468 to JRV and FA, KotK grant 2016/10728/2603 to AC). DT is Senior Clinical Investigator FWO - Fund for Scientific Research Flanders. GF is recipient of a post-doctoral mandate sponsored by KOOR of the University Hospitals Leuven. European Union's Horizon 2020 research and innovation program under grant agreement No 824110 - EASI-Genomics (JRV) and Institutional support from the KU Leuven, C1- C14/18/092, C14/22/125 to JRV and C3/20/100 to JRV and YM. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethical committee of the University Hospitals Leuven (study protocols S62285, S62795, S63983, S66450, S59207 and S51375) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study is in controlled access data storage in EGA under EGAS00001007493 and is available upon reasonable request. MetDecode is available on GitHub as a Python package: * cfDNA : cell-free DNA TOO : tissue of origin CNA : copy number alterations FFPE : formalin-fixed paraffin-embedded WGBS : whole genome bisulfite sequencing NNLS : non-negative least squares MSE : mean squared error HGSOC : high-grade serous ovarian carcinoma WBC : white blood cells CBC : complete blood counting TF : tumour fraction MSS : microsatellite stable LGSOC : low-grade serous carcinoma BRCA : breast carcinoma CERCA : cervical carcinoma COLCA : colorectal carcinoma OVCA : ovarian carcinoma NA : not assigned SVR : support vector regression