# Cell-free DNA methylation tests

Source: https://onco.cc/technologies/cfdna-methylation-testing/  
OnCo record `cfdna-methylation-testing` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Blood tests that read chemical marks on fragments of DNA shed by tumours; the marks tell cancer DNA from normal DNA and hint at where the cancer is.

## Summary

Cancer cells carry characteristic DNA methylation patterns that survive in the cell-free DNA shed into blood. Methylation-based tests use bisulfite or enzymatic conversion followed by targeted sequencing to detect a cancer signal and predict its tissue of origin; the multi-cancer early detection test Galleri works this way, and Guardant's Shield, the first blood test approved by the FDA for colorectal cancer screening in 2024, combines methylation with other cfDNA signals. Methylation also underpins some minimal residual disease assays.

## Fields

- Kind: Technology
- Status: approved
- Last checked: 2026-09-04
- Principle: Extract cfDNA from plasma, convert unmethylated cytosines, sequence targeted regions, and classify methylation patterns against reference tumour and normal profiles.
- Since: 2024
- Strengths: Tissue-agnostic cancer signal; Can point to the tissue of origin; Approved use in colorectal screening
- Limitations: Sensitivity for early-stage cancers is modest; False positives and unclear follow-up pathways; Outcome benefit of multi-cancer screening still under trial

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cell-free_fetal_DNA
- Wikipedia: https://en.wikipedia.org/wiki/Cell-free_fetal_DNA

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Early Detection & Screening](https://onco.cc/fronts/early-detection/)
- technologies: [Bladder EpiCheck urine methylation test](https://onco.cc/technologies/bladder-epicheck/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Multi-cancer early detection (MCED)](https://onco.cc/technologies/mced/)
- drugs: [CancerFind](https://onco.cc/drugs/cancerfind/), [EpiPanGI Dx](https://onco.cc/drugs/epipangi-dx/), [Galleri](https://onco.cc/drugs/galleri/), [OverC Multi-Cancer Detection Blood Test](https://onco.cc/drugs/overc-mcdbt/), [PanSeer](https://onco.cc/drugs/panseer/), [Shield MCD (Shield Multi-Cancer Detection)](https://onco.cc/drugs/shield-mcd/), [SPOT-MAS](https://onco.cc/drugs/spot-mas/)
- key papers: [Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set](https://onco.cc/key-papers/paper-klein-ccga3-mced-validation-ann-oncol-2021/), [Effect of Screening with Multicancer Early-Detection Test on Late-Stage Cancer Diagnosis](https://onco.cc/key-papers/paper-nhs-galleri-primary-nejm-2026/), [EpiPanGI Dx: A Cell-free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers](https://onco.cc/key-papers/paper-epipangi-dx-clin-cancer-res-2021/), [Evaluation of cell-free DNA approaches for multi-cancer early detection](https://onco.cc/key-papers/paper-jamshidi-ccga1-cfdna-approaches-cancer-cell-2022/), [Exploration of multi-omics liquid biopsy approaches for multi-cancer early detection: The PROMISE study](https://onco.cc/key-papers/paper-promise-innovation-2026/), [Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study](https://onco.cc/key-papers/paper-symplify-lancet-oncol-2023/), [Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization](https://onco.cc/key-papers/paper-spot-mas-elife-2023/), [Non-invasive early detection of cancer four years before conventional diagnosis using a blood test](https://onco.cc/key-papers/paper-panseer-nat-commun-2020/), [Performance and safety of a multi-cancer early detection test: the PATHFINDER 2 study](https://onco.cc/key-papers/paper-pathfinder-2-nat-med-2026/), [Performance of a multi-biomarker class, multi-cancer early detection (MCED) blood test in a prospectively collected cohort](https://onco.cc/key-papers/paper-cancerguard-mp-classifier-cebp-2026/), [Performance of a multi-cancer early detection test in the randomized controlled NHS-Galleri trial](https://onco.cc/key-papers/paper-nhs-galleri-performance-nat-med-2026/), [Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA](https://onco.cc/key-papers/paper-liu-ccga2-methylation-ann-oncol-2020/), [Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and independent validation studies](https://onco.cc/key-papers/paper-gao-thunder-ann-oncol-2023/)
- terms: [CCGA: the Circulating Cell-free Genome Atlas behind the Galleri methylation test](https://onco.cc/terms/ccga-study/), [Tumour-informed versus tumour-naive ctDNA assays](https://onco.cc/terms/tumour-informed-assay/)
- trials: [NHS-Galleri](https://onco.cc/trials/nhs-galleri/), [PATHFINDER 2](https://onco.cc/trials/pathfinder-2/)
- roadmaps: [ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment](https://onco.cc/roadmaps/ctdna-tests/)
- companies: [IMBdx](https://onco.cc/companies/imbdx/), [Singlera Genomics](https://onco.cc/companies/singlera/)

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