# Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA

Source: https://onco.cc/key-papers/paper-liu-ccga2-methylation-ann-oncol-2020/  
OnCo record `paper-liu-ccga2-methylation-ann-oncol-2020` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The study that chose methylation as the basis of the Galleri test: in 6,689 people it found cancers of more than 50 types with few false positives, though only about one in five stage I cancers.

## Summary

A prospective case-control substudy of the Circulating Cell-free Genome Atlas (NCT02889978) and STRIVE (NCT03085888): 6,689 participants (2,482 with cancer of more than 50 types, 4,207 without) were divided into training and validation sets, and plasma cell-free DNA underwent bisulfite sequencing of a panel of more than 100,000 methylation regions. In validation, specificity was 99.3% (95% CI 98.3 to 99.8). Stage I to III sensitivity was 67.3% in 12 prespecified cancer types and 43.9% in all cancer types. Across all cancer types sensitivity was 18% at stage I, 43% at stage II, 81% at stage III and 93% at stage IV. Tissue of origin was predicted in 96% of samples with a cancer-like signal and was accurate in 93% of those.

## Fields

- Kind: Key paper
- Last checked: 2026-10-29
- Journal: Annals of Oncology
- Year: 2020
- DOI: 10.1016/j.annonc.2020.02.011
- Authors: Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, CCGA Consortium
- Findings: Specificity 99.3% in the validation set.; All cancer types: stage I 18%, stage II 43%, stage III 81%, stage IV 93% sensitivity.; Tissue of origin accurate in 93% of samples where it was predicted.
- What it means: Methylation patterns can flag many cancers and point to the organ, but the cancers most worth catching early were the ones least often found.
- Caveats: Case-control design with cancers already diagnosed; screening performance is lower.; Sponsored by GRAIL.

## Sources

- Annals of Oncology 2020: CCGA second substudy: https://doi.org/10.1016/j.annonc.2020.02.011
- PubMed: https://pubmed.ncbi.nlm.nih.gov/33506766/
- ClinicalTrials.gov NCT02889978: https://clinicaltrials.gov/study/NCT02889978

## Connected records

- fronts: [Early Detection & Screening](https://onco.cc/fronts/early-detection/)
- technologies: [Cell-free DNA methylation tests](https://onco.cc/technologies/cfdna-methylation-testing/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Multi-cancer early detection (MCED)](https://onco.cc/technologies/mced/)
- drugs: [Galleri](https://onco.cc/drugs/galleri/)
- companies: [GRAIL](https://onco.cc/companies/grail/)
- trials: [CCGA (Circulating Cell-free Genome Atlas)](https://onco.cc/trials/ccga/), [STRIVE (GRAIL breast screening cohort)](https://onco.cc/trials/strive-grail/)
- people: [Charles Swanton](https://onco.cc/people/charles-swanton/), [Eric A. Klein](https://onco.cc/people/eric-klein/)
- journals: [Annals of Oncology](https://onco.cc/journals/annals-of-oncology/)

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