# Inferring gene expression from cell-free DNA fragmentation profiles

Source: https://onco.cc/key-papers/paper-esfahani-epic-seq-nat-biotechnol-2022/  
OnCo record `paper-esfahani-epic-seq-nat-biotechnol-2022` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

How DNA fragments in blood are cut at the start of each gene predicted how active that gene was, enough to tell lung and lymphoma subtypes apart.

## Summary

Promoter fragmentation entropy is an epigenomic cell-free DNA feature that predicts RNA expression at individual genes. EPIC-seq applies it with targeted sequencing of promoters. In 329 blood samples from 201 patients with cancer and 87 healthy adults it classified subtypes of lung carcinoma and diffuse large B-cell lymphoma, and in serial samples from patients on PD-1 or PD-L1 inhibitors the inferred expression profiles correlated with clinical response.

## Fields

- Kind: Key paper
- Last checked: 2026-11-04
- Journal: Nature Biotechnology
- Year: 2022
- DOI: 10.1038/s41587-022-01222-4
- Authors: Esfahani MS, Hamilton EG, Mehrmohamadi M, et al.
- Findings: 329 samples from 201 patients with cancer and 87 healthy adults.; Lung carcinoma and DLBCL subtypes classified from blood.; Histology accuracy 87% above 5% mean allele fraction and 73% below 1% (full text).
- What it means: Gene expression, not only mutation, can be inferred from blood, and the method keeps some accuracy below 1 per cent tumour DNA. That is still far above residual-disease levels.
- Caveats: Accuracy falls with tumour fraction.; Not tested for oestrogen receptor or TROP2.

## Sources

- Esfahani et al., Nat Biotechnol 2022: https://doi.org/10.1038/s41587-022-01222-4
- PubMed: https://pubmed.ncbi.nlm.nih.gov/35361996/

## Connected records

- cancers: [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/)
- technologies: [cfDNA fragmentomics](https://onco.cc/technologies/fragmentomics/), [EPIC-seq (expression inference from cell-free DNA)](https://onco.cc/technologies/epic-seq/)
- terms: [Cell-free DNA (cfDNA)](https://onco.cc/terms/cfdna/), [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/)
- journals: [Nature Biotechnology](https://onco.cc/journals/nature-biotechnology/)

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