Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas

Amanda Frydendahl; Adam J. Widman; Nadia Øgaard; Anushri Arora; Daniel Halmos; Jesper Nors; Johanne Ahrenfeldt; Tenna V. Henriksen; Christina Demuth; Line Raaby; Mads Heilskov Rasmussen; Christina Therkildsen; Dan A. Landau; Claus L. Andersen

doi:10.1002/1878-0261.13803

Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas

Amanda Frydendahl, Adam J. Widman, Nadia Øgaard, Anushri Arora, Daniel Halmos, Jesper Nors, Johanne Ahrenfeldt, Tenna V. Henriksen, Christina Demuth, Line Raaby, Mads Heilskov Rasmussen, Christina Therkildsen, Dan A. Landau, Claus L. Andersen^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

The presence of circulating tumor DNA (ctDNA) in patients with colorectal adenomas remains uncertain. Studies using tumor-agnostic approaches report ctDNA in 10–15% of patients, though with uncertainty as to whether the signal originates from the adenoma. To obtain an accurate estimate of the proportion of patients with ctDNA, a sensitive tumor-informed strategy is preferred, as it ensures the detected signal originates from the adenoma. Here, tumor-informed whole-genome sequencing-based ctDNA analysis (MRD-EDGE^SNV) was applied to two independent cohorts. Cohort 1, comprising 93 patients with stage III colorectal cancer (CRC) and 40 healthy individuals, was used to establish the signal threshold at 95% specificity. This threshold was then applied to Cohort 2, consisting of 22 patients with symptomatic and 20 with asymptomatic adenomas. In stage III, MRD-EDGE^SNV had an area under the curve of 0.98. ctDNA was detected in 50% and 25% of patients with symptomatic and asymptomatic adenomas, respectively. The median adenoma plasma tumor fraction was 5.9 × 10⁻⁵. These finding not only demonstrate the feasibility of ctDNA detection in patients with colorectal adenomas, but also provides an estimate of the necessary sensitivity required to detect these lesions, paving the way for future ctDNA-based screening strategies.

Original language	English
Journal	Molecular Oncology
ISSN	1574-7891
DOIs	https://doi.org/10.1002/1878-0261.13803
Publication status	Published - 20 Jan 2025

Keywords

adenomas
circulating tumor DNA
colorectal cancer
early detection
whole-genome sequencing

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Frydendahl, A., Widman, A. J., Øgaard, N., Arora, A., Halmos, D., Nors, J., Ahrenfeldt, J., Henriksen, T. V., Demuth, C., Raaby, L., Rasmussen, M. H., Therkildsen, C., Landau, D. A., & Andersen, C. L. (2025). Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas. Molecular Oncology. https://doi.org/10.1002/1878-0261.13803

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title = "Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas",

abstract = "The presence of circulating tumor DNA (ctDNA) in patients with colorectal adenomas remains uncertain. Studies using tumor-agnostic approaches report ctDNA in 10–15% of patients, though with uncertainty as to whether the signal originates from the adenoma. To obtain an accurate estimate of the proportion of patients with ctDNA, a sensitive tumor-informed strategy is preferred, as it ensures the detected signal originates from the adenoma. Here, tumor-informed whole-genome sequencing-based ctDNA analysis (MRD-EDGESNV) was applied to two independent cohorts. Cohort 1, comprising 93 patients with stage III colorectal cancer (CRC) and 40 healthy individuals, was used to establish the signal threshold at 95% specificity. This threshold was then applied to Cohort 2, consisting of 22 patients with symptomatic and 20 with asymptomatic adenomas. In stage III, MRD-EDGESNV had an area under the curve of 0.98. ctDNA was detected in 50% and 25% of patients with symptomatic and asymptomatic adenomas, respectively. The median adenoma plasma tumor fraction was 5.9 × 10−5. These finding not only demonstrate the feasibility of ctDNA detection in patients with colorectal adenomas, but also provides an estimate of the necessary sensitivity required to detect these lesions, paving the way for future ctDNA-based screening strategies.",

keywords = "adenomas, circulating tumor DNA, colorectal cancer, early detection, whole-genome sequencing",

author = "Amanda Frydendahl and Widman, {Adam J.} and Nadia {\O}gaard and Anushri Arora and Daniel Halmos and Jesper Nors and Johanne Ahrenfeldt and Henriksen, {Tenna V.} and Christina Demuth and Line Raaby and Rasmussen, {Mads Heilskov} and Christina Therkildsen and Landau, {Dan A.} and Andersen, {Claus L.}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",

year = "2025",

month = jan,

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doi = "10.1002/1878-0261.13803",

language = "English",

journal = "Molecular Oncology",

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T1 - Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas

AU - Frydendahl, Amanda

AU - Widman, Adam J.

AU - Øgaard, Nadia

AU - Arora, Anushri

AU - Halmos, Daniel

AU - Nors, Jesper

AU - Ahrenfeldt, Johanne

AU - Henriksen, Tenna V.

AU - Demuth, Christina

AU - Raaby, Line

AU - Rasmussen, Mads Heilskov

AU - Therkildsen, Christina

AU - Landau, Dan A.

AU - Andersen, Claus L.

PY - 2025/1/20

Y1 - 2025/1/20

N2 - The presence of circulating tumor DNA (ctDNA) in patients with colorectal adenomas remains uncertain. Studies using tumor-agnostic approaches report ctDNA in 10–15% of patients, though with uncertainty as to whether the signal originates from the adenoma. To obtain an accurate estimate of the proportion of patients with ctDNA, a sensitive tumor-informed strategy is preferred, as it ensures the detected signal originates from the adenoma. Here, tumor-informed whole-genome sequencing-based ctDNA analysis (MRD-EDGESNV) was applied to two independent cohorts. Cohort 1, comprising 93 patients with stage III colorectal cancer (CRC) and 40 healthy individuals, was used to establish the signal threshold at 95% specificity. This threshold was then applied to Cohort 2, consisting of 22 patients with symptomatic and 20 with asymptomatic adenomas. In stage III, MRD-EDGESNV had an area under the curve of 0.98. ctDNA was detected in 50% and 25% of patients with symptomatic and asymptomatic adenomas, respectively. The median adenoma plasma tumor fraction was 5.9 × 10−5. These finding not only demonstrate the feasibility of ctDNA detection in patients with colorectal adenomas, but also provides an estimate of the necessary sensitivity required to detect these lesions, paving the way for future ctDNA-based screening strategies.

AB - The presence of circulating tumor DNA (ctDNA) in patients with colorectal adenomas remains uncertain. Studies using tumor-agnostic approaches report ctDNA in 10–15% of patients, though with uncertainty as to whether the signal originates from the adenoma. To obtain an accurate estimate of the proportion of patients with ctDNA, a sensitive tumor-informed strategy is preferred, as it ensures the detected signal originates from the adenoma. Here, tumor-informed whole-genome sequencing-based ctDNA analysis (MRD-EDGESNV) was applied to two independent cohorts. Cohort 1, comprising 93 patients with stage III colorectal cancer (CRC) and 40 healthy individuals, was used to establish the signal threshold at 95% specificity. This threshold was then applied to Cohort 2, consisting of 22 patients with symptomatic and 20 with asymptomatic adenomas. In stage III, MRD-EDGESNV had an area under the curve of 0.98. ctDNA was detected in 50% and 25% of patients with symptomatic and asymptomatic adenomas, respectively. The median adenoma plasma tumor fraction was 5.9 × 10−5. These finding not only demonstrate the feasibility of ctDNA detection in patients with colorectal adenomas, but also provides an estimate of the necessary sensitivity required to detect these lesions, paving the way for future ctDNA-based screening strategies.

KW - adenomas

KW - circulating tumor DNA

KW - colorectal cancer

KW - early detection

KW - whole-genome sequencing

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M3 - Journal article

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SN - 1574-7891

JO - Molecular Oncology

JF - Molecular Oncology

ER -

Whole-genome sequencing of cell-free DNA reveals DNA of tumor origin in plasma from patients with colorectal adenomas

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Keywords

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