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Open Access 01-12-2022 | Colorectal Cancer | Research

Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients

Authors: Ariane Hallermayr, Tobias Wohlfrom, Verena Steinke-Lange, Anna Benet-Pagès, Florentine Scharf, Ellen Heitzer, Ulrich Mansmann, Christopher Haberl, Maike de Wit, Holger Vogelsang, Markus Rentsch, Elke Holinski-Feder, Julia M. A. Pickl

Published in: Journal of Hematology & Oncology | Issue 1/2022

Abstract

Background

Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile.

Methods

Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring.

Results

We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA.

Conclusion

In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring.

Trial registration DRKS00012890.

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Title: Somatic copy number alteration and fragmentation analysis in circulating tumor DNA for cancer screening and treatment monitoring in colorectal cancer patients
Authors: Ariane Hallermayr
Tobias Wohlfrom
Verena Steinke-Lange
Anna Benet-Pagès
Florentine Scharf
Ellen Heitzer
Ulrich Mansmann
Christopher Haberl
Maike de Wit
Holger Vogelsang
Markus Rentsch
Elke Holinski-Feder
Julia M. A. Pickl
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Colorectal Cancer
Colorectal Cancer
Published in: Journal of Hematology & Oncology / Issue 1/2022
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-022-01342-z

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