학술논문
Impact of Whole Genome Doubling on Detection of Circulating Tumor DNA in Colorectal Cancer.
Document Type
Article
Author
Kabel, Jonas; Henriksen, Tenna Vesterman; Demuth, Christina; Frydendahl, Amanda; Rasmussen, Mads Heilskov; Nors, Jesper; Birkbak, Nicolai J.; Madsen, Anders Husted; Løve, Uffe S.; Andersen, Per Vadgaard; Kolbro, Thomas; Monti, Alessio; Thorlacius-Ussing, Ole; Gögenur, Mikail; Kildsig, Jeppe; Schlesinger, Nis Hallundbæk; Bondeven, Peter; Iversen, Lene Hjerrild; Gotschalck, Kåre Andersson; Andersen, Claus Lindbjerg
Source
Subject
*DNA
*SEQUENCE analysis
*GENETIC mutation
*BIOPSY
*CONFIDENCE intervals
*MULTIVARIATE analysis
*COLORECTAL cancer
*CANCER patients
*GENOME-wide association studies
*GENOMES
*DESCRIPTIVE statistics
*RESEARCH funding
*EXTRACELLULAR space
*TUMOR markers
*LOGISTIC regression analysis
*DATA analysis software
*ODDS ratio
*NUCLEIC acids
*LONGITUDINAL method
*BLOOD
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Language
ISSN
2072-6694
Abstract
Simple Summary: Measurements of circulating tumor DNA is a promising new tool in early detection of cancer and the detection of residual cancer disease. To ensure a high test sensitivity, detailed knowledge about factors that may influence circulating tumor DNA levels is needed. To this end, we investigate a cancer phenomenon in which tumor cells undergo a doubling of the entire genome, thus containing double the normal amount of DNA. We test the hypothesis that DNA from these genome-doubled tumors is more easily detected in blood plasma samples compared to non-genome-doubled tumors. We found that the probability of detecting circulating tumor DNA was higher among genome-doubled tumors than non-genome-doubled tumors. The results thus indicate that increased amounts of tumor-cell DNA lead to increased amounts of tumor DNA in the circulation. Objective: Circulating tumor DNA (ctDNA) is a candidate biomarker of cancer with practice-changing potential in the detection of both early and residual disease. Disease stage and tumor size affect the probability of ctDNA detection, whereas little is known about the influence of other tumor characteristics on ctDNA detection. This study investigates the impact of tumor cell whole-genome doubling (WGD) on the detection of ctDNA in plasma collected preoperatively from newly diagnosed colorectal cancer (CRC) patients. Methods: WGD was estimated from copy numbers derived from whole-exome sequencing (WES) data of matched tumor and normal DNA from 833 Danish CRC patients. To explore if tumor WGD status impacts ctDNA detection, we applied tumor-informed ctDNA analysis to preoperative plasma samples from all patients. Results: Patients with WGD+ tumors had 53% increased odds of being ctDNA positive (OR = 1.53, 95%CI: 1.12–2.09). After stratification for UICC stage, the association persisted for Stage I (OR = 2.44, 95%CI: 1.22–5.03) and Stage II (OR = 1.76, 95%CI: 1.11–2.81) but not for Stage III (OR = 0.83, 95%CI: 0.44–1.53) patients. Conclusion: The presence of WGD significantly increases the probability of detecting ctDNA, particularly for early-stage disease. In patients with more advanced disease, the benefit of WGD on ctDNA detection is less pronounced, consistent with increased DNA shedding from these tumors, making ctDNA detection less dependent on the amount of ctDNA released per tumor cell. [ABSTRACT FROM AUTHOR]