Abstract
Assays measuring cell-free DNA (cfDNA) in blood have widespread potential in modern medicine. However, a comprehensive understanding of cfDNA dynamics in healthy individuals is required to assist in the design of assays that maximise the signal driven by pathological changes, while excluding fluctuations that are part of healthy physiological processes. The menstrual cycle involves major remodelling of endometrial tissue and associated apoptosis, yet there has been little investigation of the impact of the menstrual cycle on cfDNA levels. Paired plasma samples were collected from 40 healthy women on menstruating (M) and non-menstruating (NM) days of their cycle. We measured total cfDNA by targeting ALU repetitive sequences and measured endothelial-derived cfDNA by methylation-specific qPCR targeting an endothelium-unique unmethylated CDH5 DNA region. CfDNA integrity and endothelial cfDNA concentration, but not total cfDNA, are consistent across time between NM and M. No significant changes in total (ALU-115 p = 0.273; ALU-247 p = 0.385) or endothelial cell specific (p = 0.301) cfDNA were observed, leading to the conclusion that menstrual status at the time of diagnostic blood collection should not have a significant impact on the quantitation of total cfDNA and methylation-based cancer assays.
Highlights
Cell-free DNA in blood is a promising source of biomarkers for a range of conditions such as cancer detection and transplantation [1]
It is generally accepted that Cell-free DNA (cfDNA) is released into the blood due to cells dying via apoptosis and is linked to inflammation [2]. cfDNA can be released into the blood in healthy individuals, patients with benign diseases and patients with cancer, and it is important to distinguish between amounts of cfDNA from different cells of origin when developing cfDNA based biomarkers
CfDNA levels fluctuated up to 7.7-fold between the NM and M blood draws, and we found little to no correlation in cfDNA concentration between the two phases as measured with either ALU-115 or ALU-247 (Fig 1B)
Summary
Cell-free DNA (cfDNA) in blood is a promising source of biomarkers for a range of conditions such as cancer detection and transplantation [1]. It is generally accepted that cfDNA is released into the blood due to cells dying via apoptosis and is linked to inflammation [2]. CfDNA can be released into the blood in healthy individuals, patients with benign diseases and patients with cancer, and it is important to distinguish between amounts of cfDNA from different cells of origin when developing cfDNA based biomarkers. Total and endothelial CfDNA in healthy menstruating women (NLY) (https://www.education.gov.au/researchtraining-program), Beth Yarrow Memorial Award in Medical Science (NLY) Edu.au/sites/default/files/UNSW%20Beth% 20Yarrow%20Memorial%20Award%20in% 20Medical%20Science%20-%20Guidelines_v1% 2028FEB2019.pdf), Translational Cancer Research Network supported by the Cancer Institute NSW (NLY) (http://www.tcrn.unsw.edu.au/tcrn-grants), GO Research Fund (CEH), Ovarian Cancer Research Foundation (KW) (GA-2018-14) (https:// www.ocrf.com.au/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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