Intermittent
hypoxia (IH) a hallmark characteristic of
obstructive sleep apnea (OSA), is proposed as a major determinant of processes involving
tumor growth, invasion and
metastasis. To examine whether
circulating DNA (
cirDNA) in blood plasma reflects changes in
tumor cells under IH conditions, we used a xenografted murine model. Mice engrafted with TC1 epithelial
lung cancer cells and controls were exposed to IH or room air (RA) conditions. Plasma
cirDNA amounts were significantly increased in mice exposed to IH (p<0.05). Significant associations between plasma
cirDNA concentrations and
tumor size, weight and invasiveness also emerged (p<0.05). Using a methylation microarray-based approach, we identified 2,094 regions showing significant differential
cirDNA modifications. Systems biology analyses revealed an association with molecular pathways deregulated in
cancer progression and with distal and TSS-associated
transcription factor binding sites. We detected clusters of highly variable regions in chromosomes 7, 13, 14 and X, which may highlight hotspots for
DNA deletions. Single locus displayed high intragroup variation, suggesting cellular heterogeneity within the tissue may be associated to
cirDNA release. Thus, exposures to IH increase the shedding of
cirDNA into circulation, which carries epigenetic modifications that may characterize cell populations within the
tumor that preferentially release their
DNA upon IH exposure.