Clinical Research Papers:
Tumor circulating DNA profiling in xenografted mice exposed to intermittent hypoxia
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Rene Cortese1, Isaac Almendros1, Yang Wang1 and David Gozal1
1 Department of Pediatrics, Section of Pediatric Sleep Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, IL
David Gozal, email:
Keywords: Obstructive sleep apnea, Intermittent hypoxia, Circulating DNA, Xenograft, Epigenetics, DNA methylation
Received: September 08, 2014 Accepted: November 15, 2014 Published: November 16, 2014
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.
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