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Sub-nucleosomal organization in urine cell-free DNA

Havell Markus, Jun Zhao, Tania Contente-Cuomo, View ORCID ProfileElizabeth Raupach, Ahuva Odenheimer-Bergman, Sydney Connor, Bradon R. McDonald, Elizabeth Hutchins, Marissa McGilvery, Michelina C. de la Maza, Kendall Van Keuren-Jensen, Patrick Pirrotte, Ajay Goel, Carlos Becerra, Daniel D. Von Hoff, Scott A. Celinski, Pooja Hingorani, View ORCID ProfileMuhammed Murtaza
doi: https://doi.org/10.1101/696633
Havell Markus
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Jun Zhao
1Translational Genomics Research Institute, Phoenix, AZ, USA
2Phoenix Children’s Hospital, Phoenix, AZ, USA
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Tania Contente-Cuomo
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Elizabeth Raupach
1Translational Genomics Research Institute, Phoenix, AZ, USA
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  • ORCID record for Elizabeth Raupach
Ahuva Odenheimer-Bergman
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Sydney Connor
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Bradon R. McDonald
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Elizabeth Hutchins
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Marissa McGilvery
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Michelina C. de la Maza
2Phoenix Children’s Hospital, Phoenix, AZ, USA
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Kendall Van Keuren-Jensen
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Patrick Pirrotte
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Ajay Goel
3Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX, USA
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Carlos Becerra
3Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX, USA
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Daniel D. Von Hoff
1Translational Genomics Research Institute, Phoenix, AZ, USA
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Scott A. Celinski
3Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX, USA
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Pooja Hingorani
2Phoenix Children’s Hospital, Phoenix, AZ, USA
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Muhammed Murtaza
1Translational Genomics Research Institute, Phoenix, AZ, USA
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  • ORCID record for Muhammed Murtaza
  • For correspondence: mmurtaza@tgen.org
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Abstract

Cell-free DNA (cfDNA) in urine is a promising analyte for noninvasive diagnostics. However, urine cfDNA is highly fragmented and whether characteristics of these fragments reflect underlying genomic architecture is unknown. Here, we perform comprehensive characterization of fragmentation patterns in urine cfDNA. We show modal size and genome-wide distribution of urine cfDNA fragments are consistent with transient protection from degradation by stable intermediates of nucleosome disassembly. Genome-wide nucleosome occupancy and fragment sizes in urine cfDNA are informative of cell of origin and renal epithelial cells are amongst the highest contributors in urine. Compared to a nucleosome occupancy map based on control urine samples, we observe a higher fraction of fragments with aberrant ends in cancer patients, distinguishing cancer samples with an area under the curve of 0.89. Our results demonstrate sub-nucleosomal organization in urine cfDNA and are proof-of-principle that genome-wide fragmentation analysis of urine cfDNA can enable cancer diagnostics.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 11, 2019.
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Sub-nucleosomal organization in urine cell-free DNA
Havell Markus, Jun Zhao, Tania Contente-Cuomo, Elizabeth Raupach, Ahuva Odenheimer-Bergman, Sydney Connor, Bradon R. McDonald, Elizabeth Hutchins, Marissa McGilvery, Michelina C. de la Maza, Kendall Van Keuren-Jensen, Patrick Pirrotte, Ajay Goel, Carlos Becerra, Daniel D. Von Hoff, Scott A. Celinski, Pooja Hingorani, Muhammed Murtaza
bioRxiv 696633; doi: https://doi.org/10.1101/696633
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Sub-nucleosomal organization in urine cell-free DNA
Havell Markus, Jun Zhao, Tania Contente-Cuomo, Elizabeth Raupach, Ahuva Odenheimer-Bergman, Sydney Connor, Bradon R. McDonald, Elizabeth Hutchins, Marissa McGilvery, Michelina C. de la Maza, Kendall Van Keuren-Jensen, Patrick Pirrotte, Ajay Goel, Carlos Becerra, Daniel D. Von Hoff, Scott A. Celinski, Pooja Hingorani, Muhammed Murtaza
bioRxiv 696633; doi: https://doi.org/10.1101/696633

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