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Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA

Author

Listed:
  • Gulfem D. Guler

    (Bluestar Genomics)

  • Yuhong Ning

    (Bluestar Genomics)

  • Chin-Jen Ku

    (Bluestar Genomics)

  • Tierney Phillips

    (Bluestar Genomics)

  • Erin McCarthy

    (Bluestar Genomics)

  • Christopher K. Ellison

    (Bluestar Genomics)

  • Anna Bergamaschi

    (Bluestar Genomics)

  • Francois Collin

    (Bluestar Genomics)

  • Paul Lloyd

    (Bluestar Genomics)

  • Aaron Scott

    (Bluestar Genomics)

  • Michael Antoine

    (Bluestar Genomics)

  • Wendy Wang

    (Bluestar Genomics)

  • Kim Chau

    (Bluestar Genomics)

  • Alan Ashworth

    (UCSF Helen Diller Family Comprehensive Cancer Center)

  • Stephen R. Quake

    (Stanford University
    Chan Zuckerberg Biohub)

  • Samuel Levy

    (Bluestar Genomics
    Bluestar Genomics)

Abstract

Pancreatic cancer is often detected late, when curative therapies are no longer possible. Here, we present non-invasive detection of pancreatic ductal adenocarcinoma (PDAC) by 5-hydroxymethylcytosine (5hmC) changes in circulating cell free DNA from a PDAC cohort (n = 64) in comparison with a non-cancer cohort (n = 243). Differential hydroxymethylation is found in thousands of genes, most significantly in genes related to pancreas development or function (GATA4, GATA6, PROX1, ONECUT1, MEIS2), and cancer pathogenesis (YAP1, TEAD1, PROX1, IGF1). cfDNA hydroxymethylome in PDAC cohort is differentially enriched for genes that are commonly de-regulated in PDAC tumors upon activation of KRAS and inactivation of TP53. Regularized regression models built using 5hmC densities in genes perform with AUC of 0.92 (discovery dataset, n = 79) and 0.92–0.94 (two independent test sets, n = 228). Furthermore, tissue-derived 5hmC features can be used to classify PDAC cfDNA (AUC = 0.88). These findings suggest that 5hmC changes enable classification of PDAC even during early stage disease.

Suggested Citation

  • Gulfem D. Guler & Yuhong Ning & Chin-Jen Ku & Tierney Phillips & Erin McCarthy & Christopher K. Ellison & Anna Bergamaschi & Francois Collin & Paul Lloyd & Aaron Scott & Michael Antoine & Wendy Wang &, 2020. "Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18965-w
    DOI: 10.1038/s41467-020-18965-w
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    Cited by:

    1. Jonathan J. Swietlik & Stefanie Bärthel & Chiara Falcomatà & Diana Fink & Ankit Sinha & Jingyuan Cheng & Stefan Ebner & Peter Landgraf & Daniela C. Dieterich & Henrik Daub & Dieter Saur & Felix Meissn, 2023. "Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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