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

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, Kim Chau, Alan Ashworth, Stephen R. Quake and Samuel Levy ()
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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
Samuel Levy: Bluestar Genomics

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18965-w

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