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

Nat Commun. 2020 Oct 19;11(1):5270. doi: 10.1038/s41467-020-18965-w.

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.

MeSH terms

  • 5-Methylcytosine / analogs & derivatives*
  • 5-Methylcytosine / metabolism
  • Adult
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / metabolism
  • Cell-Free Nucleic Acids / blood
  • Cell-Free Nucleic Acids / genetics
  • Cell-Free Nucleic Acids / metabolism*
  • Cohort Studies
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • GATA4 Transcription Factor / genetics
  • GATA4 Transcription Factor / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pancreatic Neoplasms / blood
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • TEA Domain Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Biomarkers, Tumor
  • Cell-Free Nucleic Acids
  • DNA-Binding Proteins
  • GATA4 Transcription Factor
  • GATA4 protein, human
  • Homeodomain Proteins
  • Nuclear Proteins
  • TEA Domain Transcription Factors
  • TEAD1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine

Supplementary concepts

  • Pancreatic Carcinoma