Research Papers:

Cell-free DNA promoter hypermethylation in plasma as a predictive marker for survival of patients with pancreatic adenocarcinoma

Stine Dam Henriksen _, Poul Henning Madsen, Anders Christian Larsen, Martin Berg Johansen, Inge Søkilde Pedersen, Henrik Krarup and Ole Thorlacius-Ussing

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Oncotarget. 2017; 8:93942-93956. https://doi.org/10.18632/oncotarget.21397

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Stine Dam Henriksen1,2,3,4, Poul Henning Madsen5, Anders Christian Larsen1, Martin Berg Johansen6, Inge Søkilde Pedersen5, Henrik Krarup4,5 and Ole Thorlacius-Ussing1,3,4

1Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark

2Department of General Surgery, Hospital of Vendsyssel, Hjørring, Denmark

3Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

4Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark

5Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark

6Unit of Clinical Biostatistics and Bioinformatics, Aalborg University Hospital, Aalborg, Denmark

Correspondence to:

Stine Dam Henriksen, email: [email protected]

Keywords: biomarker, epigenetics, methylation, pancreatic cancer, prognosis

Received: December 12, 2016    Accepted: September 13, 2017    Published: September 30, 2017


Introduction: Few prognostic biomarkers are available for pancreatic cancer. The aim of this study is to examine the correlation between the survival of pancreatic adenocarcinoma patients and hypermethylated genes in plasma-derived cell-free DNA.

Methods: Consecutive patients with pancreatic adenocarcinoma were prospectively included and staged according to the TNM classification. Methylation-specific PCR of 28 genes was conducted. A survival prediction model independent of cancer stage and stage-specific survival prediction models were developed by multivariable Cox regression analysis using backward stepwise selection.

Results: Ninety-five patients with pancreatic adenocarcinoma were included. Patients with more than 10 hypermethylated genes had a HR of 2.03 (95% CI; 1.15-3.57) compared to patients with fewer hypermethylated genes. Three survival prediction models were developed: Total group; (American Society of Anesthesiologists score (ASA)=3, GSTP1, SFRP2, BNC1, SFRP1, TFPI2, and WNT5A) Risk groups 2, 3 and 4 had a HR of 2.65 (95% CI; 1.24-5.66), 4.34 (95% CI; 1.98-9.51) and 21.19 (95% CI; 8.61-52.15), respectively, compared to risk group 1. Stage I-II; (ASA=3, SFRP2, and MESTv2) Risk groups 2, 3 and 4 had a HR of 4.83 (95% CI; 2.01-11.57), 9.12 (95% CI; 2.18-38.25) and 70.90 (95% CI; 12.63-397.96), respectively, compared to risk group 1. Stage IV; (BMP3, NPTX2, SFRP1, and MGMT) Risk group 2 had a HR of 5.23 (95% CI; 2.13-12.82) compared to risk group 1.

Conclusion: Prediction models based on cell-free DNA hypermethylation stratified pancreatic adenocarcinoma patients into risk groups according to survival. The models have the potential to work as prognostic biomarkers. However, further validation of the results is required to substantiate the findings.

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