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Promoter hypermethylation in plasma‐derived cell‐free DNA as a prognostic marker for pancreatic adenocarcinoma staging
Author(s) -
Henriksen Stine Dam,
Madsen Poul Henning,
Larsen Anders Christian,
Johansen Martin Berg,
Pedersen Inge Søkilde,
Krarup Henrik,
ThorlaciusUssing Ole
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31024
Subject(s) - dna methylation , adenocarcinoma , cancer research , plasma cell , medicine , oncology , dna , cell free fetal dna , biology , pathology , gene , cancer , genetics , gene expression , pregnancy , fetus , prenatal diagnosis , multiple myeloma
Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell‐free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work‐up and treatment. Patients were staged according to the TNM classification. Methylation‐specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety‐five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51–8.66), 7.00 (95% CI; 5.93–8.07) and 6.77 (95% CI; 5.08–8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88–11.60)). The prediction model ( SEPT9v2 , SST , ALX4 , CDKN2B , HIC1 , MLH1 , NEUROG1 , and BNC1 ) enabled the differentiation of stage IV from stage I‐III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model ( MLH1 , SEPT9v2 , BNC1 , ALX4 , CDKN2B , NEUROG1, WNT5A , and TFPI2 ) enabled the differentiation of stage I‐II from stage III‐IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell‐free DNA promoter hypermethylation has the potential to be blood‐based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required.