Methylated cell-free DNA profiles of patients with pancreatic ductal adenocarcinoma

Mosia, Mpho
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The high mortality rates of pancreatic ductal adenocarcinoma (PDAC) are largely attributed to a delayed diagnosis, of which in advanced disease, patients are unable to receive surgical resection with curative intent. Clinical presentations and genetic features shared between PDAC and other pancreatic conditions such as chronic pancreatitis (CP) are insufficient to facilitate the disease and often lead to diagnostic uncertainty at an early stage. The purpose of this study was to develop sensitive and specific non-invasive markers to aid in the detection and disease monitoring of PDAC. Here, circulating cell-free DNA (cfDNA) isolated from plasma samples of patients with PDAC (n= 155) and two control groups consisting of patients with either CP (n= 46) or critical limb ischemia (CLI) (n= 88) revealed significant differences in measured concentrations between the three patient groups (p= 0.006-Kruskal-Wallis test).When two groups were compared with each other using the Wilcoxon rank-sum test, observable differences were seen between the two pancreatic diseases: PDAC and CP (p= 0.002), and between the two controls: CP and the CLI groups (p= 0.007). A strong association was also observed in elevated cfDNA levels of CLI patients with HIV (p= 0.03), indicating a poor prognosis for patients. Results from methylationspecific PCR (MSP) in age-matched patient samples showed promoter methylation to account for the loss of Smad4 in late-stage PDAC; with an observed association with overall increasing cfDNA levels (p= 0.03).This study indicates the potential clinical utility of cfDNA as a non-invasive tool to predict disease progression both quantitatively and qualitatively, as well as to trace epigenetic changes in tumour markers associated with PDAC. Further investigation to identify hypermethylated genes in cfDNA for the early detection of PDAC is warranted.
A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Science, Johannesburg 2017
Pancreatic Ductal Adenocarcinoma (PDAC)