Profiling tumour heterogeneity through circulating tumour DNA in patients with pancreatic cancer
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Patricia Adamo1,*, Caroline M. Cowley1,*, Christopher P. Neal2, Vilas Mistry1, Karen Page1, Ashley R. Dennison2, John Isherwood2, Robert Hastings3, JinLi Luo3, David A. Moore1, J. Howard Pringle1, L. Miguel Martins4, Catrin Pritchard1, Margaret Manson1 and Jacqui A. Shaw1
1Department of Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK
2Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
3Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK
4MRC Toxicology Unit, Leicester, UK
*These authors have contributed equally to this work
Jacqui A. Shaw, email: [email protected]
Keywords: ctDNA, cfDNA, pancreatic ductal adenocarcinomas, KRAS, liquid biopsy
Received: January 31, 2017 Accepted: July 14, 2017 Published: August 14, 2017
The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed late so that surgery is rarely curative. Earlier detection could significantly increase the likelihood of successful treatment and improve survival. The aim of the study was to provide proof of principle that point mutations in key cancer genes can be identified by sequencing circulating free DNA (cfDNA) and that this could be used to detect early PDACs and potentially, premalignant lesions, to help target early effective treatment. Targeted next generation sequencing (tNGS) analysis of mutation hotspots in 50 cancer genes was conducted in 26 patients with PDAC, 14 patients with chronic pancreatitis (CP) and 12 healthy controls with KRAS status validated by digital droplet PCR. A higher median level of total cfDNA was observed in patients with PDAC (585 ng/ml) compared to either patients with CP (300 ng/ml) or healthy controls (175 ng/ml). PDAC tissue showed wide mutational heterogeneity, whereas KRAS was the most commonly mutated gene in cfDNA of patients with PDAC and was significantly associated with a poor disease specific survival (p=0.018). This study demonstrates that tNGS of cfDNA is feasible to characterise the circulating genomic profile in PDAC and that driver mutations in KRAS have prognostic value but cannot currently be used to detect early emergence of disease. Importantly, monitoring total cfDNA levels may have utility in individuals “at risk” and warrants further investigation.
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