Circulating cell-free DNA is a reliable tool to detect hot spot mutations in intraductal papillary mucinous neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is the most common cancer type of the pancreas. The three PDAC precursor lesions are: (i) pancreatic intraepithelial neoplasia (PanIN), (ii) mucinous cystic neoplasm (MCN), and (iii) IPMN. In contrast, serous cystadenomas are strictly benign cystic neoplastic lesions and rarely require surgery. Frequently, differential diagnosis of neoplastic cysts remains cumbersome. Thus, non-invasive diagnostic stratification would be welcome. Such a test should allow both discrimination of (i) IPMN from strictly benign pancreatic cysts but also (ii) low- from high-grade IPMN.

Little is known about the molecular alterations of IPMN, but GNAS mutations have been described to promote IPMN formation. A tumor-derived fraction of cell-free DNA (cfDNA) circulating in the bloodstream represents the mutational makeup of tumors and could be a tool for non-invasive monitoring. We demonstrate that cfDNA levels discriminate controls from a cohort of Fukuoka-negative branch-duct IPMN but also from pancreatic cancer. Furthermore, GNAS mutations were detected in IPMN patients but were absent in serous cystadenoma (SCA) and in controls. These findings establish cfDNA and targeted genotyping as a diagnostic tool for IPMN.