Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features

Thirty pancreatic tissues with concurrent ductal adenocarcinoma and IPMN yielded 168 mapped, microdissected lesions analysed for mutations in 18 pancreatic cancer genes and tumour suppressor expression. Twelve cancers shared driver mutations with all concurrent IPMNs (sequential subtype, less diverse incipient foci and frequent GNAS mutations); eleven shared some (branch-off subtype, identical KRAS but different GNAS mutations despite adjacency, with whole-exome and methylation analysis indicating clonal origin and later divergence); ten had drivers not found in the IPMNs (de novo subtype). TP53 and SMAD4 expression improved subtype discrimination. Branch-off patients had longer disease-free survival than de novo or sequential patients.