Frequent and complex interplay between KRAS and GNAS in MNAs. (a) High frequency of co-existing KRAS and GNAS mutations is uncommon in neoplastic lesions. Bar graphs represent the frequency of activating mutations in KRAS and GNAS oncogenes among various neoplasms reported in COSMIC (v63 database) or in IPMN  or MNA (this study). Only tissues with more than 10 evaluated samples are reported. (b) Simplified representation of the cross-talk between Ras and PKA pathway and the likely impact on MNA progression. Co-existing activating mutations in KRAS and GNAS can coordinately deregulate multiple oncogenic signaling pathways (Wnt, hedgehog, and TGFβ-SMAD) triggering initiation and progression of MNAs. Symbiotic (dark blue), synergistic (light blue), and antagonistic (dark red) signals triggered by mutations in GNAS and KRAS oncogenes, and possibly members of the TGFβ-SMAD pathway may all contribute to the metastatic progression of MNA.