Clinicopathological significance of somatic RNF43 mutation and aberrant expression of ring finger protein 43 in intraductal papillary mucinous neoplasms of the pancreas

Mutations in RNF43, which encodes the ubiquitin E3 ligase ring finger protein 43, were recently found in intraductal papillary mucinous neoplasms of the pancreas. We evaluated somatic mutations of RNF43 and the expression of ring finger protein 43 as well as their associations with the molecular and clinicopathological features in 176 surgically resected intraductal papillary mucinous neoplasms. Frozen tissues were available for 57 cases and were used for next-generation sequencing analysis of the entire coding exons of RNF43. Formalin-fixed and paraffin-embedded tissues from all 176 cases were used for the immunohistochemical analysis of the expression of ring finger protein 43. Mutations detected with the next-generation sequencing analysis were validated by using Sanger sequencing. Statistical analysis was used to evaluate the associations between RNF43 aberrations and molecular and clinicopathological features including GNAS mutations, KRAS mutations, loss of SMA and MAD4 homologue expression, tumor protein 53 overexpression, tumor grade, histological type, mural nodule detection, macroscopic type, stage, recurrence, and survival. Somatic RNF43 mutations were found in 8 (14%) of the 57 examined cases, and included 5 frameshift mutations (p.F69fs, p.S264fs, p.L311fs, p.R363fs, and p.V490fs), 1 non-sense mutation (p.Q153X), and 2 missense mutations (p.I164N and p.P310A). The expression of ring finger protein 43 was downregulated in 52 (29.5%) of the 176 examined cases. RNF43 mutations were significantly associated with the downregulated expression of ring finger protein 43 (P=0.011), GNAS mutation (P=0.020), and mural nodule detection (P=0.038). The expression of ring finger protein 43 was not associated with any clinicopathological features except RNF43 mutation. These results indicate that RNF43 mutation might cause downregulation of the expression of ring finger protein 43 and play a crucial role and associate synergistically with GNAS mutation during development of intraductal papillary mucinous neoplasm of the pancreas.