Whole Exome Sequencing Reveals Wnt Pathway Mutations in Biliary Papillary Neoplasms

Original abstract

This study aimed to elucidate the genetic landscape of biliary papillary neoplasms. Of 28 cases examined, 7 underwent whole exome sequencing, while the remaining 21 were used for validation studies with targeted sequencing. In the whole exome sequencing study, 4/7 cases had mutations in either APC or CTNNB1, both of which belong to the Wnt/β-catenin pathway. Somatic mutations were also identified in genes involved in RAS signaling (KRAS, BRAF), a cell cycle regulator (CDC27), histone methyltransferase (KMT2C, KMT2D), and DNA mismatch repair (MSH3, MSH6, PMS1). Combined with discovery and validation cohorts, mutations in APC or CTNNB1 were observed in 6/28 subjects (21%) and were mutually exclusive. When the cases were classified into intraductal papillary neoplasms of the bile duct (IPNBs, n=14) and papillary cholangiocarcinomas (n=14) based on the recently proposed classification criteria, mutations in APC and CTNNB1 appeared to be entirely restricted to IPNBs with 6/14 cases (43%) harboring mutations in either gene. These genetic alterations were detected across the 3 nonintestinal histologic types. In immunohistochemistry, the aberrant cytoplasmic and/or nuclear expression of β-catenin was found in not only 5/6 IPNBs with APC or CTNNB1 mutations, but also 6/8 cases with wild-type APC and CTNNB1 (total 79%). In addition, APC and CTNNB1 alterations were exceptional in nonpapillary cholangiocarcinomas (n=29) with a single case harboring CTNNB1 mutation (3%). This study demonstrated recurrent mutations in APC and CTNNB1 in nonintestinal-type IPNBs, suggesting that activation of the Wnt/β-catenin signaling pathway is relevant to the development and progression of IPNBs.