Whole Exome Sequencing of Biliary Tubulopapillary Neoplasms Reveals Common Mutations in Chromatin Remodeling Genes

The molecular carcinogenesis of intraductal tubulopapillary neoplasms (ITPN), recently described as rare in the pancreato-biliary tract with a favorable prognosis despite high incidence associated adenocarcinoma, is still poorly understood. To identify driver genes, chromosomal gains and losses, mutational signatures, key signaling pathways, potential therapeutic targets, profile 11 biliary 6 pancreatic ITPNs, invasive adenocarcinoma 14/17 cases, are studied by whole exome sequencing (WES). WES 17 ITPNs reveals common copy number variants (CNVs) broadly distributed across genome, recurrent deletions primarily 1p36 9p21 affecting tumor suppressors CHD5 CDKN2A, respectively, 1q prominent oncogene AKT3. identified somatic nucleotide (SNVs) involve few core pathways genetic heterogeneity diverse spectra: Chromatin remodeling, cell cycle, DNA damage/repair. An OncoKB search identifies putative actionable genomic targets 35% cases (6/17), including missense mutations FGFR2 gene (2/11, 18%). Our results show that SNV classical cancer typically carcinogenesis, were absent (KRAS, IDH1/2, GNAS, others) to (TP53 SMAD4, 6%, respectively) ITPNs. Mutational signature pattern analysis predominance an age-related pattern. findings highlight ITPN cholangiocarcinoma display commonalities, particular genes chromatin remodeling pathway, appear, therefore, more closely related than ductal adenocarcinoma.