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

Abstract

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

Intraductal tubulopapillary neoplasm (ITPN) of the pancreas: a distinct entity among pancreatic tumors

“…A final consideration of the genetic landscape of pancreatic ITPN should be reserved for chromatin remodelers, such as MLL genes and BAP1 , which seemed to be more altered in this type of lesion compared with that in conventional PDAC (although the comparison with existing datasets did not show statistical significance). Notably, a recent study on the biliary counterpart of ITPN, based on whole‐exome sequencing, confirmed the important role played by this class of genes in the whole ITPN spectrum 93 . In addition to mutations in chromatin remodelers, other correspondences of pancreatic ITPN with the biliary counterparts, further highlighting their similarities, included the common IHC profile and frequent chromosome 1q gains 93 …”

“…93 In addition to mutations in chromatin remodelers, other correspondences of pancreatic ITPN with the biliary counterparts, further highlighting their similarities, included the common IHC profile and frequent chromosome 1q gains. 93…”

“…Notably, a recent study on the biliary counterpart of ITPN, based on whole-exome sequencing, confirmed the important role played by this class of genes in the whole ITPN spectrum. 93 In addition to mutations in chromatin remodelers, other correspondences of pancreatic ITPN with the biliary counterparts, further highlighting their similarities, included the common IHC profile and frequent chromosome 1q gains. 93…”

Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review

“…Genetic alterations reported in ITPN are CDKN2A/p16 and TP53[ 108 ]. Very recently, Gross et al [ 109 ] performed whole exome sequencing of ITPN and demonstrated a high genetic diversity with recurrent copy number variants (CNVs) (loss of chromosome 1p36 and others), and only a few recurrent somatic mutations in TG, SLIT2, FGFR2, and HMCN1. They also identified cell cycle, chromatin remodelling, and DNA damage/repair as key signalling pathways in these neoplasms.…”

Arid1a: A Gatekeeper in the Development of Pancreatic Cancer From a Rare Precursor Lesion

“…ITPN has unique genetic characteristics, including chromatin remodeling and phosphoinositide 3-kinase pathway mutations. 10,11 Owing to the rarity of this precursor lesion, the molecular mechanism and gene profiles are still unclear. In this issue of Gastroenterology, Fukunaga et al 12 identified a novel function of Arid1a in ITPN that has not been investigated in this disease before.…”