Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma

Abstract

Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2 fusions (FGFR2-CEP55, FGFR2-SASS6, DISP1-FGFR2, FGFR2-TXLNA, and FGFR2-VCL) and 1/18 (5.5%) had STRN-ALK fusion. Intraductal tubulopapillary neoplasm is a distinct clinicopathologic entity in the pancreas. Although its intraductal nature and some clinicopathologic features resemble those of intraductal papillary mucinous neoplasm, our results suggest that intraductal tubulopapillary neoplasm has distinguishing genetic characteristics. Some of these mutated genes are potentially targetable. Future functional studies will be needed to determine the consequences of these gene alterations.

Intrapancreatic recurrence of intraductal tubulopapillary neoplasm (ITPN) 16 years after the initial surgery for noninvasive ITPN: a case report

“…The three lesions in this study were genetically consistent with these characteristics, whereas none of the lesions harbored any KRAS/GNAS/BRAF mutations. Some studies have shown that ITPN can also be linked to PIK3CA mutations [ 24 – 26 ], but this was not observed in the present case. However, PIK3CA mutations occur in less than 30% of cases; thus, ITPN is still highly probable despite its absence in our samples.…”

“…About 40 to 60% of IPMNs reportedly harbor GNAS mutations alone, and the vast majority of IPMNs harbor KRAS and/or GNAS mutations [ 21 – 23 ]. Conversely, ITPN lacks KRAS/GNAS/BRAF mutations [ 2 , 24 – 26 ]. The three lesions in this study were genetically consistent with these characteristics, whereas none of the lesions harbored any KRAS/GNAS/BRAF mutations.…”

Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells

“…Thus, the initial studies based on the analysis of only very limited number of IPTN tumors showed, at variance with IPMN tumors, a low frequency of KRAS (0–10%), GNAS (0–25%), TP53 (= −23%), SMAD4 (0–10%) and RNF43 (0–10%) mutations; more frequent were the CDKN2A alterations (54%) reviewed in [ 70 ]. In a recent study, Basturk and coworkers reported the analysis of the molecular abnormalities occurring in 22 IPTN tumors, showing that: most of the previously-reported IPMN genetic abnormalities were absent; loss of CDKN2A was observed in 25% of cases; MAPK genes were not frequently altered; chromatin remodeling genes (such as MLL1 , MLL2 , MLL3 , BAP1 ) were altered in 32% of cases; PI3K pathway genes were altered in 27% of cases; finally, 18% of tumors displayed FGFR2 fusions [ 71 ]. According to these data, it was concluded that IPTN is a distinct clinicopathologic entity and is genetically distinct from IPMN and PDAC [ 71 ].…”

Gene expression profiling in aggressive digital papillary adenocarcinoma sheds light on the architecture of a rare sweat gland carcinoma

“…Research has established that somatic FGFR2 alterations play a crucial role in the origin of numerous solid tumours and that alterations in the activity (overexpression) are associated with a poor outcome in certain cancer types. Interestingly, many of these malignancies display a papillary structure and/or an adenocarcinoma morphology like ADPA, pointing to common underlying molecular mechanisms . Oncogenic activation of FGFR2 is supposed to have a key role in the dysregulation of cell division (proliferation), cell movement and in the development of new blood vessels that nourish a growing tumour .…”