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

  

Authors:	Basturk, O.; Berger, M. F.; Yamaguchi, H.; Adsay, V.; Askan, G.; Bhanot, U. K.; Zehir, A.; Carneiro, F.; Hong, S. M.; Zamboni, G.; Dikoglu, E.; Jobanputra, V.; Wrzeszczynski, K. O.; Balci, S.; Allen, P.; Ikari, N.; Takeuchi, S.; Akagawa, H.; Kanno, A.; Shimosegawa, T.; Morikawa, T.; Motoi, F.; Unno, M.; Higuchi, R.; Yamamoto, M.; Shimizu, K.; Furukawa, T.; Klimstra, D. S.
Article Title:	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.
Keywords:	immunohistochemistry; mitogen activated protein kinase; adult; clinical article; human tissue; aged; cancer surgery; unclassified drug; genetic trait; sequence analysis; frameshift mutation; missense mutation; clinical feature; histopathology; cancer recurrence; lymph node metastasis; pancreaticoduodenectomy; gene targeting; tumor localization; unindexed drug; gene amplification; tumor volume; intraductal papillary mucinous tumor; mutational analysis; medical record review; phosphatidylinositol 3 kinase; gene rearrangement; gene identification; pancreas tumor; tumor protein; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; gene fusion; gene loss; genomics; pancreas adenocarcinoma; pancreatectomy; heterozygosity loss; mucin 1; cyclin dependent kinase inhibitor 2a; tumor gene; chromosome 1q; nonsense mutation; fibroblast growth factor receptor 2; distal pancreatectomy; dna methyltransferase 3b; chromatin assembly and disassembly; interferon regulatory factor 4; chromosome 1p; dna methyltransferase 3a; mucin 5ac; mucin 2; surgical margin; copy number variation; mucin 6; antibody labeling; peroperative complication; indel mutation; embryonic ectoderm development protein; next generation sequencing; mapk signaling; lymph vessel metastasis; bap1 protein; pbrm1 protein; human; male; female; priority journal; article; whole genome sequencing; mll2 protein; whole exome sequencing; cep55 protein; pancreas tissue; alk protein; disp1 protein; inpp4a protein; mll1 protein; mll3 protein; pik3ca protein; pik3cb protein; sass6 protein; strn protein; txlna protein; vcl protein; pancreatic intraductal tubulopapillary neoplasm
Journal Title:	Modern Pathology
Volume:	30
Issue:	12
ISSN:	0893-3952
Publisher:	Nature Research
Date Published:	2017-08-05
Start Page:	1760
End Page:	1772
Language:	English
DOI:	10.1038/modpathol.2017.60
PROVIDER:	scopus
PUBMED:	28776573
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85034240350&doi=10.1038%2fmodpathol.2017.60&partnerID=40&md5=a0fe4f103a3f639e2eb6e032c2f72d41
Notes:	Article -- Export Date: 2 January 2018 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/119588