Document Detail


Whole-exome sequencing of pancreatic neoplasms with acinar differentiation.
MedLine Citation:
PMID:  24293293     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole-exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations/carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations/tumour (range 12-189). The mean fractional allelic loss (FAL) was 0.27 (range 0-0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescence in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumours (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2 and PALB2 (one tumour each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumours (17%), BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%) and BAP1 in one (4%). Perhaps most importantly, we found that more than one-third of these carcinomas have potentially targetable genetic alterations, including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.
Authors:
Yuchen Jiao; Raluca Yonescu; G Johan A Offerhaus; David S Klimstra; Anirban Maitra; James R Eshleman; James G Herman; Weijie Poh; Lorraine Pelosof; Christopher L Wolfgang; Bert Vogelstein; Kenneth W Kinzler; Ralph H Hruban; Nickolas Papadopoulos; Laura D Wood
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pathology     Volume:  232     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2014 Mar 
Date Detail:
Created Date:  2014-02-10     Completed Date:  2014-04-03     Revised Date:  2014-06-10    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  428-35     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MeSH Terms
Descriptor/Qualifier:
Acinar Cells / chemistry*,  pathology
Carcinoma, Acinar Cell / genetics*,  pathology,  surgery
Cell Differentiation / genetics*
Chromosomes, Human
DNA Mutational Analysis*
DNA, Neoplasm / analysis*
Exome*
Female
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Humans
In Situ Hybridization, Fluorescence
Male
Middle Aged
Mutation*
Pancreatic Neoplasms / genetics*,  pathology,  surgery
Phenotype
Tumor Markers, Biological / genetics*
Grant Support
ID/Acronym/Agency:
CA43460/CA/NCI NIH HHS; CA62924/CA/NCI NIH HHS; P30 CA006973/CA/NCI NIH HHS; P50 CA062924/CA/NCI NIH HHS; R37 CA043460/CA/NCI NIH HHS; T32 CA009071/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Neoplasm; 0/Tumor Markers, Biological
Comments/Corrections

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