PMID- 24293293
OWN - NLM
STAT- MEDLINE
DCOM- 20140403
LR  - 20220330
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Print)
IS  - 0022-3417 (Linking)
VI  - 232
IP  - 4
DP  - 2014 Mar
TI  - Whole-exome sequencing of pancreatic neoplasms with acinar differentiation.
PG  - 428-35
LID - 10.1002/path.4310 [doi]
AB  - 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.
CI  - Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by 
      John Wiley & Sons, Ltd.
FAU - Jiao, Yuchen
AU  - Jiao Y
AD  - Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns 
      Hopkins University, Baltimore, MD, USA.
FAU - Yonescu, Raluca
AU  - Yonescu R
FAU - Offerhaus, G Johan A
AU  - Offerhaus GJ
FAU - Klimstra, David S
AU  - Klimstra DS
FAU - Maitra, Anirban
AU  - Maitra A
FAU - Eshleman, James R
AU  - Eshleman JR
FAU - Herman, James G
AU  - Herman JG
FAU - Poh, Weijie
AU  - Poh W
FAU - Pelosof, Lorraine
AU  - Pelosof L
FAU - Wolfgang, Christopher L
AU  - Wolfgang CL
FAU - Vogelstein, Bert
AU  - Vogelstein B
FAU - Kinzler, Kenneth W
AU  - Kinzler KW
FAU - Hruban, Ralph H
AU  - Hruban RH
FAU - Papadopoulos, Nickolas
AU  - Papadopoulos N
FAU - Wood, Laura D
AU  - Wood LD
LA  - eng
GR  - R37 CA043460/CA/NCI NIH HHS/United States
GR  - T32 CA009071/CA/NCI NIH HHS/United States
GR  - CA62924/CA/NCI NIH HHS/United States
GR  - CA43460/CA/NCI NIH HHS/United States
GR  - UL1 TR001079/TR/NCATS NIH HHS/United States
GR  - P50 CA062924/CA/NCI NIH HHS/United States
GR  - P30 CA006973/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (DNA, Neoplasm)
RN  - Pancreatoblastoma
SB  - IM
MH  - Acinar Cells/*chemistry/pathology
MH  - Biomarkers, Tumor/*genetics
MH  - Carcinoma, Acinar Cell/*genetics/pathology/surgery
MH  - Cell Differentiation/*genetics
MH  - Chromosomes, Human
MH  - *DNA Mutational Analysis
MH  - DNA, Neoplasm/*analysis
MH  - *Exome
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Genetic Predisposition to Disease
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Male
MH  - Middle Aged
MH  - *Mutation
MH  - Pancreatic Neoplasms/*genetics/pathology/surgery
MH  - Phenotype
PMC - PMC4048021
MID - NIHMS546227
OTO - NOTNLM
OT  - acinar cell carcinoma
OT  - carcinoma
OT  - genetics
OT  - pancreas
OT  - pancreatoblastoma
OT  - sequencing
COIS- Conflict of Interest: Under agreements between the Johns Hopkins University, 
      Genzyme, Myriad Genetics, Exact Sciences, Inostics, Qiagen, Invitrogen and 
      Personal Genome Diagnostics, N.P., B.V., K.W.K., and R.H.H. are entitled to a 
      share of the royalties received by the University on sales of products related to 
      genes and technologies described in this manuscript. N.P., B.V. and K.W.K. are 
      co-founders of Inostics and Personal Genome Diagnostics, are members of their 
      Scientific Advisory Boards, and own Inostics and Personal Genome Diagnostics 
      stock, which is subject to certain restrictions under Johns Hopkins University 
      policy.
EDAT- 2013/12/03 06:00
MHDA- 2014/04/04 06:00
PMCR- 2014/06/06
CRDT- 2013/12/03 06:00
PHST- 2013/08/29 00:00 [received]
PHST- 2013/11/12 00:00 [revised]
PHST- 2013/11/24 00:00 [accepted]
PHST- 2013/12/03 06:00 [entrez]
PHST- 2013/12/03 06:00 [pubmed]
PHST- 2014/04/04 06:00 [medline]
PHST- 2014/06/06 00:00 [pmc-release]
AID - 10.1002/path.4310 [doi]
PST - ppublish
SO  - J Pathol. 2014 Mar;232(4):428-35. doi: 10.1002/path.4310.