PMID- 22825585
OWN - NLM
STAT- MEDLINE
DCOM- 20130409
LR  - 20220410
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 18
IP  - 17
DP  - 2012 Sep 1
TI  - CpG island methylator phenotype-positive tumors in the absence of MLH1 
      methylation constitute a distinct subset of duodenal adenocarcinomas and are 
      associated with poor prognosis.
PG  - 4743-52
LID - 10.1158/1078-0432.CCR-12-0707 [doi]
AB  - PURPOSE: Little information is available on genetic and epigenetic changes in 
      duodenal adenocarcinomas. The purpose was to identify possible subsets of 
      duodenal adenocarcinomas based on microsatellite instability (MSI), DNA 
      methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, 
      and prognosis. EXPERIMENTAL DESIGN: Demographics, tumor characteristics, and 
      survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS 
      and BRAF mutations, MSI, MLH1 methylation, and CpG island methylator phenotype 
      (CIMP) status was conducted. A Cox proportional hazard model was built to predict 
      survival. RESULTS: CIMP(+) was detected in 27 of 99 (27.3%) duodenal 
      adenocarcinomas and was associated with MSI (P = 0.011) and MLH1 methylation (P < 
      0.001), but not with KRAS mutations (P = 0.114), as compared with CIMP(-) tumors. 
      No BRAF V600E mutation was detected. Among the CIMP(+) tumors, 15 (55.6%) were 
      CIMP(+)/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed that tumors 
      classified by CIMP, CIMP/MLH1 methylation status, or CIMP/MSI status could 
      predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), whereas 
      CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 
      0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a 
      significant prognostic value in both OS (P < 0.001) and TTR (P = 0.023). Patients 
      with CIMP(+)/MLH1-U tumors had the worst OS and TTR. CONCLUSIONS: Our results 
      showed existence of CIMP in duodenal adenocarcinomas. The combination of 
      CIMP(+)/MLH1-U seems to be independently associated with poor prognosis in 
      patients with duodenal adenocarcinomas. This study also suggests that BRAF 
      mutations are not involved in duodenal tumorigenesis, MSI, or CIMP development.
CI  - (c)2012 AACR.
FAU - Fu, Tao
AU  - Fu T
AD  - Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
FAU - Pappou, Emmanouil P
AU  - Pappou EP
FAU - Guzzetta, Angela A
AU  - Guzzetta AA
FAU - Jeschke, Jana
AU  - Jeschke J
FAU - Kwak, Ruby
AU  - Kwak R
FAU - Dave, Pujan
AU  - Dave P
FAU - Hooker, Craig M
AU  - Hooker CM
FAU - Morgan, Richard
AU  - Morgan R
FAU - Baylin, Stephen B
AU  - Baylin SB
FAU - Iacobuzio-Donahue, Christine A
AU  - Iacobuzio-Donahue CA
FAU - Wolfgang, Christopher L
AU  - Wolfgang CL
FAU - Ahuja, Nita
AU  - Ahuja N
LA  - eng
GR  - K23 CA127141/CA/NCI NIH HHS/United States
GR  - R01 CA140599/CA/NCI NIH HHS/United States
GR  - CA127141/CA/NCI NIH HHS/United States
GR  - CA140599/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120723
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (KRAS protein, human)
RN  - 0 (MLH1 protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 3.6.1.3 (MutL Protein Homolog 1)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing/genetics/metabolism
MH  - Adenocarcinoma/metabolism/pathology
MH  - Aged
MH  - *CpG Islands/genetics
MH  - DNA Methylation/*genetics
MH  - *Duodenal Neoplasms/metabolism/pathology
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Microsatellite Instability
MH  - Middle Aged
MH  - MutL Protein Homolog 1
MH  - *Nuclear Proteins/genetics/metabolism
MH  - Prognosis
MH  - Proportional Hazards Models
MH  - Proto-Oncogene Proteins/genetics/metabolism
MH  - Proto-Oncogene Proteins B-raf/genetics/metabolism
MH  - Proto-Oncogene Proteins p21(ras)
MH  - ras Proteins/genetics/metabolism
PMC - PMC3482463
MID - NIHMS395850
COIS- Disclosure of Potential Conflicts of Interest S.B.B has commercial grant funding 
      and serves on the advisory board for MDx Health Inc. and BioNumerik 
      Pharmaceuticals Inc.
EDAT- 2012/07/25 06:00
MHDA- 2013/04/10 06:00
PMCR- 2013/09/01
CRDT- 2012/07/25 06:00
PHST- 2012/07/25 06:00 [entrez]
PHST- 2012/07/25 06:00 [pubmed]
PHST- 2013/04/10 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - 1078-0432.CCR-12-0707 [pii]
AID - 10.1158/1078-0432.CCR-12-0707 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2012 Sep 1;18(17):4743-52. doi: 10.1158/1078-0432.CCR-12-0707. 
      Epub 2012 Jul 23.