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. 2012 Sep 1;18(17):4743-52.
doi: 10.1158/1078-0432.CCR-12-0707. Epub 2012 Jul 23.

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

Tao Fu  1 , Emmanouil P Pappou, Angela A Guzzetta, Jana Jeschke, Ruby Kwak, Pujan Dave, Craig M Hooker, Richard Morgan, Stephen B Baylin, Christine A Iacobuzio-Donahue, Christopher L Wolfgang, Nita Ahuja
Affiliations

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

Tao Fu et al. Clin Cancer Res. .

Abstract

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.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Heat map demonstrating relationship of specific gene methylation, KRAS mutations, MSI status, and categorization as CIMP+ and CIMP− in duodenal adenocarcinomas. IVD, In vitro-methylated DNA (M.SssI-reference); PMR, percent of methylated reference.
Figure 2
Figure 2
Immunohistochemistry analysis of MLH1 expression in normal duodenal tissue and duodenal adenocarcinoma. (A), normal duodenal tissue stained with anti-MLH1 antibody showing positive nuclear staining for MLH1, particularly in the crypts. (B and C), tumors with MSS/MLH1-U stained with anti-MLH1 antibody showing positive nuclear staining for MLH1. (D–I), tumors with MLH1-M stained with anti-MLH1 antibody showing no or low MLH1 expression (D and E, two tumors with MSI/MLH1-M; F, G, H, and I, four tumors with MSS/MLH1-M).
Figure 3
Figure 3
Kaplan-Meier survival estimates of overall survival and time-to-recurrence in patients with CIMP+ and CIMP− duodenal adenocarcinomas. (A) overall survival, (B) time-to-recurrence.
Figure 4
Figure 4
Kaplan-Meier survival estimates of overall survival and time-to-recurrence in patients with duodenal adenocarcinomas. Overall survival in (A) groups classified by CIMP/MLH1 methylation status, (C) groups classified by CIMP/MSI status. Time-to-recurrence in (B) groups classified by CIMP/MLH1 methylation status, (D) groups classified by CIMP/MSI status. The P values shown have been pooled over strata.
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