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, 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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4743-4752
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number17
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

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CpG Islands
Methylation
Adenocarcinoma
Phenotype
Microsatellite Instability
Neoplasms
Mutation
Survival
Kaplan-Meier Estimate
DNA Methylation
Proportional Hazards Models
Epigenomics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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

In: Clinical Cancer Research, Vol. 18, No. 17, 01.09.2012, p. 4743-4752.

Research output: Contribution to journalArticle

Fu, T, Pappou, EP, Guzzetta, AA, Jeschke, J, Kwak, R, Dave, P, Hooker, CM, Morgan, R, Baylin, SB, Iacobuzio-Donahue, CA, Wolfgang, CL & Ahuja, N 2012, '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', Clinical Cancer Research, vol. 18, no. 17, pp. 4743-4752. https://doi.org/10.1158/1078-0432.CCR-12-0707
Fu, Tao ; Pappou, Emmanouil P. ; Guzzetta, Angela A. ; Jeschke, Jana ; Kwak, Ruby ; Dave, Pujan ; Hooker, Craig M. ; Morgan, Richard ; Baylin, Stephen B. ; Iacobuzio-Donahue, Christine A. ; Wolfgang, Christopher L. ; Ahuja, Nita. / 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. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 17. pp. 4743-4752.
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title = "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",
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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T1 - 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

AU - Fu, Tao

AU - Pappou, Emmanouil P.

AU - Guzzetta, Angela A.

AU - Jeschke, Jana

AU - Kwak, Ruby

AU - Dave, Pujan

AU - Hooker, Craig M.

AU - Morgan, Richard

AU - Baylin, Stephen B.

AU - Iacobuzio-Donahue, Christine A.

AU - Wolfgang, Christopher L.

AU - Ahuja, Nita

PY - 2012/9/1

Y1 - 2012/9/1

N2 - 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.

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.

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