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, 07/27/2012
Fu T et al. – Our results demonstrate existence of CIMP in duodenal adenocarcinomas. The combination of CIMP+/MLH1-U appears 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.
Methods- 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 performed.
- A Cox proportional hazard model was built to predict survival.
- 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 to 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 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), while 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 regarding both OS (P < 0.001) and TTR (P = 0.023).
- Patients with CIMP+/MLH1-U tumors had the worst OS and TTR.
