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.