CpG Island Methylator Phenotype–Positive Tumors in the Absence ofMLH1Methylation 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 performed. 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 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. Conclusions 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.

CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas

“…In our previous paper investigating duodenal cancers, we had defined CIMP positivity as greater than 3 out of 5 markers methylation. 38 Although CIMP-high may be more stringent to classify CIMP status, when we used that classification in duodenal adenomas, we failed to see any relationship between CIMP and clinicopathologic features beyond villous subtype, race, and larger size. We believe this is due to the sample size in our study.…”

“…This association has been seen previously in duodenal adenocarcinomas as well as in CRC. 22,38 This is not particularly surprising as MLH1 is a component of the classical CIMP panel. However, another component of this panel, p16, is poorly represented in duodenal adenomas in this study (7.4%) and did not correlate with CIMP+.…”

Methylation Silencing of ULK2, an Autophagy Gene, Is Essential for Astrocyte Transformation and Tumor Growth

“…While the majority of the cancer genome, which includes non CpG islands of repetitive DNA sequence genome, is subjected to undermethylation, hypermethylation is seen in CpG islands present at the promoters of many genes (29,30). Further, CpG Island Methylator Phenotype (CIMP) identifies a distinct molecular subtype in a number of cancers including glioblastoma (6,31,32). In glioblastoma, G-CIMP tumors appear to be enriched with pro neural subtype tumors and IDH1 mutations (6).…”

The CpG Island Methylator Phenotype: What's in a Name?

“…Therefore, selecting a CIMP panel tightly associated with BRAF mutation may not be entirely relevant to quantifying or identifying CIMP in endometrial tumors. Similarly, results from a recent study on duodenal adenocarcinomas suggest that BRAF mutations are not involved in duodenal tumorigenesis, MSI, or CIMP development (38). If one hypothesizes that CIMP is a general phenomenon, then the cause of CIMP should also be general and similar across different cancer types.…”

“…[20][21][22], hepatocellular (23)(24)(25)(26), lung (27,28), ovarian (29), pancreatic (30), prostate (31), and renal cell (32) cancers, as well as in leukemia (33)(34)(35)(36), melanoma (37), duodenal adenocarninomas (38), adrenocortical carcinomas (39), and neuroblastomas (40,41). The primary purpose of these studies was to determine if CIMP is also present in these cancers, and if it can be used to distinguish between known phenotypes of the respective cancer type.…”