The Role of the CpG Island Methylator Phenotype in Colorectal Cancer Prognosis Depends on Microsatellite Instability Screening Status

Dahlin, Anna M.; Palmqvist, Richard; Henriksson, Maria L.; Jacobsson, Maria; Eklöf, Vincy; Rutegård, Jörgen; Öberg, Åke; Guelpen, Bethany Van

doi:10.1158/1078-0432.ccr-09-2594

Cited by 156 publications

(169 citation statements)

References 46 publications

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“…[20][21][22][23] It has been argued that CpG island methylation phenotype-positive tumors constitute a distinct subtype of colorectal cancer, and have been variously associated with different features such as BRAF mutation, KRAS mutation, favorable prognosis and adverse outcome. [24][25][26][27][28][29][30]42 These differences are likely related to different criteria used for defining CpG island methylation phenotype-positive status, as well as the number and type of markers used. The role of methylation in signet ring cell carcinoma has not been systematically explored.…”

Section: Discussionmentioning

confidence: 99%

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Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with highlevel microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotypepositive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

“…Some, but not all, studies have shown that CpG island methylation phenotype-positive phenotype is associated with aggressive behavior. [26][27][28][29][30] BRAF is a downstream gene in the KRAS pathway. BRAF V600E mutation occurs in 34-80% of cancers with high level of microsatellite instability and 5-15% of microsatellite-stable cancers.…”

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Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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“…Along with others, we have reported a worse prognosis in colorectal cancer patients with CIMP-low or CIMP-high, compared with CIMPnegative tumors, particularly in combination with MSS. 4,[9][10][11][12] However, results from other large studies have not been entirely consistent, [13][14][15][16][17][18] and consensus has thus not been reached. One factor contributing to the discrepancy of results in the many studies is the lack of information regarding BRAF mutation, which has shown to be a major confounding factor in studies of CIMP status and colorectal cancer patient survival.…”

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confidence: 95%

“…One factor contributing to the discrepancy of results in the many studies is the lack of information regarding BRAF mutation, which has shown to be a major confounding factor in studies of CIMP status and colorectal cancer patient survival. 12,14,15,17 Some studies have focused on the clinical importance of the host response in terms of tumor infiltrating immune cells. Presence of peri-and intratumoral inflammatory cells has consistently been associated with a better prognosis in colorectal cancer.…”

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Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

et al. 2011

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The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eightgene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score Z7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score r4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P ¼ 0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

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“…Jass, 14 Jass et al 15 and Young et al 16 were the first to notify and to report the differences between these cancers. [14][15][16] Several studies have since focused on and addressed this issue, [17][18][19][20] showing that CIMP-H microsatellite-unstable colorectal cancers exhibit increased incidence rates in female patients, increased localization to the proximal large bowel, later age of onset, more frequent poor differentiation, increased frequency of BRAF mutation, increased nodal metastasis, and shortened survival time.…”

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Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status

et al. 2013

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Although the presence of MLH1 methylation in microsatellite-unstable colorectal cancer generally indicates involvement of the CpG island methylator phenotype (CIMP) in the development of the tumor, these two conditions do not always correlate. A minority of microsatellite-unstable colorectal cancers exhibit discordance between CIMP and MLH1 methylation statuses. However, the clinicopathological features of such microsatellite-unstable colorectal cancers with discrepant MLH1 methylation and CIMP statuses remain poorly studied. Microsatellite-unstable colorectal cancers (n ¼ 220) were analyzed for CIMP and MLH1 methylation statuses using the MethyLight assay. Based on the combinatorial CIMP and MLH1 methylation statuses, the microsatellite-unstable colorectal cancers were grouped into four subtypes (CIMP-high (CIMP-H) MLH1 methylation-positive (MLH1m þ ), CIMP-H MLH1 methylation-negative, CIMP-low/0 (CIMP-L/0) MLH1m þ , and CIMP-L/0 MLH1 methylation-negative), which were compared in terms of their associations with clinicopathological and molecular features. The CIMP-L/0 MLH1 methylation-negative and CIMP-H MLH1m þ subtypes were predominant, comprising 63.6 and 24.1% of total microsatellite-unstable colorectal cancers, respectively. The discordant subtypes, CIMP-H MLH1 methylation-negative and CIMP-L/0 MLH1m þ , were found in 5 and 7% of microsatellite-unstable colorectal cancers, respectively. The CIMP-H MLH1 methylation-negative subtype exhibited elevated incidence rates in male patients and was associated with larger tumor size, more frequent loss of MSH2 expression, increased frequency of KRAS mutation, and advanced cancer stage. The CIMP-L/0 MLH1m þ subtype was associated with onset at an earlier age, a predominance of MLH1 loss, and earlier cancer stage. None of the CIMP-L/0 MLH1m þ subtype patients succumbed to death during the follow-up. Our findings suggest that the discordant subtypes of colorectal cancers exhibit distinct clinicopathological and molecular features, although the proportion of discordant subtypes is low. The microsatellite-unstable colorectal cancers of the same CIMP status tended to exhibit different clinicopathological features depending on MLH1 methylation status.

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The Role of the CpG Island Methylator Phenotype in Colorectal Cancer Prognosis Depends on Microsatellite Instability Screening Status

Cited by 156 publications

References 46 publications

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor

Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status

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