Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer

Sánchez, Julián; Krumroy, Lisa; Plummer, Sarah J.; Aung, Phyu P.; Merkulova, Alona; Skacel, Marek; DeJulius, Kathryn L.; Manilich, Elena; Church, James M.; Casey, Graham; Kalady, Matthew F.

doi:10.1002/bjs.6683

Cited by 98 publications

(83 citation statements)

References 40 publications

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“…However, this subgroup tends to be small, and statistically significant results have rarely been reported, and contradictive results have recently been reported (25).…”

Section: Discussionmentioning

confidence: 84%

“…Although promoter hypermethylation in multiple genes has been related to a poor prognosis in CRC in some previous studies (16,17), several reports have noted a better prognosis or null associations (5,6,(18)(19)(20)(21)(22)(23)(24)(25)(26). A poor prognosis in CIMP-high CRC patients might result from other factors closely related to CIMP, such as the BRAF V600E mutation, rather than to an effect of the phenotype itself (20,22,26,27).…”

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confidence: 94%

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

Dahlin

Palmqvist

Henriksson

et al. 2010

Clinical Cancer Research

156

147

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Purpose: The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation.Experimental Design: Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umeå Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry.Results: CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMPnegative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected.Conclusions: In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research. Clin Cancer Res; 16(6); 1845-55. ©2010 AACR.

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“…However, this subgroup tends to be small, and statistically significant results have rarely been reported, and contradictive results have recently been reported (25).…”

Section: Discussionmentioning

confidence: 84%

mentioning

confidence: 94%

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

Dahlin

Palmqvist

Henriksson

et al. 2010

Clinical Cancer Research

156

147

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“…Tumors containing >30% unstable markers were classified as microsatellite unstable while tumors containing zero unstable markers were deemed microsatellite stable. Mutation analysis for BRAF and KRAS was conducted as previously described (Sanchez et al 2009). Additional clinical data for each cancer specimen are provided in Supplemental Table 6.…”

Section: Methods Sample Selection and Preparationmentioning

confidence: 99%

Unique DNA methylome profiles in CpG island methylator phenotype colon cancers

Choi

et al. 2011

Genome Res.

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A subset of colorectal cancers was postulated to have the CpG island methylator phenotype (CIMP), a higher propensity for CpG island DNA methylation. The validity of CIMP, its molecular basis, and its prognostic value remain highly controversial. Using MBD-isolated genome sequencing, we mapped and compared genome-wide DNA methylation profiles of normal, non-CIMP, and CIMP colon specimens. Multidimensional scaling analysis revealed that each specimen could be clearly classified as normal, non-CIMP, and CIMP, thus signifying that these three groups have distinctly different global methylation patterns. We discovered 3780 sites in various genomic contexts that were hypermethylated in both non-CIMP and CIMP colon cancers when compared with normal colon. An additional 2026 sites were found to be hypermethylated in CIMP tumors only; and importantly, 80% of these sites were located in CpG islands. These data demonstrate on a genome-wide level that the additional hypermethylation seen in CIMP tumors occurs almost exclusively at CpG islands and support definitively that these tumors were appropriately named. When these sites were examined more closely, we found that 25% were adjacent to sites that were also hypermethylated in non-CIMP tumors. Thus, CIMP is also characterized by more extensive methylation of sites that are already prone to be hypermethylated in colon cancer. These observations indicate that CIMP tumors have specific defects in controlling both DNA methylation seeding and spreading and serve as an important first step in delineating molecular mechanisms that control these processes.

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“…Although there is no consensus panel for the determination of CIMP status, this eight-gene panel has been thoroughly validated 50,51 and the included methylation marker genes have been used in several large CIMP studies. [15][16][17]50 In order to account for the amount of input bisulfite-treated DNA, one reaction amplifying the repetitive ALU sequence was also run for each DNA sample. M.SssI-treated DNA (presumably fully methylated) served as a methylated reference in control reactions to account for the efficiency of PCR amplification, and for use in standard curve reactions.…”

Section: Methylation Analysismentioning

confidence: 99%

“…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.…”

mentioning

confidence: 98%

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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Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer

Abstract: Colorectal cancers are molecularly and clinically heterogeneous. These different molecular phenotypes may reflect variable prognosis.

Cited by 98 publications

References 40 publications

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

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

Unique DNA methylome profiles in CpG island methylator phenotype colon cancers

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

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