CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer: a new trick for an old dog

Rijnsoever, Marius van; Joseph, David; Elsaleh, Hany; Iacopetta, Barry

doi:10.1016/s0360-3016(02)03228-5

Cited by 137 publications

(188 citation statements)

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“…6 However, prognostic features and chemotherapy responses according to CIMP status in colorectal cancer were controversial. 1,7,9,[38][39][40][41][42] More importantly, although HSP110wt expression was an independent prognostic factor in the present analysis, CIMP status was not ( Table 2). In addition, it is difficult to find a molecular mechanistic connection between the HSP110wt expression level and the CIMP status because HSP110 mutation is a genetic alteration, whereas CIMP is an epigenetic change.…”

Section: Discussionmentioning

confidence: 53%

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

Kim

Rhee

et al. 2014

Modern Pathology

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It has been recently suggested that the expression levels of mutant HSP110 could be a prognostic marker in colorectal cancer with a high level of microsatellite instability (MSI-H). The aim of our study was to validate the prognostic significance of HSP110 mutation using immunohistochemistry and DNA testing in MSI-H colorectal cancer. Wild-type HSP110 (HSP110wt)-specific immunohistochemistry was performed in 168 MSI-H colorectal cancer tissues, and their expression levels were evaluated using a four-tier scoring system (0/1 þ /2 þ /3 þ ). Of these tissues, 167 cases were analyzed for HSP110 T 17 deletion. Associations with clinicopathological, molecular and survival parameters were statistically analyzed. The low-level expression of HSP110wt (0/1 þ ) was observed in 40 MSI-H colorectal cancers (24%) and was significantly related to large HSP110 T 17 deletions (Z 4 bp, Po0.001). In survival analysis, patients with low HSP110wt expression (0/1 þ ) showed better diseasefree survival compared with those with high expression (2 þ /3 þ ; P ¼ 0.005). This significance in survival difference was maintained in patients with 5-fluorouracil-based chemotherapy-treated tumors (P ¼ 0.024) and in those with stage III/IV tumors (P ¼ 0.032). Multivariate analysis confirmed the role of HSP110wt expression as an independent prognostic factor (P ¼ 0.016, hazard ratio ¼ 4.32). In MSI-H colorectal cancer, a low expression of HSP110wt is associated with large HSP110 T 17 deletions and better clinical outcome. Immunohistochemistry of HSP110wt can be a simple and valuable tool for the prognostic and therapeutic stratification of patients with MSI-H colorectal cancer.

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Section: Discussionmentioning

confidence: 53%

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

Kim

Rhee

et al. 2014

Modern Pathology

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“…The CpG island methylator phenotype has worse prognosis (Van Rijnsoever et al, 2003;Ward et al, 2003) and is linked to the folate pathway (Kawakami et al, 2003). This latter pathway has been implicated in toxicity to 5FU (Pinedo and Peters, 1988).…”

Section: Discussionmentioning

confidence: 99%

Failure to complete adjuvant chemotherapy is associated with adverse survival in stage III colon cancer patients

et al. 2007

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Two recent North American studies have shown that completion of 5-fluorouracil (5FU)-based adjuvant chemotherapy is a major prognostic factor for the survival of elderly stage III colon cancer patients. The aim of the present study was to confirm this finding in a population-based series from Australia. The study cohort comprised 851 stage III colon cancer patients treated by surgery alone and 461 who initiated the Mayo chemotherapy regime. One-third of patients who initiated chemotherapy failed to complete more than three cycles of treatment. Independent predictors for failure to complete were treatment in district or rural hospitals, low socioeconomic index and treatment by a low-volume surgeon. Patients who failed to complete chemotherapy showed worse cancer-specific survival compared not only to those who completed treatment (HR ¼ 2.24; 95% confidence interval (CI) (1.66 -3.03), Po0.001) but also to those treated by surgery alone (HR ¼ 1.37; 95% CI (1.09 -1.72), P ¼ 0.008). The current and previous studies demonstrate the importance of completing adjuvant 5-FU-based chemotherapy for colon cancer. Further prospective studies are required to identify better the physiological and socioeconomic factors responsible for failure to complete chemotherapy so that appropriate improvements in health service delivery can be made.

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“…To compare the frequencies of methylation index 4-10 (or [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] in CACNA1G, for example, we limited the denominator to tumors with CACNA1G methylation index 44 (methylation positive) ( Table 1). This was because, compared to CIMP-high tumors, CIMP-low tumors had a higher proportion of tumors negative for CACNA1G methylation (methylation index o4), which, if included in the denominator, would have by itself decreased Table 1).…”

Section: Low-level Methylation At An Individual Promoter Was Common Imentioning

confidence: 99%

“…[7][8][9][10] Although controversial, CIMP may have prognostic implications in colorectal cancer. [11][12][13][14] In contrast to CIMP-high in colorectal cancer, the concept of CIMP-low (with less widespread CIMPspecific promoter methylation) is still emerging. 15,16 While CIMP-high colorectal cancer is associated with female sex and BRAF mutation, CIMP-low is associated with KRAS mutation.…”

mentioning

confidence: 99%

CpG island methylator phenotype-low (CIMP-low) colorectal cancer shows not only few methylated CIMP-high-specific CpG islands, but also low-level methylation at individual loci

et al. 2008

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The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct phenotype in colorectal cancer. However, the concept of CIMP-low with less extensive CpG island methylation is still evolving. Our aim is to examine whether density of methylation in individual CpG islands was different between CIMP-low and CIMP-high tumors. Utilizing MethyLight technology and 889 population-based colorectal cancers, we quantified DNA methylation (methylation index, percentage of methylated reference) at 14 CpG islands, including 8 CIMP-high-specific loci (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1). Methylation positivity in each locus was defined as methylation index44. Low-level methylation (methylation index40, o20) in each CIMP-high-specific locus was significantly more common in 340 CIMP-low tumors (1/8-5/8 methylation-positive loci) than 133 CIMP-high tumors (Z6/8 methylation-positive loci) and 416 CIMP-0 tumors (0/8 methylation-positive loci) (Pr0.002). In the other six loci (CHFR, HIC1, IGFBP3, MGMT, MINT31 and WRN), which were not highly specific for CIMP-high, low-level methylation, was not persistently more prevalent in CIMP-low tumors. In conclusion, compared to CIMP-high and CIMP-0 tumors, CIMP-low colorectal cancers show not only few methylated CIMP-high-specific CpG islands, but also more frequent low-level methylation at individual loci. Our data may provide supporting evidence for a difference in pathogenesis of DNA methylation between CIMP-low and CIMP-high tumors. Modern Pathology (2008) 21, 245-255; doi:10.1038/modpathol.3800982; published online 18 January 2008 Keywords: colon cancer; CpG island methylator phenotype; DNA methylation; promoter; MethyLight; CIMP-low Epigenetic aberrations are important mechanisms in human carcinogenesis. 1 A number of tumor suppressor genes are silenced by promoter methylation in colorectal cancers. 1,2 A subset of colorectal cancers have been shown to exhibit widespread promoter methylation, which is referred to as the CpG island methylator phenotype (CIMP). 1,3 CIMPhigh colorectal tumors have a distinct clinical, pathologic and molecular profile, such as associations with proximal tumor location, female sex, poor tumor differentiation, inactive WNT/b-catenin (CTNNB1) and high BRAF and low TP53 mutation rates, 4-6 independent of microsatellite instability status. 7-10 Although controversial, CIMP may have prognostic implications in colorectal cancer. [11][12][13][14] In contrast to CIMP-high in colorectal cancer, the concept of CIMP-low (with less widespread CIMPspecific promoter methylation) is still emerging. 15,16 While CIMP-high colorectal cancer is associated with female sex and BRAF mutation, CIMP-low is associated with KRAS mutation. 17 Thus, CIMP-low cannot be explained by a simple mixture of CIMPhigh and CIMP-0 (CIMP-negative). 17 We have also demonstrated a possible link between CIMP-low, microsatellite instability-low, MGMT methylation and KRAS mutation in colorectal cancer. 18 18q loss of heterozy...

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CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer: a new trick for an old dog

Cited by 137 publications

References 0 publications

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer

Failure to complete adjuvant chemotherapy is associated with adverse survival in stage III colon cancer patients

CpG island methylator phenotype-low (CIMP-low) colorectal cancer shows not only few methylated CIMP-high-specific CpG islands, but also low-level methylation at individual loci

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