Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers

Kuismanen, Shannon A.; Holmberg, Mari T.; Salovaara, Reijo; Schweizer, Pascal; Aaltonen, Lauri A.; Chapelle, Albert de la; Nyström‐Lahti, Minna; Peltomäki, Païvi

doi:10.1073/pnas.96.22.12661

Cited by 106 publications

(74 citation statements)

References 28 publications

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“…In support of this notion, MSI in tumours from older patients is predominantly due to promoter hypermethylation and epigenetic silencing of hMLH1. [11][12][13][14] In contrast, most MSI tumours in early onset patients in the current study (65%) were associated with germline MMR gene mutations. MSI in HNPCC tumours has also been shown to be due primarily to mutation and allele loss rather than promoter methylation.…”

Section: Discussionmentioning

confidence: 81%

“…In the older age group, 75% of MSI tumours were proximal, whereas 33% of microsatellite stable tumors were proximal (p Ͻ 0.009). This age-dependent difference in distribution of MSI tumours is intriguing and suggests that other factors may impact on the molecular basis of defective DNA MMR in tumours in different age groups, 14 including enviromental exposure to methylating agents in the diet. Thus, the proportion of germline MMR mutation carriers in each cohort probably explains differences in tumour distribution and survival reported previously.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 The principal mechanism responsible for MSI in these age groups is epigenetic gene inactivation by hypermethylation of the hMLH1 promoter. [11][12][13][14] Hypermethylation of this promoter is associated with increasing age and proximal tumour location. 14 In contrast to epigenetic mechanisms that cause the MSI phenotype in tumours arising in older patients, MSI observed in colorectal cancers diagnosed before age Ͻ 30 years is predominantly due to germline DNA MMR gene mutations.…”

mentioning

confidence: 99%

“…[11][12][13][14] Hypermethylation of this promoter is associated with increasing age and proximal tumour location. 14 In contrast to epigenetic mechanisms that cause the MSI phenotype in tumours arising in older patients, MSI observed in colorectal cancers diagnosed before age Ͻ 30 years is predominantly due to germline DNA MMR gene mutations. 9,15 Hence, there are age-dependent differences in the molecular basis of tumour MSI.…”

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confidence: 99%

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Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Farrington

McKinley

Carothers

et al. 2002

Intl Journal of Cancer

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It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n ‫؍‬ 118; non-age-selected, n ‫؍‬ 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p ϳ 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Farrington

McKinley

Carothers

et al. 2002

Intl Journal of Cancer

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“…Hypermethylation of the MLH1 promoter, as seen in these two individuals, is invariably associated with transcriptional silence of the gene 20 . Methylation of MLH1 has also been observed in normal colonic tissue adjacent to MSI tumors 21 , and although its relationship to tumor development is not clear, it may be a precursor event 22 . An individual with hypermethylation of MLH1 in peripheral blood and LOH in his colon tumor has been reported 23 ; our results support the speculation that this reflected a germline defect in one allele.…”

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confidence: 99%

Germline epimutation of MLH1 in individuals with multiple cancers

2004

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Epigenetic silencing can mimic genetic mutation by abolishing expression of a gene. We hypothesized that an epimutation could occur in any gene as a germline event that predisposes to disease and looked for examples in tumor suppressor genes in individuals with cancer. Here we report two individuals with soma-wide, allele-specific and mosaic hypermethylation of the DNA mismatch repair gene MLH1. Both individuals lack evidence of genetic mutation in any mismatch repair gene but have had multiple primary tumors that show mismatch repair deficiency, and both meet clinical criteria for hereditary nonpolyposis colorectal cancer. The epimutation was also present in spermatozoa of one of the individuals, indicating a germline defect and the potential for transmission to offspring. Germline epimutation provides a mechanism for phenocopying of genetic disease. The mosaicism and nonmendelian inheritance that are characteristic of epigenetic states could produce patterns of disease risk that resemble those of polygenic or complex traits.Epigenetic silencing is a stable but reversible alteration of gene function mediated by histone modification, cytosine methylation, the binding of nuclear proteins to chromatin and interactions among these 1,2 . It does not require, or generally involve, changes in DNA sequence. Errors in the elaborate apparatus of epigenetic silencing possessed by higher eukaryotes can lead to 'epimutation' 3-5 , which we define as epigenetic silencing of a gene that is not normally silenced, or epigenetic activation of a gene that is normally silent. Germline epimutations are known in plants, examples being methylation and transcriptional silencing of the gene Lcyc in toadflax (Linaria vulgaris) 6 , paramutation in maize 5,7 and the clark kent alleles of SUPERMAN in Arabidopsis thaliana 8 . Similar phenomena in mammals could be an unrecognized source of phenotypic effects, which might manifest as disease. The increasingly detailed understanding of the genetics of human disease suggests a strategy to identify epimutations: screen for methylation of known disease-associated genes in affected individuals who do not carry a mutation in the relevant gene. Tumor suppressors are good candidates for this strategy because there is a clear relationship between their inactivation and the development of cancer. Germline mutations in tumor suppressor genes can predispose to cancer 9 . Tumor suppressors are also commonly methylated (and inactivated) in the course of neoplastic progression 10 , but the causal relationship between hypermethylation and tumorigenesis has not been established.We hypothesized that some individuals are predisposed to develop cancer because they carry germline epimutations of tumor suppressor genes. We selected 94 individuals for this study: 18 with hyperplastic polyposis 11 , 11 with personal histories of colorectal cancer and 65 with a family history of colorectal cancer but without deleterious germline changes in MSH2, MLH1 or APC 12 . We screened a subset of 44 individuals for promoter met...

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Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability

Gafà

Maestri

Matteuzzi

et al. 2000

Cancer

187

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Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers

Cited by 106 publications

References 28 publications

Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Evidence for an age‐related influence of microsatellite instability on colorectal cancer survival

Germline epimutation of MLH1 in individuals with multiple cancers

Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability

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