Inverse Relationship between Microsatellite Instability and K-ras and p53 Gene Alterations in Colon Cancer

Samowitz, Wade S.; Holden, Joseph A.; Curtin, Karen; Edwards, Sandra L.; Walker, Adrianne R.; Lin, Heather A.; Robertson, Margaret; Nichols, Melanie F.; Gruenthal, Kristin M.; Lynch, Beverly J.; Leppert, M.; Slattery, Martha L.

doi:10.1016/s0002-9440(10)64102-8

Cited by 168 publications

(119 citation statements)

References 36 publications

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“…FXR promoter methylation was higher in MSI-H and hypermutated tumors and lower in KRAS mutant tumors. Hypermutated tumors often segregate with MSI-H tumors whereas KRAS tumors segregate with MSI-low and nonhypermutated (4,35). Thus an inverse methylation pattern of FXR, higher methylation in MSI-H tumors and lower methylation in KRAS mutant tumors, suggests two distinct mechanisms of FXR silencing: 1) DNA methylation in MSI-H and 2) KRAS signaling in MSI-low tumors.…”

Section: G55 Mechanisms Of Fxr Silencing In Colon Cancermentioning

confidence: 99%

FXR silencing in human colon cancer by DNA methylation and KRAS signaling

Bailey

Zhan

Maru

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Farnesoid X receptor (FXR) is a bile acid nuclear receptor described through mouse knockout studies as a tumor suppressor for the development of colon adenocarcinomas. This study investigates the regulation of FXR in the development of human colon cancer. We used immunohistochemistry of FXR in normal tissue ( n = 238), polyps ( n = 32), and adenocarcinomas, staged I–IV ( n = 43, 39, 68, and 9), of the colon; RT-quantitative PCR, reverse-phase protein array, and Western blot analysis in 15 colon cancer cell lines; NR1H4 promoter methylation and mRNA expression in colon cancer samples from The Cancer Genome Atlas; DNA methyltransferase inhibition; methyl-DNA immunoprecipitation (MeDIP); bisulfite sequencing; and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) knockdown assessment to investigate FXR regulation in colon cancer development. Immunohistochemistry and quantitative RT-PCR revealed that expression and function of FXR was reduced in precancerous lesions and silenced in a majority of stage I-IV tumors. FXR expression negatively correlated with phosphatidylinositol-4, 5-bisphosphate 3 kinase signaling and the epithelial-to-mesenchymal transition. The NR1H4 promoter is methylated in ∼12% colon cancer The Cancer Genome Atlas samples, and methylation patterns segregate with tumor subtypes. Inhibition of DNA methylation and KRAS silencing both increased FXR expression. FXR expression is decreased early in human colon cancer progression, and both DNA methylation and KRAS signaling may be contributing factors to FXR silencing. FXR potentially suppresses epithelial-to-mesenchymal transition and other oncogenic signaling cascades, and restoration of FXR activity, by blocking silencing mechanisms or increasing residual FXR activity, represents promising therapeutic options for the treatment of colon cancer.

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Section: G55 Mechanisms Of Fxr Silencing In Colon Cancermentioning

confidence: 99%

FXR silencing in human colon cancer by DNA methylation and KRAS signaling

Bailey

Zhan

Maru

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…MSI was assessed in tumors using a panel of 10 tetranucleotide repeats, 3 BAT-26 and TGF␤RII. These markers have been compared with each other and with the Bethesda Consensus Panel and have been found to yield similar results.…”

Section: Msimentioning

confidence: 99%

“…These markers have been compared with each other and with the Bethesda Consensus Panel and have been found to yield similar results. 3 The primer sequences and polymerase chain reaction (PCR) conditions for these repeats were as described previously. 4,16,17 Both tumor and normal DNA from each individual were PCR amplified with these 12 primer sets.…”

Section: Msimentioning

confidence: 99%

“…3,4 People with inherited mutations of mismatch repair genes develop MSI in colon tumors; causes of MSI in sporadic colon tumors are largely unknown. 5 In our previous evaluation of lifestyle factors associated with MSI we found that cigarette smoking is specifically associated with MSI tumors, whereas other factors such as physical activity, body size, and use of aspirin and non-steroidal anti-inflammatory drugs appear to be related equally to MSIϩ and MSIϪ tumors.…”

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confidence: 99%

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Dietary intake and microsatellite instability in colon tumors

et al. 2001

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Microsatellite instability (MSI) occurs in approximately 15% of colon tumors. Other than relatively rare mutations in mismatch repair genes, the causes of MSI are not generally known. The purpose of this study was to determine if dietary intake of nutrients previously reported as being associated with colon cancer relate specifically to the MSI disease pathway. Data from a population-based case-control study of adenocarcinoma of the colon were used to evaluate associations between dietary intake and MSI. Participants were between 30 and 79 years of age at time of diagnosis and included both men and women. Dietary intake data were obtained from a computerized diet history questionnaire. MSI was evaluated in several ways: by a panel of 10 tetranucleotide repeats, and by 2 mononucleotide repeats, BAT-26 and TGF␤RII. A total of 1,510 cases had valid study data and tumor DNA on which we were able to obtain MSI status. Cases with and without MSI were compared with dietary data reported by 2,410 population-based controls to determine dietary associations that may be different for these 2 subsets of cases. We compared dietary intake for cases with and without MSI to further determine associations that are specific to the MSI disease pathway. Key words: colon cancer; diet; microsatellite instability; alcohol; cigarette smokingDiet has been repeatedly implicated in the etiology of colon cancer. 1,2 Inconsistencies in observed associations across studies could stem from individual dietary components being associated with certain types of tumors and disease pathways, but not with colon cancer overall. Ability to examine diet in relationship to specific disease end points, as determined by specific mutations in tumors, should enhance our understanding of the disease process and the role of diet in that process.Microsatellite instability (MSI) occurs in approximately 15% of colon tumors. 3,4 People with inherited mutations of mismatch repair genes develop MSI in colon tumors; causes of MSI in sporadic colon tumors are largely unknown. 5 In our previous evaluation of lifestyle factors associated with MSI we found that cigarette smoking is specifically associated with MSI tumors, whereas other factors such as physical activity, body size, and use of aspirin and non-steroidal anti-inflammatory drugs appear to be related equally to MSIϩ and MSIϪ tumors. 6 Although dietary factors, to our knowledge, have not been examined with MSI in tumors, it is reasonable to hypothesize that components of diet, especially those that may be influenced by cigarette smoking, could influence development of unstable tumors. Alcohol could lead to unstable tumors independently or in combination with cigarette smoking. 7 Dietary antioxidants may decrease risk of unstable tumors through their role in reducing oxygen free radicals generated by cigarette smoke. 8 Other dietary factors hypothesized to influence cell growth and apoptosis, such as calcium, vitamin D and glycemic index, could be hypothesized as being associated with MSI in tumors. 9 In this ...

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“…20 However, instability in BAT-26, a component of the consensus panel, has been shown to be highly correlated with generalized tetranucleotide repeat instability 19 and with the Bethesda panel itself in the Utah subset of the current study. 21 Germline DNA was sequenced to determine mutations in hMLH1 and hMSH2 22 for the Utah and KPMCP portions of the population since these 2 geographic participants are more population based and would provide more accurate estimates of the proportion of colon cancer attributed to these inherited mutations.…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

Associations between family history of colorectal cancer and genetic alterations in tumors

Slattery

Curtin

Schaffer

et al. 2001

Intl Journal of Cancer

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A family history of colorectal cancer has been consistently associated with an increased risk of developing colon cancer. However, there is limited information on the association between family history of colorectal cancer and genetic alterations that occur in colon tumors. In this study, we evaluate the association among genetic alterations of Ki-ras and p53, microsatellite instability and having a family history of colorectal cancer in a study of incident colon cancer cases (n ‫؍‬ 1993) and population-based controls (n ‫؍‬ 2,410). Although there was a slight nonsignificant increase in risk of having an unstable tumor among those with a family history of colorectal cancer, this increase in risk disappeared after excluding those people with a known mutation in either of the mismatch repair genes hMLH1 or hMSH2. A family history of colorectal cancer was not associated with Ki-ras mutations overall, although those with a G to T mutation of the second base of codon 12 were more likely to have a family history of colorectal cancer than were those without this specific type of Ki-ras mutation. Cases with p53 mutations were less likely to have a family history of colorectal cancer than were cases without a p53 mutation. We believe that, given the general lack of association between having a family history of colorectal cancer and genetic alterations in tumors, these alterations are acquired through disease pathways that involve exposure from diet, lifestyle or other environmental factors.

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Inverse Relationship between Microsatellite Instability and K-ras and p53 Gene Alterations in Colon Cancer

Cited by 168 publications

References 36 publications

FXR silencing in human colon cancer by DNA methylation and KRAS signaling

FXR silencing in human colon cancer by DNA methylation and KRAS signaling

Dietary intake and microsatellite instability in colon tumors

Associations between family history of colorectal cancer and genetic alterations in tumors

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