Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MLH1 -93 G>A promoter polymorphism has been reported to be associated with an increased risk of microsatellite unstable colorectal cancer. Other than microsatellite instability, however, the genetic and most epigenetic changes of tumors associated with this polymorphism have not been studied. We evaluated associations between the -93 G>A polymorphism and CpG island methylator phenotype (CIMP), BRAF V600E mutations, and MLH1 methylation in tumors from a sample of 1,211 individuals with colon cancer and 1,968 controls from Utah, Northern California, and Minnesota. The -93 G>A polymorphism was determined by the five prime nuclease assay. CIMP was determined previously by methylation-specific PCR of CpG islands in MLH1, methylated in tumors (MINT)1, MINT2, MINT31, and CDKN2A (p16). The BRAF V600E mutation was determined by sequencing exon 15. The MLH1 -93 G>A promoter polymorphism was associated with CIMP (odds ratio (OR) 3.44, 95% confidence interval (CI) 1.85, 6.42), MLH1 methylation (OR 4.16, 95%CI 2.20, 7.86), BRAF mutations (OR 4.26, 95%CI 1.83, 9.91), and older age at diagnosis (OR 3.65, 95%CI 2.08, 6.39) in microsatellite unstable tumors. These associations were not observed in stable tumors. Increased age at diagnosis and tumor characteristics of microsatellite unstable tumors associated with MLH1 -93 G>A suggests the polymorphism is acting at a relatively late stage of colorectal carcinogenesis to drive CIMP+ tumors down the microsatellite instability pathway.
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PMID:The MLH1 -93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer. 1861 80

The geldanamycin derivatives 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) are promising chemotherapeutic drugs that inhibit heat shock protein 90 (HSP90) function. Previous studies have shown that 17-AAG/DMAG treatment induces the degradation of mutant BRAF (V600E) and inhibits the activation of mitogen-activated protein/extracellular signal-regulated kinase 1/2 (MEK1/2). We have found, however, that HSP90 inhibition alone is not sufficient for efficient BRAF(V600E) degradation in some cells. HSP90 inhibitors structurally unrelated to geldanamycin, radicicol and novobiocin, while inducing the degradation of the HSP90 client protein RAF-1 fail to induce BRAF(V600E) degradation or inhibit MEK1/2 activation in HT29 human colon cancer cells. Moreover, after treatment with 17-DMAG, the kinase activity of residual, undegraded BRAF(V600E) was also lost. Incubation of cells with a reactive oxygen species (ROS) scavenger, N-acetyl cysteine, partially restored kinase activity and also partially prevented BRAF(V600E) degradation due to 17-DMAG treatment. Conversely, treatment with the ROS producing drug menadione clearly inhibited MEK1/2 and reduced BRAF(V600E). These results suggest that in addition to direct inhibition of HSP90, the antitumor effect of geldanamycin and its derivatives is also mediated though the production of ROS, which may directly inactivate tumorigenic mutant BRAF(V600E).
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PMID:Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives. 1867 57

We have identified an alternative pathway of tumorigenesis in sporadic colon cancer, involving microsatellite instability due to mismatched repair methylation, which may be driven by mutations in the BRAF gene (V600E). Colorectal cancer (CRC) is the most common cancer in the world, and African Americans show a higher incidence than other populations in the United States. We analyzed sporadic CRCs in Omani (of African origin, N = 61), Iranian (of Caucasian origin, N = 53) and African American (N = 95) patients for microsatellite instability, expression status of mismatched repair genes (hMLH1, hMSH2) and presence of the BRAF (V600E) mutation. In the Omani group, all tumors with BRAF mutations were located in the left side of the colon, and for African Americans, 88% 7 of tumors with BRAF mutations were found in the right side of the colon. In African Americans, 31% of tumors displayed microsatellite instability at two or more markers (MSI-H), while this rate was 26% and 13% for tumors in the Iranian and Omani groups, respectively. A majority of these MSI-H tumors were located in the proximal colon (right side) in African American and Iranian subjects, whereas most were located in the distal colon (left side) in Omani subjects. Defects in hMLH1 gene expression were found in 77% of MSI-H tumors in both African Americans and Iranians and in 38% of tumors in Omanis. BRAF mutations were observed in all subjects: 10% of tumors in African Americans (8/82), 2% of tumors in Iranians (1/53), and 19% of tumors in Omanis (11/59). Our findings suggest that CRC occurs at a younger age in Omani and Iranian patients, and these groups showed a lower occurrence of MSI-H than did African American patients. Our multivariate model suggests an important and significant role of hMLH1 expression and BRAF mutation in MSI-H CRC in these populations. The high occurrence of MSI-H tumors in African Americans may have significant implications for treatment, since patients with MSI-H lesions display a different response to chemotherapeutic agents such as 5-fluorouracil.
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PMID:Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study. 1871 23

Our understanding of somatic alterations in colon cancer has evolved from a concept of a series of events taking place in a single sequence to a recognition of multiple pathways. An oncogenetic tree is a model intended to describe the pathways and sequence of somatic alterations in carcinogenesis without assuming that tumors will fall in mutually exclusive categories. We applied this model to data on colon tumor somatic alterations. An oncogenetic tree model was built using data on mutations of TP53, KRAS2, APC, and BRAF genes, methylation at CpG sites of MLH1 and TP16 genes, methylation in tumor (MINT) markers, and microsatellite instability (MSI) for 971 colon tumors from a population-based series. Oncogenetic tree analysis resulted in a reproducible tree with three branches. The model represents methylation of MINT markers as initiating a branch and predisposing to MSI, methylation of MHL1 and TP16, and BRAF mutation. APC mutation is the first alteration in an independent branch and is followed by TP53 mutation. KRAS2 mutation was placed a third independent branch, implying that it neither depends on, nor predisposes to, the other alterations. Individual tumors were observed to have alteration patterns representing every combination of one, two, or all three branches. The oncogenetic tree model assumptions are appropriate for the observed heterogeneity of colon tumors, and the model produces a useful visual schematic of the sequence of events in pathways of colon carcinogenesis.
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PMID:Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors. 1876 47

The mitogenic extracellular kinase 1/2 (MEK1/2) inhibitor, PD0325901, has potent activity in a number of cancer cell types in vitro. In SKMEL-28 human melanoma cells (BRAF mutant), the drug rapidly decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein levels. We investigated if 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography ([18F]FLT-PET) could be used to image changes in cell proliferation following MEK1/2 inhibition in vivo. Mice bearing SKMEL-28 and human colon cancer HCT116 (K-RAS mutant) xenografts were treated daily with PD0325901 at 25 mg/kg and imaged by dynamic [18F]FLT-PET after 1 and 10 days of initiating treatment. The drug decreased tumor [18F]FLT uptake after 1 and 10 days of treatment compared with control animals. The normalized (maximal) [18F]FLT uptake in SKMEL-28 xenografts (at 60 minutes; NUVmax) after 1 day of vehicle or PD0325901 therapy was 1.81 +/- 0.18 versus 1.23 +/- 0.10, respectively (P = 0.03). In this model, NUVmax after 10 days was 2.07 +/- 0.40 versus 1.08 +/- 0.14, respectively (P = 0.03). The corresponding values for HCT116 tumors were 2.30 +/- 0.84 versus 1.88 +/- 0.36 (P = 0.045) after 1 day, and 1.97 +/- 0.13 versus 1.00 +/- 0.03 (P = 0.03) after 10 days. Similar changes were found for other [18F]FLT retention variables. The drug decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein. Tumor [18F]FLT-PET variables correlated with proliferation as measured by Ki67 labeling index (r > or = 0.6; P > or = 0.003). In summary, [18F]FLT-PET is a sensitive imaging biomarker for detecting the antiproliferative effect of MEK1/2 inhibition by PD0325901.
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PMID:Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. 1879 Jul 89

Several advances in recent years have focused increasing attention on the role of the RAF-MEK-ERK1/2 pathway in promoting cell survival. The demonstration that BRAF is a human oncogene mutated at high frequency in melanoma, thyroid and colon cancer has provided a pathophysiological context, whilst the description of potent and highly selective inhibitors of BRAF or MEK has allowed a more informed and rational intervention in both normal and tumour cells. In addition, separate studies have uncovered new mechanisms by which the ERK1/2 pathway can control the activity or abundance of members of the BCL-2 protein family to promote cell survival. It is now apparent that various oncogenes co-opt ERK1/2 signalling to de-regulate these BCL-2 proteins and this contributes to, and even underpins, survival signalling in some tumours. New oncogene-targeted therapies allow direct or indirect inhibition of ERK1/2 signalling and can cause quite striking tumour cell death. In other cases, inhibition of the ERK1/2 pathway may be more effective in combination with other conventional and novel therapeutics. Here, we review recent advances in our understanding of how the ERK1/2 pathway regulates BCL-2 proteins to promote survival, how this is de-regulated in tumour cells and the opportunities this might afford with the use of new targeted therapies.
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PMID:Tumour cell survival signalling by the ERK1/2 pathway. 1884 9

The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P < 0.001). KRAS mutations were more associated with CIMP-High and CIMP-Low status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status [CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37-2.51; CIMP-High, HR, 2.90; 95% CI, 1.53-5.49 compared with No-CIMP]. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer.
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PMID:Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. 1892 29

Genome-wide DNA hypomethylation plays has an important role in genomic instability and colorectal carcinogenesis. However, the relationship between cellular DNA methylation level and patient outcome remains uncertain. Using 643 colon cancers in two independent prospective cohorts, we quantified DNA methylation in repetitive long interspersed nucleotide element-1 (LINE-1) elements using pyrosequencing, which is a good indicator of global DNA methylation level. We used Cox proportional hazard models to calculate hazard ratios (HRs) of colon cancer-specific and overall mortality, adjusting for patient and tumoral features, including CpG island methylator phenotype (CIMP). Statistical tests were two-sided. LINE-1 hypomethylation was linearly associated with a statistically significant increase in colon cancer-specific mortality (for a 30% decrease in LINE-1 methylation: multivariable HR = 2.37, 95% confidence interval [CI] = 1.42 to 3.94; P(trend) < .001) and overall mortality (multivariable HR = 1.85, 95% CI = 1.25 to 2.75; P(trend) = .002). The association was consistent across the two independent cohorts and strata of clinical and molecular characteristics, including sex, age, tumor location, stage, and CIMP, microsatellite instability, KRAS, BRAF, p53, and chromosomal instability status. In conclusion, tumoral LINE-1 hypomethylation is independently associated with shorter survival among colon cancer patients.
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PMID:A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. 1903 68

JC virus has a transforming gene encoding JC virus T-antigen (JCVT). JCVT may inactivate wild-type p53, cause chromosomal instability (CIN), and stabilize beta-catenin. A link between JCVT and CpG island methylator phenotype (CIMP) has been suggested. However, no large-scale study has examined the relations of JCVT with molecular alterations, clinical outcome, or prognosis in colon cancer. We detected JCVT expression (by immunohistochemistry) in 271 (35%) of 766 colorectal cancers. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other loci (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, WRN) by MethyLight. We examined loss of heterozygosity in 2p, 5q, 17q, and 18q. JCVT was significantly associated with p53 expression (P < .0001), p21 loss (P < .0001), CIN (>/=2 chromosomal segments with LOH; P < .0001), nuclear beta-catenin (P = .006), LINE-1 hypomethylation (P = .002), and inversely with CIMP-high (P = .0005) and microsatellite instability (MSI) (P < .0001), but not with PIK3CA mutation. In multivariate logistic regression analysis, the associations of JCVT with p53 [adjusted odds ratio (OR), 8.45; P < .0001], CIN (adjusted OR, 2.53; P = .003), cyclin D1 (adjusted OR, 1.57; P = .02), LINE-1 hypomethylation (adjusted OR, 1.97 for a 30% decline as a unit; P = .03), BRAF mutation (adjusted OR, 2.20; P = .04), and family history of colorectal cancer (adjusted OR, 0.64; P = .04) remained statistically significant. However, JCVT was no longer significantly associated with CIMP, MSI, beta-catenin, or cyclooxygenase-2 expression in multivariate analysis. JCVT was unrelated with patient survival. In conclusion, JCVT expression in colorectal cancer is independently associated with p53 expression and CIN, which may lead to uncontrolled cell proliferation.
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PMID:JC virus T-antigen in colorectal cancer is associated with p53 expression and chromosomal instability, independent of CpG island methylator phenotype. 1910 35

The Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway is involved in cellular responses relevant to tumorigenesis, including cell proliferation, invasion, survival, and angiogenesis. 2-[4-[(1E)-1-(Hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl]ethan-1-ol (GDC-0879) is a novel, potent, and selective B-Raf inhibitor. The objective of this study was to characterize the relationship between GDC-0879 plasma concentrations and tumor growth inhibition in A375 melanoma and Colo205 colon cancer xenografts and to understand the pharmacodynamic (PD) marker response requirements [phosphorylated (p)MEK1 inhibition] associated with tumor growth inhibition in A375 xenografts. Estimates of GDC-0879 plasma concentrations required for tumor stasis obtained from fitting tumor data to indirect response models were comparable, at 4.48 and 3.27 microM for A375 and Colo205 xenografts, respectively. This was consistent with comparable in vitro potency of GDC-0879 in both cell lines. The relationship between GDC-0879 plasma concentrations and pMEK1 inhibition in the tumor was characterized in A375 xenografts after oral doses of 35, 50, and 100 mg/kg. Fitting pMEK1 inhibition to an indirect response model provided an IC(50) estimate of 3.06 microM. pMEK1 inhibition was further linked to A375 tumor volume data from nine different GDC-0879 dosing regimens using an integrated pharmacokinetic-PD model. A simulated PD marker response curve plot of K (rate constant describing tumor growth inhibition) versus pMEK1 inhibition generated using pharmacodynamic parameters estimated from this model, showed a steep pMEK1 inhibition-response curve consistent with an estimated Hill coefficient of approximately equal 8. A threshold of >40% pMEK1 inhibition is required for tumor growth inhibition, and a minimum of approximately 60% pMEK1 inhibition is required for stasis in A375 xenografts treated with GDC-0879.
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PMID:Pharmacodynamics of 2-[4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl]ethan-1-ol (GDC-0879), a potent and selective B-Raf kinase inhibitor: understanding relationships between systemic concentrations, phosphorylated mitogen-activated protein kinase kinase 1 inhibition, and efficacy. 1914 58


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