Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sessile serrated polyps (SSPs) have been implicated in the pathogenesis of proximal colonic carcinomas, but they lack well-defined diagnostic criteria and their features overlap considerably with those of microvesicular hyperplastic polyps (MVHPs). We have noted that morphologic features of SSPs are often present in small, distally located MVHPs, suggesting that these polyps represent points on a continuum, rather than distinct entities. We evaluated the molecular features of diminutive (<1 cm) nondysplastic serrated polyps that met at least 4 of the 7 "SSP-like" morphologic criteria, but occurred throughout the colorectum, and compared them with SSPs and MVHPs. Fifty nondysplastic serrated polyps (6 SSPs, 31 study polyps, and 13 MVHPs) were evaluated for Ki-67, O6-methylguanine methyltransferase, MUC2, and MUC5AC expression, and also their BRAF and KRAS mutational status. The study polyps and SSPs were similar; 52% and 50% expressed MUC5AC, and 87% and 100% harbored BRAF mutations, respectively, compared with 15% and 46% of MVHPs (P < or = 0.05, all comparisons). O6-methylguanine methyltransferase expression in the study polyps (29%) was intermediate between that of SSPs (83%, P=0.02) and MVHPs (15%, P=0.04). We conclude that the pathologic and molecular features of diminutive, distally located nondysplastic serrated polyps are often indistinguishable from proximally located SSPs, although convincing evidence linking the former to appreciable colorectal cancer risk is entirely lacking. Thus, we propose that, at present, the term "sessile serrated polyp" be restricted to large (> or = 1 cm), proximally located polyps with a presumed biologic risk, until prospective data regarding the natural history of small, distal lesions are available.
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PMID:Serrated polyps with "intermediate features" of sessile serrated polyp and microvesicular hyperplastic polyp: a practical approach to the classification of nondysplastic serrated polyps. 1830 Aug 10

Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and beta-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.
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PMID:PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. 1851 90

The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive (EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not been previously investigated. In the present study, we analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH+ patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. PI3KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role in primary resistance. The potential prognostic implication of IGF1R expression merits further evaluation.
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PMID:Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. 1857 88

More than half of all colorectal carcinomas are known to exhibit an activated mitogen-activated protein kinase pathway. The NF1 gene, a negative regulator of KRAS, has not previously been examined in a series of colorectal cancer. In the present study, primary colorectal carcinomas stratified according to microsatellite instability status were analyzed. The whole coding region of NF1 was analyzed for mutations using denaturing high-performance liquid chromatography and sequencing, and the copy number alterations of NF1 were examined using multiple ligation-dependent probe amplification and real-time polymerase chain reaction. The mutational hot spots in KRAS and BRAF were sequenced, and promoter hypermethylation status of RASSF1A was assessed with a methylation-specific polymerase chain reaction. One sample had two missense mutations in NF1, whereas nine additional tumors had intronic mutations likely to affect exon splicing. Interestingly, 8 of these 10 tumors were microsatellite-unstable. Four other tumors showed a duplication of NF1. Mutations in KRAS and BRAF were mutually exclusive and were present at 40% and 22%, respectively. RASSF1A was hypermethylated in 31% of the samples. We show that the RAS signaling network is extensively dysregulated in colorectal carcinomas, because more than 70% of the tumors had an alteration in one or more of the four examined components.
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PMID:RAS signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1A. 1859 2

Loss of genomic imprinting is an epigenetic alteration of some cancers involving the absence of parental origin-specific expression of imprinted genes. Loss of genomic imprinting of insulin-like growth factor II is often detected in colorectal cancer. However, the genetic alterations accompanied by colorectal cancer with insulin-like growth factor II loss of genomic imprinting have not been fully determined. Genomic DNA samples were collected from 52 colorectal cancer tissues and analyzed. The loss of insulin-like growth factor II genomic imprinting status was determined by assessing the demethylation of the insulin-like growth factor II differentially methylated region using bisulfite sequencing. The molecular signatures were also examined: genetic mutations of KRAS, BRAF, and PIK3CA; the expression of CTNNB1 and TP53; and microsatellite instability status. Several cases of colorectal cancer with normal insulin-like growth factor II imprinting were located in the distal colon; in contrast, colorectal cancer with loss of genomic imprinting tended to be found in the proximal colon (22.7 versus 56.6%). The PIK3CA gene mutation was highly detected in normal imprinting tumors compared to colorectal cancers with insulin-like growth factor II loss of genomic imprinting (27.3% versus 6.7%). In multivariate analysis of these clinicopathologic and molecular factors of tumors, statistically significant relationships were observed among the proximal location of the tumor (odds ratio, 12.9; 95% confidence interval, 1.52-110.13), PIK3CA genetic mutation (odds ratio, 0.082; 95% confidence interval, 0.01-0.73), and insulin-like growth factor II genomic imprinting status. Our findings indicate that colorectal cancers with demethylation of the insulin-like growth factor II gene are distinct from normal imprinting tumors, both in clinical and genetic features.
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PMID:Genetic alterations in colorectal cancers with demethylation of insulin-like growth factor II. 1861 47

Oncogenic KRAS mutations are associated with resistance to anti-EGFR therapy in colorectal carcinoma. Since anti-EGFR monoclonal antibodies are employed in clinical practice in advanced colorectal cancer, KRAS mutations have become an important predictor of therapy outcome. Mutational analysis of KRAS was performed on 163 adenocarcinoma samples. Exons 1-3 of KRAS were analyzed using SSCP and sequencing. Fifty seven (35%) carcinomas had missense point mutations in one of codons 12, 13, 59, 61, 117. In accordance with the published data, missense mutations in codons 12 (66%) and 13 (22%) were the most frequent. Mutations in codons 59 and 117 occurred with the same frequency as in codon 61. The only detected insertion occurred in exon 2. 15-bp insertion resulted in tandem duplication of codons 62-66. Presumably, 5 additional amino acids affected switch II conformation and sustained Ras activity due to decreased GTP hydrolysis. We report this unusual new type mutation.
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PMID:KRAS mutation profile in colorectal carcinoma and novel mutation--internal tandem duplication in KRAS. 1866 74

Microsatellite instability (MSI) is regarded as reflecting defective DNA mismatch repair (MMR). MMR defects lead to an increase in point mutations, as well as repeat instability, on the genome. However, despite the highly unstable microsatellites, base substitutions in representative oncogenes or tumor suppressors are extremely infrequent in MSI-positive tumors. Recently, the heterogeneity in MSI-positive colorectal tumors is pointed out, and the 'hereditary' and 'sporadic settings' are proposed. Particularly in the former, base substitution mutations in KRAS are regarded as relatively frequent. We sequenced the KRAS gene in a panel of 76 human colorectal carcinomas in which the MSI status has been determined. KRAS mutations were detected in 22 tumors (28.9%). Intriguingly, all of the KRAS-mutant MSI-H (high) tumors harbored sequence alterations in an essential MMR gene, MLH1, which implies that KRAS mutation more frequently and almost exclusively occurs in MMR gene-mutant MSI-H tumors. Furthermore, in contrast with the prevailing viewpoint, some of these tumors are derived from sporadic colorectal cancer patients. The tight connection between MMR gene mutation and KRAS mutation may suggest previously unrecognized complexities in the relationship between MSI and the mutator phenotype derived from defective MMR.
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PMID:Exclusive KRAS mutation in microsatellite-unstable human colorectal carcinomas with sequence alterations in the DNA mismatch repair gene, MLH1. 1869 54

Colorectal cancer (CRC) is the second most common cancer in Germany; there are more than 70,000 new cases annually. It is most commonly a disease of the elderly, and its relative and absolute frequency has risen during the last decades. CRC remains a major clinical and health economy challenge. Progress has been made in patient management and CRC treatment. Screening colonoscopy was introduced in Germany in 2002, and five new therapeutic agents have been approved since 2001, i.e. capecitabine, oxaliplatin, cetuximab, bevacizumab and panitumumab; guidelines have been published, and 48 interdisciplinary CRC centres have been certified in Germany in compliance with DIN EN ISO 9001:2000. Despite these advancements, targeted treatment of CRC is still in its infancy. Until 2007, no predictive biomarkers were used to tailor the adjuvant or palliative chemotherapy of CRC. KRAS genotyping was recently introduced as predictive biomarker, since only tumors carrying a wildtype were found to respond to treatment with panitumumab. Among the tumors with KRAS wildtype, only 40-53% (equivalent to 20-30% of all CRC patients) will benefit from treatment, and the remainder are still enrolled for "non-targeted" treatment. Thus there is still a great need for predictive biomarkers that are able to tailor patient treatment at different stages of the disease.
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PMID:[Molecular targets for colon cancer. VEGF, EGFR - and what else?]. 1881 Apr 46

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

MUTYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to colorectal cancer, caused by constitutional biallelic mutations in the base excision repair (BER) gene MUTYH. Colorectal tumours from MAP patients display an excess of somatic G>T mutations in the APC and KRAS genes due to defective BER function. To date, few extracolonic manifestations have been observed in MAP patients, and the clinical spectrum of this condition is not yet fully established. Recently, one patient with a diagnosis of endometrial cancer and biallelic MUTYH mutations has been described. We here report on two additional unrelated MAP patients with biallelic MUTYH germline mutations who developed endometrioid endometrial carcinoma. The endometrial tumours were evaluated for PTEN, PIK3CA, KRAS, BRAF and CTNNB1 mutations. A G>T transversion at codon 12 of the KRAS gene was observed in one tumour. A single 1bp frameshift deletion of PTEN was observed in the same sample. Overall, these findings suggest that endometrial carcinoma is a phenotypic manifestations of MAP and that inefficient repair of oxidative damage can be involved in its pathogenesis.
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PMID:Endometrial cancer and somatic G>T KRAS transversion in patients with constitutional MUTYH biallelic mutations. 1898 Aug


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