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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The multistep genetic model of colorectal carcinogenesis is based on the concept of the adenoma-carcinoma sequence. The adenoma-carcinoma sequence theory has been generally accepted for polypoid early colorectal cancers (ECCs). On the other hand, an increasing number of nonpolypoid (superficial) ECC have been reported. Nonpolypoid (superficial) ECCs show distinct characteristics histologically and genetically, and some claim these lesions may develop by de novo type carcinogenesis. In fact, clinicopathologic studies have shown that most nonpolypoid (superficial) cancers have no adenomatous lesions in the surrounding area. Genetic analyses have also revealed that nonpolypoid (superficial) ECCs show a pattern of genetic alterations different from that of polypoid ECCs. The K-ras mutation rate is lower in nonpolypoid (superficial) ECCs than in polypoid ECCs, but there is no significant difference in the p53 mutation rate between two types of tumor. During the development of ECCs, the K-ras gene seems to determine the macroscopic configuration: whether polypoid or nonpolypoid (superficial). These results suggest that nonpolypoid (superficial) ECCs originate from a pathway different from the conventional genetic pathway that follows the adenoma-carcinoma sequence. However, this does not mean that this new pathway is following de novo type carcinogenesis, because there is a possibility that nonpolypoid (superficial) adenomas, or so-called flat adenomas, develop into nonpolypoid (superficial) ECCs following the adenoma-carcinoma sequence. At the present time, there is still not enough evidence to conclude whether nonpolypoid (superficial) ECC is derived from de novo carcinogenesis or the conventional adenoma-carcinoma sequence. Further analysis, especially concerning APC gene mutation in ECCs, is essential to elucidate the carcinogenesis of nonpolypoid (superficial) ECCs.
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PMID:Colorectal carcinogenesis based on molecular biology of early colorectal cancer, with special reference to nonpolypoid (superficial) lesions. 1103 87

Serum hypergastrinemia promotes the growth of colorectal adenocarcinoma. Some colorectal adenomas express cholecystokinin B/gastrin receptor mRNA, and thus hypergastrinemia may increase progression through the adenoma-carcinoma sequence. This was investigated in the multiple intestinal neoplasia APC(Min-/+) mouse. Serum gastrin levels in APC(Min-/+) mice were elevated 5-6-fold by oral administration of omeprazole (75 mg/kg). Terminal tumor burden was monitored by onset of anemia. A labeling index was generated by immunohistochemical detection of bromodeoxyuridine incorporation. Serum gastrin was neutralized by antigastrin antibodies raised in situ by use of a gastrin immunogen, Gastrimmune. Hypergastrinemia resulted in reduced survival of the APC(Min-/+) mice from a median survival of 13 weeks in the controls to 10 weeks following omeprazole treatment (P < 0.00001, log-rank test). The labeling indices of adenomas from the small and large intestines of omeprazole-treated mice were increased 35 and 29%, respectively (P < 0.05 and P < 0.025, respectively). Gastrimmune immunization reversed both the survival effect and the increased proliferation resulting from serum hypergastrinemia. Hypergastrinemia may promote the progression of existing premalignant colonic lesions by increasing proliferation. Clinical investigations should determine whether this occurs in the human scenario, considering the widespread use of proton pump inhibitors.
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PMID:Hypergastrinemia promotes adenoma progression in the APC(Min-/+) mouse model of familial adenomatous polyposis. 1121 60

To clarify the carcinogenic factors--whether it is the kind of carcinogen or their length of exposure--that determine whether colorectal cancer develops from an adenoma or develops de novo in the absence of an adenoma, we histopathologically analyzed a total of 229 rat colon tumors induced by administration of 1,2-dimethyl-hydrazine (DMH) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for three or 15 weeks. In the three-week-exposure groups, 71% of DMH-induced carcinomas and 82% of MNNG-induced carcinomas coexisted with low-grade dysplasia (adenomatous remnant). However, in the 15-week-exposure groups, lowgrade dysplasia was observed in only 10% of DMH-induced and 27% of MNNG-induced carcinomas. Even in the tumors smaller than 20 mm3, it was observed in only 10% of DMH-induced and 32% of MNNG-induced carcinomas. Furthermore, carcinomas without low-grade dysplasia predominated from the initial period of tumor occurrence. Next, we investigated association of K-ras and APC gene mutations with these carcinogenesis patterns in 80 tumors. K-ras mutations were not detected in any tumors induced by three weeks of exposure. However, in the 15-week-exposure groups, this mutation was observed in 57% of DMH-induced tumors and 13% of MNNG-induced tumors. APC mutations in the region homologous to the human mutation cluster region were observed in only 6% of tumors. Thus, our results suggest that the carcinogenesis patterns in rat colon are dependent on the length of exposure to carcinogen and that K-ras mutations were partly involved in a subset of them.
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PMID:Differences in carcinogenesis by the length of carcinogen exposure period in rat colon. 1127 Jul 74

In 1990, Longacre and Fenoglio-Preiser introduced "serrated adenoma (SA)" combining architectural and cytological features of hyperplastic polyp and adenomatous epithelium. It has been reported that intramucosal carcinoma occurs in 10% of SAs. Although there have been many reports on SAs, its histogenesis and natural history still remain unknown. To clarify the genetic changes in SA, APC mutations in 28 SAs, 4 adenocarcinomas in/with SAs, 12 tubular adenomas (TAs) and 10 adenocarcinomas in/with TAs were evaluated in the present study. After polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) analyses, gene mutations were confirmed by direct sequencing. No APC mutation was detected in adenocarcinomas in/with SAs, and only one SA without adenocarcinoma (3.8%) was found to be positive for APC gene mutation, whereas the mutations were found in 66.7% of TAs and in 50% of adenocarcinomas in/with TAs. The frequency of APC gene mutation in SAs was significantly lower than that in control sporadic TAs. These findings suggest that SAs are genetically different from TAs.
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PMID:Infrequent APC mutations in serrated adenoma. 1131 65

Although the APC protein is known to participate in cellular proliferation and apoptosis, APC mutations have been thought to play a major role in the early stage of colorectal tumorigenesis. The somatic APC mutation of exon 15 was assessed to determine its impact on various stages of colorectal tumorigenesis. The colorectal neoplastic tissues of serial array studied included sporadic adenomas (group 1, n = 36), adenomas (group 2, n = 33), and carcinomas (group 3, n = 32) in the synchronous adenoma and carcinoma as well as sporadic carcinomas (group 4, n = 36). Aberrant DNA was detected by protein truncation test and confirmed by direct sequencing. The mutation prevalence was 36.1% in group 1, 45.5% in group 2, 59.4% in group 3, and 41.7% in group 4 with no differences among the groups. Among the 18 patients with synchronous adenoma and carcinoma, 9 had mutation in their adenomas and 12 in their carcinomas. The mutation loci and patterns did not differ in adenomas and carcinomas. Mutations in the mutation cluster region (MCR) were much more frequent than in the preceding region of MCR, i.e., 85.7% vs. 14.3%. The mutation prevalence of villous adenomas appeared greater than that of tubular adenoma (3/21 vs. 3/4). Predominant pathogenic mutations at MCR suggest that the APC mutation is implicated in all stages of colorectal tumorigenesis.
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PMID:Mutations at the APC exon 15 in the colorectal neoplastic tissues of serial array. 1135 15

We report a 63-year-old lady with Cronkhite-Canada syndrome, who developed colorectal cancer. A hemicolectomy was performed, and the tumor specimen was prepared for DNA-analysis and immunohistochemical screening. We found a mutation of p53 gene without APC- and ras-gene alteration and expression of erbB2-protooncogen. The polyps in non-hereditary Cronkhite-Canada-syndrom are neither adenomatous nor hyperplastic, but patients often develop colorectal cancers. The steps of mutation do not follow the adenoma-carcinoma sequence, first described by Vogelstein 1988. This and previous observations suggest that carcinogenesis in Cronkhite-Canada syndrome follows another independent sequence.
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PMID:[Colorectal carcinoma in Cronkhite-Canada syndrome]. 1141 16

Pseudomyxoma peritonei (PMP) is a clinical syndrome characterized by mucinous ascites and peritoneal lesions composed of histologically bland to low-grade adenomatous mucinous epithelium within pools of extracellular mucin, often with an associated mucinous adenoma of the appendix. There is evidence that the peritoneal lesions in PMP are clonally derived from the associated appendiceal adenoma. Little is known about the molecular genetic alterations or hereditary factors involved in the development of appendiceal mucinous tumors and PMP. We report the only known example of appendiceal mucinous adenomas in identical twin brothers, one of whom developed PMP. We analyzed the status of the K-RAS and APC genes in these tumors using digital polymerase chain reaction and digital single nucleotide polymorphism (SNP) assay. Identical K-RAS mutations were detected in the appendiceal adenoma and peritoneal tumor from the twin with PMP, whereas the adenoma from the other twin harbored a different mutation. Digital SNP analysis demonstrated loss of heterozygosity of APC only in the adenoma from the twin without PMP but not from the appendiceal or peritoneal tumors of the twin with PMP. The adjacent normal tissue in each case retained both APC alleles. The K-RAS mutational analysis supports the view that PMP is clonally derived from the associated appendiceal mucinous adenoma. The lack of loss of heterozygosity of APC in the adenoma and peritoneal tumor from the twin with PMP suggests that loss of heterozygosity of APC is not necessarily involved in the development of all appendiceal adenomas or PMP. The different types of mutations in K-RAS and the different allelic status of the APC locus in the tumors from both twins suggest that mutation in K-RAS and loss of heterozygosity of APC occurs somatically in adenomas and is independent of the identical genetic background of the twins.
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PMID:Molecular genetic analysis of appendiceal mucinous adenomas in identical twins, including one with pseudomyxoma peritonei. 1147 97

Several substances interfering with colorectal carcinogenesis may reduce or prevent adenoma formation in familial adenomatous polyposis (FAP), an inherited predisposition to colorectal cancer. This study determined the expression of genes coding for putative anticancer targets (COX-2, iNOS, MMP-7, ODC, PKCbeta, PPARgamma, RXRalpha, RXRbeta, RXRgamma) in FAP patients to provide one of the rationales for the design of chemotherapy and -prevention strategies. Gene expression was assessed by TaqMan analysis in colonic tissue of 9 FAP patients with mutations in the APC gene (APCpos), 5 FAP patients without identified genetic defect (APCneg), and 3 healthy individuals. Among the examined genes, PKCbeta and MMP-7 were most consistently altered in adenoma tissue relative to matched mucosa. Intriguingly, ODC was clearly overexpressed in polyps from APCpos but not APCneg patients. Furthermore, PKCbeta, MMP-7, ODC, and COX-2 as well as all RXRs displayed altered expression in apparently healthy FAP mucosa as opposed to that of healthy individuals. Our data suggests PKCbeta and MMP-7 to be the most suited as anticancer targets among the genes studied.
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PMID:Expression of putative anticancer targets in familial adenomatous polyposis and its association with the APC mutation status. 1171 87

Familial adenomatous polyposis (FAP) is a dominantly inherited colorectal tumor predisposition that results from germ-line mutations in the APC gene (chromosome 5q21). FAP shows substantial phenotypic variability: classical polyposis patients develop more than 100 colorectal adenomas, whereas those with attenuated polyposis (AAPC) have fewer than 100 adenomas. A further group of individuals, so-called "multiple" adenoma patients, have a phenotype like AAPC, with 3-99 polyps throughout the colorectum, but mostly have no demonstrable germ-line APC mutation. Routine mutation detection techniques fail to detect a pathogenic APC germ-line mutation in approximately 30% of patients with classical polyposis and 90% of those with AAPC/multiple adenomas. We have developed a real-time quantitative multiplex PCR assay to detect APC exon 14 deletions. When this technique was applied to a set of 60 classical polyposis and 143 AAPC/multiple adenoma patients with no apparent APC germ-line mutation, deletions were found exclusively in individuals with classical polyposis (7 of 60, 12%). Fine-mapping of the region suggested that the majority (6 of 7) of these deletions encompassed the entire APC locus, confirming that haploinsufficiency can result in a classical polyposis phenotype. Screening for germ-line deletions in APC mutation-negative individuals with classical polyposis seems warranted.
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PMID:Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas. 1186 15

Colorectal cancer (CRC) is the second most common fatal malignancy in the Western world, with more than 150,000 new cases accounting for 55,000 deaths in the United States every year. Surgical resection is an effective treatment for localized disease, achieving a 5-year survival rate of 90%; but chemotherapy and other novel treatments for metastatic disease remain ineffective. There have been significant efforts to identify risk factors associated with the development of CRC and to explore potential preventive therapies. Both genetic and epigenetic factors contribute to the development of colorectal cancer. Specific genetic changes in proto-oncogenes, tumor suppressor genes, and DNA mismatch repair genes have led to a genetic model of CRC. Cooperative genetic aberrations involving APC (adenomatous polyposis coli), beta-catenine, K-ras, and p53 are involved in the multistep adenoma-carcinoma sequence of CRC. Emerging data have implicated cyclooxygenase-2 (COX-2) and prostanoid production in the pathogenesis of colorectal carcinoma. Several reports indicate a close relation between the intake of nonsteroidal antiinflammatory drugs (NSAIDs) and a decreased risk for developing colorectal cancer. Epidemiologic studies indicate a 40% to 50% reduction in mortality due to colorectal cancer in individuals taking NSAIDs (e.g., aspirin). Epigenetic factors including age, diet, angiogenesis, and immune responses also appear to contribute to the development of CRC. Combining knowledge of the genetic and epigenetic events implicated in this disease may allow a broader understanding of the pathogenesis of CRC. These developments may yield benefits in earlier detection and in the design of better antitumor interventions.
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PMID:New strategies for colorectal cancer prevention and treatment. 1194 69


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