Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have recently demonstrated that inherited defects of the base excision repair gene MYH predispose to multiple colorectal adenomas and carcinoma. Three affected siblings from a single British family were identified as Y165C/G382D compound heterozygotes and both missense mutations were shown to be functionally compromised. Here, we report the identification of seven further unrelated patients with >100 colorectal adenomas (six with colorectal cancer) and biallelic germline mutations in MYH: four were homozygous for truncating mutations, two were homozygous for Y165C and one was a Y165C/G382D compound heterozygote. As predicted from studies of the bacterial and yeast orthologues of MYH, colorectal tumours from affected individuals displayed a significant excess of somatic G:C-->T:A mutations in APC, as compared to sporadic ( chi(2)=242.96, P<10(-20)) or FAP-associated ( chi(2)=194.85, P<10(-20)) colorectal tumours. The sequence immediately downstream of the somatic G:C-->T:A mutations was predominantly AA, irrespective of the nature of the germline MYH mutations. These findings confirm the role of MYH in colorectal adenoma and carcinoma predisposition.
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PMID:Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations. 1239 7

Molecular biology studies have led to the identification of two different types of colorectal carcinomas. The first group, called LOH (for loss of heterozygosity), represents 80% of colorectal cancers and is characterised by aneuploidy, allelic losses and a location in the distal colon. The second group displays phenotypic microsatellite instability (MSI-positive tumours), has a near-diploid karyotype and a relatively low frequency of allelic losses. It accounts for 15% of all colorectal cancers and for about 30% of right-sided cancers. Four different pathways have been identified as responsible for tumour progression: the WNT/Wingless, the K-ras, the Transforming growth factor (TGF) and the P53 pathways. The involvement of these pathways depends on the tumour type. In LOH-positive tumours, the WNT/Wingless pathway is activated through an APC mutation, whereas MSI+ tumours do so through a catenin stabilising mutation. The TGFb growth inhibitory pathway is altered either by mutations in the signal transduction molecules SMAD2 and SMAD4 in LOH positive tumours or by mutations of TGFbRII in MSI+ tumours. In the p53 pathway, mutations in BAX may contribute to the adenoma-carcinoma transition just as p53 mutations may do in LOH positive tumours. Until now, cancer phenotype determination has had no clinical implications. However, the predictive value of the MSI status was recently stressed as a predictive factor for response to chemotherapy. Immunohistochemistry could represent a complementary strategy to molecular biology in assessing MSI status. This simple test would allow to screen all colorectal carcinomas for MSI status, which would provide valuable management information in addition to the histological assessment for tumour stage and grade.
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PMID:[Genetic pathways in colorectal cancer: interest for the pathologist]. 1241 Jan 50

'De novo' carcinogenesis has been advocated besides 'adenoma carcinoma sequence' as another dominant pathway leading to the colorectal carcinoma. Our previous study demonstrated that brain (fetal)-type glycogen phosphorylase (BGP) positive foci in the transitional mucosa (BGP foci) have frequent p53 mutations and that the distribution of BGP foci has a close relationship with the location of 'de novo' carcinoma. The aims of the present study were to investigate further genetic alterations in the BGP foci and to clarify the mechanism of 'de novo' carcinogenesis. Twenty-eight colorectal carcinomas with invasion into submucosa or superficial muscularis propria without any adenoma component expressing immunoreactive p53 protein were selected from 168 resected specimens. Investigations of the p53, K-ras and APC mutations was performed in the BGP foci, BGP negative colorectal mucosa and 'de novo' carcinoma using PCR-SSCP and DNA squencing. In all 28 cases, immunoreactive BGP was positive in the carcinomas and the BGP foci were observed sporadically in the mucosa adjacent to the carcinoma. No K-ras mutation was observed in either carcinoma or BGP foci in any of the cases. Mutations of p53 and APC were 14 (50.0%) and 9 (32.1%) in 'de novo' carcinomas, and 11 (39.3%) and 1 (3.6%) in BGP foci, respectively. Both p53 and APC mutations were detected in 8 and 1, p53 mutation alone in 6 and 10, APC mutation alone in 1 and 0 out of 28 carcinomas and BGP positive foci, respectively. These results suggest that the BGP foci may play a very important role in the 'de novo' colorectal carcinogenesis from the frequent genetic alterations of p53, and that there may be two major pathways, i.e., the p53-APC pathway and the p53 alone pathway, from the chain of genetic alterations between BGP foci and 'de novo' carcinoma.
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PMID:Genetic pathways of 'de novo' colorectal carcinomas with reference to fetal-type glycogen phosphorylase positive foci. 1246 86

The genomic alterations in preneoplastic lesions are summarized in this review. 3p and 9p in the lung, 9p in the bladder, 8p in the prostata, 19q and 1p in oligodendroglioma, and 22q in meningioma were reported to be deleted. Somatic mutation of p53 was found in preneoplastic lesions of the esophagus, stomach, colon, thyroid, and astrocytoma. Adenoma-carcinoma sequence (Apc, ras, p53 gene alterations) in colon, LKB1 gene in Peutz-Jeghers syndrome, Smad4 in juvenile polyposis, hMSH2, hMLH1, PMS1, PMS2 genes in HNPCC, VHL gene in kidney, WT1 in Wilms tumor, RB gene in retinoblastoma, and ret gene in MEN were reportedly altered in preneoplastic lesions involved in hereditary tumors. Cervical dysplasia and papilloma of the head and neck infected by human papilloma virus and liver infected by B-type hepatitis virus are also precancerous. Genomic instability, APC gene alteration, point mutation of K-ras in preneoplastic lesions of stomach and K-ras and p16 alterations in metaplasia of pancreas were also found. Advances in research on genomic alterations in preneoplastic lesions will contribute to prevention and early detection of cancer.
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PMID:[Genomic alterations in preneoplastic lesions]. 1250 66

It is frequently stated that all but a few colorectal cancers arise in adenomatous polyps, in turn initiated by APC mutation. Moderation of this view is now required. The proportion of colorectal cancers that arises in a polypoid adenoma is likely to be around 70% [39,61]. The pre-eminence of the adenoma-carcinoma model has been influenced by two factors: (1) the need to avoid overtreatment of innocent lesions, and (2) the absence of a convincing alternative mechanism. The latter position has changed in recent years. Collectively, the alternative pathways may account for the pathogenesis of up to 30% of colorectal cancers. The alternative pathways are difficult to observe in clinical practice because the precursors may be either inconspicuous or show rapid evolution following the establishment of genetic instability. As a concept, the polyp-cancer sequence is entrenched in both specialized and student texts. This is unfortunate, because progress in prevention and early cancer detection will be delayed by the failure to adopt a critical and nondogmatic approach to the pathogenesis of colorectal cancer. The advent of DNA chip technology will catalyze the development of revised paradigms. Specifically, modern genomics will allow polyps and cancers to be grouped within pathogenic pathways on the basis of shared gene expression profiles. The era of molecular medicine has dawned for colorectal cancer.
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PMID:Pathogenesis of colorectal cancer. 1250 99

Adenomatous polyps of the jejunum/ileum in patients with familial adenomatous polyposis (FAP) are usually small (<5 mm) and are considered to be of little clinical importance. Genetic alterations in these polyps have not previously been analyzed. We herein report an extremely rare case of FAP presenting with intussusception caused by jejunal adenomas. Both somatic and germline mutations of the APC gene were detected in one of the polyps. A 40-year-old man with FAP was admitted for closure of an ileostomy that had been created because of an anastomotic leak after subtotal proctocolectomy with ileo-anal-canal anastomosis. During the follow-up after that surgery, he had occasionally complained of colicky abdominal pain, but it had quickly subsided. At the second laparotomy, for closure of the ileostomy, jejuno-jejunal intussusception was incidentally found, and segmental resection of the jejunum, including the leading point of the intussusception, was performed. There were five polyps clustered in the resected jejunum. Histologically, the polyps, ranging from 5 to 26 mm in diameter, were adenomas with moderate to severe atypia. Genetic examinations of one of the largest polyps, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and direct sequencing methods, revealed somatic (T insertion at codon 1557) and germline mutations (4 base-pair deletion at codons 181-182) of the APC gene. This is the first evidence that the coexistence of somatic and germline alterations in the APC gene is involved in the development of a jejunal adenoma causing small-bowel intussusception.
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PMID:APC gene mutations in a jejunal adenoma causing intussusception in a patient with familial adenomatous polyposis. 1252 39

Loss of APC is an initial, rate-limiting event in inherited and sporadic colorectal tumorigenesis. Rare germline APC mutations have been identified in patients with multiple colorectal adenomas. Recently, the E1317Q APC variant has been associated with a predisposition to the development of multiple colorectal adenomas. In this study, the prevalence of the E1317Q variant was examined in 182 patients with single or multiple colorectal adenomas, and in 235 controls. In all, E1317Q was identified in two of 182 patients with adenomatous polyps (1.1%) and in two of 235 controls (0.8%) (p = 0.59). The risk of harboring adenoma(s) among subjects bearing the E1317Q variant was 1.29 (95% CI 0.09-18.0). No difference in the prevalence of E1317Q between cases with single (2.0%) or multiple colorectal adenomas (0.7%) and controls (0.8%) was found. None of the subjects with a family history of colorectal cancer carried the E1317Q variant. In conclusion, our results confirm that only a very small fraction of colorectal adenomas may be associated with the presence of E1317Q.
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PMID:Prevalence of the E1317Q variant of the APC gene in Italian patients with colorectal adenomas. 1253 56

Thrombospondin 1 (TSP-1) is a multifunctional extracellular matrix protein that is an endogenous regulator of tumor angiogenesis. The effects of TSP-1 on adenoma formation and development into cancerous lesions has been evaluated in the Min(/+) (multiple intestinal neoplasia) mouse model. These mice develop multiple adenomas in the small intestine due to a mutation in the homologous APC (adenomatous polyposis coli) gene. As in its human counterpart, these adenomas may progress to carcinomas. Intestines of APC(Min/+) mice were dissected and histologic evaluation of adenomas was then conducted. Significant increases in vascularization and proliferation were observed in adenomatous, as compared with normal, mucosa. TSP-1 immunostaining revealed significant decreases in the number and intensity of positive cells in adenomas, as compared with normal mucosa. TSP-1 scores were inversely correlated with vascularity and proliferation rate. Cross breeding of mice homozygous for a deletion of the TSP-1 gene (TSP-1(-/-)) with mice heterozygous for the APC gene mutation (APC(Min/+)), resulted in animals that showed a significant increase in adenoma number and diameter. Also, histopathological examination of these adenomas showed accelerated dysplasic changes, carcinoma in situ and early invasion, compared with their APC(Min/+) littermates. Moreover, a significant decrease of TUNEL-positive cells was observed in intestinal adenomas of TSP-1(-/-)/APC(Min/+) mice. This study reports the first in vivo impact of TSP-1 during early stages of tumor initiation and development in an intestinal carcinogenesis model and demonstrates that TSP-1 affects both angiogenesis and tumor cell apoptosis.
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PMID:Thrombospondin 1--a regulator of adenoma growth and carcinoma progression in the APC(Min/+) mouse model. 1258 68

The stomach is one of the organs whose epithelial cells frequently undergo aberrant methylation of CpG islands. To date, several reports on the methylation of various genes in gastric cancer (GC) have been published. However, most of these studies have focused on cancer tissues or a single gene only and gave no information about the methylation status of specific genes in the premalignant stages or the concurrent methylation of other genes in specific lesions. We attempted to investigate methylation of multiple genes in a large sample collection of GC (n = 80), gastric adenoma (GA) (n = 79), intestinal metaplasia (IM) (n = 57), and chronic gastritis (CG) (n = 74). We determined the methylation frequency of 12 genes, including APC, COX-2, DAP-kinase, E-cadherin, GSTP1, hMLH1, MGMT, p16, p14, RASSF1A, THBS1, and TIMP3, by methylation-specific PCR. Five different classes of methylation behaviors were found: (a). genes methylated in GC only (GSTP1 and RASSF1A), (b). genes showing low methylation frequency (<12%) in CG, IM, and gastric adenoma (GA) but significantly higher methylation frequency in GC (COX-2, hMLH1, p16), (c). a gene with low and similar methylation frequency (8.8-21.3%) in four-step lesions (MGMT), (d). genes with high and similar methylation frequency (53-85%) in four-step lesions (APC and E-cadherin), and (e). genes showing an increasing tendency with or without fluctuation of the methylation frequency along the progression (DAP-kinase, p14, THBS1, and TIMP-3). The average number of methylated genes was 2.7, 3.6, 3.4, and 5.2 per 12 tested genes in CG, IM, GA, and GC, respectively. Aberrant methylation at multiple loci in the same lesions suggests an overall deregulation of the methylation control, which occurs early in multistep gastric carcinogenesis. Our results suggest that tumor-suppressor genes show a gene-type specific methylation profile along the multistep carcinogenesis and that aberrant CpG island methylation tend to accumulate along the multistep carcinogenesis.
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PMID:Profile of aberrant CpG island methylation along multistep gastric carcinogenesis. 1269 55

The Authors describe three cases of Familial Adenomatous Polyposis, (FAP), in patients of the same family, mother and two daughters, with different stages of the disease. Familial adenomatous polyposis is a mendelian dominant inherited syndrome with an incidence of 1:11,000, caused by an alteration of APC gene, which causes multiple disorders of the development ecto-, endo- and mesoderma. The syndrome is characterized by the presence of adenomatous polyps in the gastroenteric tract, mostly in colon-rectum and duodenum with demonstrated adenoma-carcinoma sequence. In the family here reported a case of familial adenomatous polyposis at the adenomatous stage and two of cancer of colon-rectum are registered. In the first case surgery had a preventive aim, and ileo-rectal anastomosis was performed; in the other two cases the treatment was Miles operation with radical intention.
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PMID:[Familial adenomatous polyposis: review of the literature and report of 3 cases]. 1272 97


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