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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HNPCC is an autosomal dominantly inherited disorder with proclivity to early onset colorectal cancer in the absence of multiple polyps of the colon. There is a predilection for proximal colonic location (70 per cent) and an excess of synchronous and metachronous colorectal cancers. HNPCC is subdivided into Lynch syndrome I, which is restricted to site-specific colon cancer susceptibility, and Lynch syndrome II, which shows all of the features of Lynch syndrome I, but in addition, patients are at inordinately increased risk for carcinoma of the endometrium, ovary, and other anatomic sites. The frequency of HNPCC is conservatively estimated to be 4 to 6 per cent of the total colorectal cancer burden. Because of the fact that the family history is underreported almost uniformly in medical practice, we believe that the true frequency of this disease may be much greater. Heterogeneity may be extant with respect to tumor association, in that in certain Lynch syndrome II kindreds, carcinoma of the pancreas, kidney, breast, and other anatomic sites may predominate. Knowledge of the natural history of HNPCC predicates surveillance and management strategies. Thus, because of the early onset of and proximal predilection for colorectal cancer, we recommend initiation of colonscopy at age 25 and annually thereafter. We also recommend guaiac testing of the stool at least twice a year. In the case of Lynch syndrome II, in addition to colonscopy, we recommend intensive surveillance for the endometrium, including aspiration biopsies. Other targeted organs, depending on the tumor spectrum in the family, should be given priority attention. Because of an excess of synchronous and metachronous colorectal cancer in HNPCC, subtotal colectomy with ileorectal anastomosis is the treatment of choice for initial colorectal cancer. In women presenting with initial colorectal cancer who have completed their families, consideration should be given to prophylactic hysterectomy and bilateral salpingo-oophorectomy at the time of surgery for colorectal cancer. Needed are biomarkers of acceptable sensitivity and specificity for the genotype, because HNPCC lacks premonitory physical signs. We believe that increased knowledge about colorectal cancer etiology and carcinogenesis can be attained through the study of families prone to the Lynch syndromes.
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PMID:Hereditary nonpolyposis colorectal cancer--Lynch syndromes I and II. 306 37

During prolonged culture (7-40 passages assayed) DNA distribution was constant in IVT-negative lines with FPC genotype and in IVT-negative lines without any known colon cancer genotype, whereas the DNA histograms of the IVT-positive lines with HNPCC genotype showed a marked change. The DNA index (DI) of greater than 1 increased sixfold in the HNPCC-A (affected) line and threefold in the HNPCC-AR (at-risk) line due to an equal increase in DI of 2 and DI of greater than 2. It is proposed that there is a possible association between the HNPCC genotype, the presence of IVT, and the marked increase in both DI of 2 and DI of greater than 2 in DNA histograms, since neither the lines with normal nor those with FPC genotypes showed these changes. The biological significance of IVT might be due to its influence on the constancy of the distribution of cellular DNA content, leading to aneuploidy, which has been known to precede in vitro tumorigenic phenotypes.
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PMID:Demonstration of altered cellular DNA content distribution in long-term colon epithelial cell lines with colon cancer genotypes. 322

This is the first report of chromosome 18 allele loss in colorectal carcinomas from FAP patients and concurrent allele losses on chromosomes 5 and 18 in sporadic colorectal cancer. This is based on our investigation of twenty-two colorectal carcinomas from sporadic cases and FAP patients which revealed tumor-specific allele loss of at least 44% at the D18S6 locus on chromosome 18 in informative cases. These results coupled with the tentative assignment of an HNPCC gene to chromosome 18 suggests that a gene on chromosome 18 may be involved in the etiology of some colon cancers. Possible mechanisms involving genetic changes on chromosome 18 in colon cancer are discussed in relation to tumor- or growth-suppressor genes.
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PMID:Chromosome 18 allele loss at the D18S6 locus in human colorectal carcinomas. 341 2

Primary genetic factors are etiologic in at least 5-10% of patients with colon cancer. The polyposis syndromes (FPC) are easily identified examples because of the spectacular number of polyps. The hereditary nonpolyposis syndromes (HNPCC), although five times more common than FPC, are usually not recognized because they do not have such a distinctive clinical, premonitory genetic marker. Colorectal cancer expression was surveyed in 10 extended, thoroughly documented HNPCC kindreds. One hundred sixteen patients were found to have 183 colorectal cancers. Despite the striking family history, less than 5% were correctly treated by subtotal colectomy. This provided a unique opportunity to study the natural history. Five findings differed significantly (p less than 0.05) from patients with sporadic colon cancer: (1) mean age of initial colon cancer diagnosed was 45.6 years; (2) 69.1% of first colon cancers were located proximal to the splenic flexure of the colon; (3) 18.1% had synchronous colon cancer; (4) 24.2% had metachronous colon cancer develop with life table analysis showing the risk for a metachronous lesion at 10 years to be 40%; and (5) only 23.3% of cancers were located in the sigmoid colon or rectum. Based on this data, it is recommended that the family history of all patients with a newly diagnosed colon cancer be evaluated for evidence of this syndrome. If an autosomal dominant inheritance pattern emerges, an in-depth genetic investigation is indicated. When HNPCC is confirmed, the following recommendations apply: a subtotal abdominal colectomy is indicated at the time of the initial colon cancer because of the risk of synchronous and metachronous lesions. The rectum should be spared in favor of careful lifetime surveillance because of the proclivity for proximal colon cancer involvement. As yet unaffected members of a newly diagnosed HNPCC kindred who are in the "direct genetic line" should be cautioned that they are at 50% risk and must begin an intensive surveillance program beginning in the third decade with careful attention to the right colon. Patients from newly diagnosed HNPCC families who have had a previous conventional colectomy for colon cancer should, at the very least, enter an intensive surveillance program; a prophylactic completion subtotal colectomy should be considered for patients who are less than totally compliant.
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PMID:Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and II). 363 93

Research on the genetic, molecular genetic, clinical features, and natural history of HNPCC has shown tremendous progress and evolution during the past 25 years. Specifically, HNPCC's autosomal dominant mode of genetic transmission has now been documented through linkage studies of the gene at 2p (MSH2) and at 3p (MLH1) with the cloning of these genes. Also, the tumor spectrum has increased, which now, in addition to carcinoma of the colon, endometrium, stomach, and ovary, includes transitional cell carcinoma of the ureter and renal pelvis, and adenocarcinomas of the small bowel and pancreas. Surveillance and management protocols for patients at high risk should include full colonoscopy since 70% of the colon cancers occur in the proximal colon. Because of the marked excess of synchronous and metachronous colorectal cancers (CRC), no less than a subtotal colectomy should be performed at the time of initial CRC. Women, in addition to colonoscopy, require endometrial aspiration biopsy. Should they develop CRC and if their procreation is completed, we recommend that they consider prophylactic hysterectomy and bilateral salpingo oophorectomy at the time of their subtotal colectomy. Now that the deleterious genes at 2p and 3p have been identified, we are offering candidates, in whom the MSH2 or MLH1 mutation has been verified, an option of prophylactic subtotal colectomy as opposed to annual life time colonoscopy. With the development of the International Hereditary Nonpolyposis Colorectal Cancer Collaborative Group, knowledge can be disseminated worldwide about the public health importance of HNPCC and the need to implement highly targeted surveillance and management strategies in all clinical practice settings.
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PMID:25 years of HNPCC. 797 96

The international collaborative group on HNPCC (ICG-HNPCC) was established in 1989. The original aims of the group were: (1) to develop minimal criteria for the identification of HNPCC, to provide a basis for uniformity in collaborative studies; (2) to improve patient and physician education about HNPCC; (3) to establish international collaborative studies, and (4) to promote the establishment of national (or regional) HNPCC registries. The administrative base of the group is attached to the Netherlands Foundation for the Detection of Hereditary Tumours at Leiden. The Netherlands. An International Informational Center on HNPCC was established at Creighton University in Omaha. The Hereditary Colon Cancer Newsletter (previously the Polyposis Newsletter) serves as a medium for communication about activities of the Group. At present, the Group has about 70 members from 23 countries, and its meetings are held annually. After a period of five years, it can be concluded that the objectives of the ICG-HNPCC have been successfully accomplished. The existence of the ICG-HNPCC has contributed to an increase in awareness of HNPCC among specialists throughout the world. Due to the rapid developments in molecular genetics in HNPCC, it seems very likely that HNPCC will be the first common hereditary cancer syndrome, which can be identified by simple blood DNA tests. The value of the ICG-HNPCC will be extremely important in finding a uniform answer to the question how to utilize DNA technology for the benefit of the human race.
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PMID:The International Collaborative Group on HNPCC. 797 4

The genetic understanding of colon cancer susceptibility is advancing very rapidly; it has already had a major impact on clinical management, and we have only seen the beginning. Genes responsible for the two well-defined familial colon cancer syndromes (APC and HNPCC) have been identified. These syndromes can now often be diagnosed by genetic rather than by endoscopic screening of the at-risk individuals in a family. Linkage analysis, although clinically cumbersome, can be performed for families with both APC and HNPCC. In some families, the mutation itself can be determined and a specific mutation assay can be used in the other at-risk members of the family. Both linkage analysis and mutational assays are still largely performed in specialized high-risk cancer clinics. For APC, a truncated protein assay performed on cells isolated from peripheral blood is now commercially available, so the genetic diagnosis of APC can be made by any clinician. It is important, however, to be able to provide appropriate genetic counseling to families before and after genetic testing for these familial colon cancer syndromes. The familial clustering of "sporadic" colon cancer has been suggested to be due to the inheritance of a susceptibility gene or genes. A family history of colon cancer has become an important stratification criteria for colon cancer screening programs. Colonoscopic screening is indicated for individuals with two or more FDRs with colon cancer or with one FDR in whom colon cancer developed under the age of 50 or so. If specific susceptibility genes for sporadic colon cancer are identified, it will be possible to target powerful primary preventive and screening programs to this high-risk population (susceptibility gene carriers).
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PMID:The genetic basis of colorectal cancer risk. 890 98

Familial risk of colon cancer is common. The rare syndromes of FAP and HNPCC account for a small fraction of familial cases. A working knowledge of these syndromes is important, however, because appropriate management can prevent most cases of colon cancer in families with these conditions. Furthermore, the genes that give rise to FAP and HNPCC have been identified, and genetic testing to find gene carriers in affected families is now commercially available. In addition to the syndromes, colon cancer commonly clusters in families. The risk of colon cancer is two to threefold increased when a first-degree relative is affected with this malignancy. The risk is further increased if multiple first-degree relatives have colon cancer or if a diagnosis in a relative is made at an age of 50 years or younger. The genetic causes of this more commonly observed of familial clustering have not been clarified, but screening based on the degree of familial risk has been suggested.
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PMID:Familial risk and colorectal cancer. 896 Aug 93

Since 1993 four genes have been identified that, when mutated, confer predisposition to a form of hereditary colon cancer (hereditary nonpolyposis colorectal cancer [HNPCC]). These genes belong to the Mut-related family of DNA mismatch repair genes whose protein products are responsible for the recognition and correction of errors that arise during DNA replication. Mutational inactivation of both copies of a DNA mismatch repair gene results in a profound repair defect demonstrable by biochemical assays, and in vivo this defect is presumed to lead to progressive accumulation of secondary mutations throughout the genome, some of which affect important growth-regulatory genes and, hence, give rise to cancer. To date, more than 70 different germline mutations have been detected in DNA mismatch repair genes and shown to be associated with HNPCC. Current evidence suggests that two genes, MSH2 and MLH1, account for roughly equal proportions of HNPCC kindreds, together being responsible for a majority of these families, but striking interethnic differences occur. Most mutations lead to truncated protein products. Mutation screening is quite demanding in HNPCC since, with a few exceptions, the predisposing mutations typically vary from kindred to kindred and individual mutations are scattered throughout the genes. Knowledge of the predisposing mutations allows genotype-phenotype correlations and forms the basis for further studies clarifying the pathogenesis of this disorder. In at-risk individuals, it allows predictive testing for cancer susceptibility and, consequently, appropriate clinical management of mutation carriers and noncarriers.
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PMID:Mutations predisposing to hereditary nonpolyposis colorectal cancer. 911 64

Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme DNA instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.
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PMID:Drastic genetic instability of tumors and normal tissues in Turcot syndrome. 941 79


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