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)

Hereditary non-polyposis colon cancer (HNPCC) is a common hereditary disease characterized by a predisposition to an early onset of colorectal cancer. The majority of the HNPCC families carry germline mutations of either hMSH2 or hMLH1 genes, whereas germline mutations of hPMS1 and hPMS2 genes have rarely been observed. Almost all of the germline mutations reported so far concern typical HNPCC families. However, there are families that display aggregations of colon cancer even though they do not fulfil all HNPCC criteria (incomplete HNPCC families) as well as sporadic cases of early onset colon cancers that could be related to germline mutations of these genes. Therefore, we screened germline mutations of hMSH2 and hMLH1 genes in 3 groups of patients from France and Turkey: typical HNPCC (n = 3), incomplete HNPCC (n = 9) and young patients without apparent familial history (n = 7). By in vitro synthesis of protein assay, heteroduplex analysis and direct genomic sequencing, we identified 1 family with hMSH2 mutation and 5 families with hMLH1 mutations. Two of the 3 HNPCC families (66%) displayed hMLH1 germline mutations. Interestingly, 4 of 9 families with incomplete HNPCC (44%) also displayed mutations of hMSH2 or hMLH1 genes. In contrast, no germline mutation of these genes was found in 7 young patients. Our results show that germline mutations of hMSH2 and hMLH1 genes contribute to a significant fraction of familial predisposition to colon cancer cases that do not fulfil all diagnostic criteria of HNPCC.
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PMID:Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families. 939 61

We estimate that 5-10% of virtually all forms of cancer are due to a primary hereditary etiology. However, a hereditary cancer diagnosis is often missed because the family history of cancer is given short shrift in medical practice. Hereditary nonpolyposis colorectal cancer (HNPCC) certainly fits this estimate, although some studies suggest that a minimum of 2% with a range as high as 10% of the total colorectal cancer burden is due to HNPCC. Mutations in one of the four mismatch repair genes, i.e., hMSH2, hMLH1, hPMS1, and hPMS2, account for about 70% of HNPCC kindreds. Other germ-line mutations are likely to be identified to account for the remainder of HNPCC patients. By far the most common HNPCC mutations involve hMSH2 and hMLH1, with hPMS1 and hPMS2 accounting for only about 3% of such families. Prior to these molecular genetic discoveries, the genetic counselor could only provide the patient with an estimate of a 50% likelihood of manifesting HNPCC based on the counselee having one or more first-degree relatives manifesting syndrome cancers in their direct genetic lineage. Because DNA testing has become available in families with known mutations, we have provided pretest group education in the form of a family information service with intensive education about the natural history, genetic risk, surveillance, and options for management of HNPCC, as well as discussion of the potential for fear, anxiety, apprehension, and insurance or employer discrimination that might impact on this DNA testing. Following informed consent, these relatives were then counseled on a one-to-one basis. Using DNA-based genetic counseling involving hMSH2 or hMLH1, we have provided this service to four extended HNPCC kindreds. Details of this genetic counseling experience on these four kindreds will be discussed.
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PMID:Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic counseling implications. 941 92

We analyzed microsatellite instability, alterations of the polyadenine tract in TGF-beta RII (transforming growth factor beta type II receptor gene), and mutations of hMSH2 and hMLH1 in 32 patients with familial colorectal cancer (29 kindreds) fulfilling the clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), defined at the 34th Annual Meeting of Japanese Society for Cancer of the Colon and Rectum (Tokushima, Japan, 1991), including five kindreds fulfilling the Amsterdam criteria. Eighteen of 32 (56%) cases were replication error positive (RER+) at two or more microsatellite loci analyzed. The clinicopathological characteristics of RER+ cases corresponded well with those reported previously. Eleven of 18 RER+ cases showed RER+ at most of the microsatellite loci examined. Among these 11 cases (10 kindreds), 3 kindreds fulfilled the Amsterdam criteria and 7 kindreds did not. For these 10 kindreds, germ-line mutations in hMSH2 and hMLH1 were detected for 6 kindreds by PCR-SSCP analysis and direct sequencing. Only two of these six fulfilled the Amsterdam criteria; more than one germ-line mutation was detected in hMSH2 and/or hMLH1. Specifically, two point mutations of hMSH2 were detected in two kindreds, one point mutation of both hMSH2 and hMLH1 was detected in one kindred, two point mutations of hMSH2 and one point mutation of hMLH1 were detected in one kindred, and two point mutations of hMLH1 and one point mutation of hMSH2 were detected in one kindred. In addition, 19 of 26 (74%) cancer lesions of these 11 cases with the RER phenotype showed alterations of the polyadenine tract in TGF-beta RII. From our data, although seven kindreds did not fulfill the Amsterdam criteria, we considered them as HNPCC. Therefore, we suggest that the "Japanese criteria" have the advantage of being able to detect more HNPCC kindreds from borderline HNPCC kindreds.
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PMID:Identification of concurrent germ-line mutations in hMSH2 and/or hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds. 941 3

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. This cancer develops as a result of the pathologic transformation of normal colonic epithelium to an adenomatous polyp and ultimately an invasive cancer. The multistep progression requires years and possibly decades and is accompanied by a number of recently characterized genetic alterations. Mutations in two classes of genes, tumor-suppressor genes and proto-oncogenes, are thought to impart a proliferative advantage to cells and contribute to development of the malignant phenotype. Inactivating mutations of both copies (alleles) of the adenomatous polyposis coli (APC) gene--a tumor-suppressor gene on chromosome 5q--mark one of the earliest events in colorectal carcinogenesis. Germline mutation of the APC gene and subsequent somatic mutation of the second APC allele cause the inherited familial adenomatous polyposis syndrome. This syndrome is characterized by the presence of hundreds to thousands of colonic adenomatous polyps. If these polyps are left untreated, colorectal cancer develops. Mutation leading to dysregulation of the K-ras protooncogene is also thought to be an early event in colon cancer formation. Conversely, loss of heterozygosity on the long arm of chromosome 18 (18q) occurs later in the sequence of development from adenoma to carcinoma, and this mutation may predict poor prognosis. Loss of the 18q region is thought to contribute to inactivation of the DCC tumor-suppressor gene. More recent evidence suggests that other tumor-suppressor genes--DPC4 and MADR2 of the transforming growth factor beta (TGF-beta) pathway--also may be inactivated by allelic loss on chromosome 18q. In addition, mutation of the tumor-suppressor gene p53 on chromosome 17p appears to be a late phenomenon in colorectal carcinogenesis. This mutation may allow the growing tumor with multiple genetic alterations to evade cell cycle arrest and apoptosis. Neoplastic progression is probably accompanied by additional, undiscovered genetic events, which are indicated by allelic loss on chromosomes 1q, 4p, 6p, 8p, 9q, and 22q in 25% to 50% of colorectal cancers. Recently, a third class of genes, DNA repair genes, has been implicated in tumorigenesis of colorectal cancer. Study findings suggest that DNA mismatch repair deficiency, due to germline mutation of the hMSH2, hMLH1, hPMS1, or hPMS2 genes, contributes to development of hereditary nonpolyposis colorectal cancer. The majority of tumors in patients with this disease and 10% to 15% of sporadic colon cancers display microsatellite instability, also know as the replication error positive (RER+) phenotype. This molecular marker of DNA mismatch repair deficiency may predict improved patient survival. Mismatch repair deficiency is thought to lead to mutation and inactivation of the genes for type II TGF-beta receptor and insulin-like growth-factor II receptor. Individuals from families at high risk for colorectal cancer (hereditary nonpolyposis colorectal cancer or familial adenomatous polyposis) should be offered genetic counseling, predictive molecular testing, and when indicated, endoscopic surveillance at appropriate intervals. Recent studies have examined colorectal carcinogenesis in the light of other genetic processes. Telomerase activity is present in almost all cancers, including colorectal cancer, but rarely in benign lesions such as adenomatous polyps or normal tissues. Furthermore, genetic alterations that allow transformed colorectal epithelial cells to escape cell cycle arrest or apoptosis also have been recognized. In addition, hypomethylation or hypermethylation of DNA sequences may alter gene expression without nucleic acid mutation.
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PMID:Molecular biology of colorectal cancer. 943 4

Hereditary nonpolyposis colorectal cancer (HNPCC), also termed Lynch syndrome, was originally called cancer family syndrome. Historically, in 1913 Aldred Warthin, a pathologist, published a family, now known as Family G, which had features of HNPCC. It was first delineated as a hereditary cancer syndrome in the mid-1960s by Lynch. There was an apparent autosomal dominant mode of inheritance of colorectal cancer and certain integral cancers, the most prominent of which was endometrial carcinoma. Prior to the discovery in 1993 and 1994 of genes (hMSH2, hMLH1, hPMS1, hPMS2) known as mis-match repair genes or mutator genes, the diagnosis of HNPCC rested exclusively upon evaluation of clinical findings in concert with a well-documented and extended pedigree. Thus, this disorder has evolved from a medical curiosity into a clinical syndrome wherein molecular biologists provided proof of its hereditary status. These discoveries should aid in elucidating its pathogenesis and carcinogenesis and in the next decade we likely will learn more about chemoprevention and surgical prophylaxis of HNPCC.
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PMID:Molecular genetics and clinical-pathology features of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome): historical journey from pedigree anecdote to molecular genetic confirmation. 949 83

Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome involving a predisposition to cancers of the colon, endometrium and several other extra-colonic sites, accounting for approximately 1-5% of all colorectal cancer cases. It is not easily recognized because of a lack of distinctive clinical markers, making diagnosis and management of this disease problematic. To provide a basis for uniformity in diagnosis of HNPCC, the Amsterdam criteria were proposed and are currently in use. More recently, the discovery of four human mismatch repair genes (hMSH2, hMLH1, hPMS1 and hPMS2) has provided novel insight into the genetic basis of this disease, and raised the possibility of genetic diagnosis for management of HNPCC patients and their family members. This report summarizes the clinicopathologic aspects of HNPCC, reviews the recent genetic findings and surveillance strategies, and suggests a novel designation of certain patients as suspected HNPCC.
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PMID:Genetic identification and management of hereditary nonpolyposis colorectal cancer. 949 60

In a search for germline mutations in the DNA mismatch repair genes hMSH2 and hMLH1 in Chinese patients with colorectal cancer we identified a novel missense mutation (V384D) in exon 12 of the hMLH1 gene in 4 out of 26 individuals. This mutation had not been observed in any of 109 German patients who either fulfill the clinical criteria of hereditary nonpolyposis colorectal cancer or had developed colorectal cancer at an early age. In a second series of experiments, DNA samples of 80 healthy. Japanese and 100 healthy Germans were examined for the presence of the V384D mutation. It was observed in 4 Japanese, but in none of the German individuals. Thus, the V384D mutation seems to be confined to the East-Asian population. Since this missense mutation occurs at a less conserved region of the hMLH1 gene, it may represent a nonfunctional polymorphism. However, a role in the pathogenesis of colorectal cancer cannot be ruled out from the present study.
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PMID:A novel missense mutation in the DNA mismatch repair gene hMLH1 present among East Asians but not among Europeans. 952 67

Approximately 10% of all epithelial ovarian carcinoma cases are associated with inheritance of an autosomal-dominant genetic mutation conferring a predisposition to cancer with variable penetrance. Two such manifestations of hereditary ovarian cancer are currently recognized: the breast and ovarian cancer syndrome and the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. The breast and ovarian cancer syndrome is linked to the BRCA1 gene on chromosome 17q and, to a lesser extent, to the BRCA2 gene on chromosome 13q. The HNPCC syndrome is caused by any one of three known genes, hMSH2, hMLH1, and hPMS2, that encode proteins involved in the same pathway of DNA mismatch repair. Genetic screening for germ-line transmission of a defective allele of these genes is now possible for high-risk individuals. Despite the rapid pace of research advances in this area, however, considerable uncertainties remain regarding factors that affect the penetrance and tissue-specific expressivity of these mutations. Current research challenges include elucidating these modifying factors, gaining a better understanding of the biological function of BRCA1 and BRCA2 products, and determining the appropriate clinical intervention for genetically predisposed patients.
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PMID:Molecular genetics of hereditary ovarian cancer. 953 90

The two most common forms of hereditary ovarian cancer are: the breast ovarian cancer syndrome, and ovarian cancer associated with HNPCC (hereditary nonpolyposis colorectal cancer) syndrome. Studies have shown that these diseases may be associated with mutations in a number of tumor suppressor genes, mainly BRCA1 and BRCA2. Malfunction of the protein products of these genes have also been found to be involved in sporadic ovarian cancer, which makes up the majority of ovarian cancer cases. HNPCC-ovarian cancer associated families reveal frequent mutations in at least four genes (hMSH2, hMLH1, hPMS1, and hPMS2) involved in the repair of mismatched DNA. With ovarian cancer being such an important health issue, the push is on to design reliable screening tests to detect defective inherited or somatic alleles in individual carriers. So far, most progress has been demonstrated in those patients with family histories of the disease who are at increased risk. The ramifications of such research may impact a variety of scientific, clinical, legal, ethical, and psychosocial issues. In addition to current treatment modalities, positive results of these tests may indicate the need for increased clinical surveillance, prophylactic treatment, and genetic counseling of patients on an individual basis. It remains to be seen whether the technology can be made reliable enough to not only benefit high-risk individuals but also the general population.
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PMID:Hereditary and sporadic ovarian cancer: genetic testing and clinical implications (review). 953 24

Microsatellite instability (MIN) due to defective mismatch repair (MMR) genes has been reported in a subset of sporadic colorectal carcinomas and in the majority of tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Among the known MMR genes, hMSH2 and hMLH1 genes are known to be predominantly altered in HNPCC patients and MIN-positive tumors. In this study, we examined MIN and the protein expression pattern of the hMSH2 and hMLH1 by Western blot and immunohistochemistry from 32 sporadic colorectal carcinomas. MIN was observed in 6 (18%) colorectal carcinomas. Of the 6 MIN-positive tumors, one case showed no expression of either protein, 3 cases showed an absence of hMSH2 protein expression, one case showed an absence of hMLH1 protein expression and one case showed no altered expression of either protein by immunohistochemistry. The decreased expression of the hMSH2 protein in a tumor compared to the normal mucosa was also observed in 5 of the 6 MIN-positive cases by Western blot analysis. All of the MIN-negative tumors showed expression of both proteins by immunohistochemistry. Thus most of the MIN-positive tumors appear to be directly related to the altered expression of these two genes and can be diagnosed by the examination of protein expression.
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PMID:Expression of hMSH2 and hMLH1 in colorectal carcinomas with microsatellite instability. 954 42


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