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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Research in hereditary forms of colorectal cancer (CRC) has increased almost logarithmically thanks in a major way to momentous discoveries in molecular genetics during the past decade. Between 10 and 20% of the total CRC burden is due to Mendelian-inherited CRC syndromes. The paradigm for hereditary CRC is familial adenomatous polyposis (FAP), wherein the APC germ-line mutation has been identified. This has contributed to the elucidation of genomic and clinical heterogeneity within the syndrome, wherein an attenuated form of FAP has been identified as a result of intragenic mutations within this large APC gene. The most common form of hereditary CRC is hereditary nonpolyposis colorectal cancer (HNPCC). Several mutator genes, namely hMSH2, hMLH1, hPMS1, hPMS2 and, more recently, hMSH6/GTBP, have been identified. These molecular genetic discoveries are providing new insights into the pathogenesis of CRC. Individuals within these kindreds who are harbingers of these germ-line mutations will benefit from screening and, one day, chemoprevention.
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PMID:Genetics of colonic cancer. 970 33

Germ-line mutations in DNA mismatch-repair genes impart a markedly elevated cancer risk, often presenting as autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC). However, there are no pathognomonic features of HNPCC, not all gene carriers have a family history of the disease, and families fulfilling the Amsterdam criteria are relatively uncommon. Genetic testing of probands with early-onset colorectal cancer, irrespective of family history, is one approach that would allow predictive genetic testing of at-risk relatives. We cloned and sequenced hMSH2 and hMLH1 introns, to optimize genomic sequencing. We then systematically analyzed the entire hMSH2 and hMLH1 genes, by genomic sequencing and in vitro synthesized-protein-truncation assay (IVSP), in 50 colorectal cancer patients <30 years of age at diagnosis. To determine polymorphic variants, 26 anonymous donors also were sequenced. All subjects analyzed had at least 1 of 37 different polymorphic or pathogenic variants. IVSP complemented genomic sequencing, by detection of mutations not identified by genomic analysis. Fourteen cancer patients (28%) had pathogenic mutations, and a number of other variants also may have had a pathogenic significance that remains to be elucidated. Tumor replication-error status was useful in targeting sequencing efforts for this cohort of young patients: sensitivity was 86%, specificity 73%, and positive and negative predictive values 63% and 90%, respectively. These data indicate that an appreciable proportion of young colon cancer probands carry a germ-line mutation in a DNA mismatch-repair gene.
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PMID:Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. 971 27

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known cancer preventives, which have been largely attributed to their antiproliferative and apoptosis-inducing activities. In this study, we show that microsatellite instability (MSI) in colorectal cancer cells deficient for a subset of the human mismatch repair (MMR) genes (hMLH1, hMSH2, and hMSH6), is markedly reduced during exposure to aspirin or sulindac [or Clinoril, which is chemically related to indomethacin (Indocin)]. This effect was reversible, time and concentration dependent, and appeared independent of proliferation rate and cyclooxygenase function. In contrast, the MSI phenotype of a hPMS2-deficient endometrial cancer cell line was unaffected by aspirin/sulindac. We show that the MSI reduction in the susceptible MMR-deficient cells was confined to nonapoptotic cells, whereas apoptotic cells remained unstable and were eliminated from the growing population. These results suggest that aspirin/sulindac induces a genetic selection for microsatellite stability in a subset of MMR-deficient cells and may provide an effective prophylactic therapy for hereditary nonpolyposis colorectal cancer kindreds where alteration of the hMSH2 and hMLH1 genes are associated with the majority of cancer susceptibility cases.
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PMID:Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. 973 31

During the last few years, the molecular basis of several cancer predisposition syndromes has been discovered which offers new tools for cancer prevention and early detection. This will be demonstrated in one of the most frequent hereditary cancer syndromes, namely the hereditary nonpolyposis colorectal cancer (HNPCC) which accounts for about 5% to 8% of CRC. Thereby, families with exclusively CRC (Lynch type I syndrome) and those with extracolonic cancers especially of endometrium, stomach, small bowel and upper urinary tract (Lynch type II syndrome) can be discriminated. At the molecular level, HNPCC is caused by germline mutations in one of the mismatch repair genes (hMSH2, hMLH1, hMSH6, hPMS2). Thus, nucleotide mispairings occurring particularly within simple repetitive genomic sequences (microsatellites) during replication are no longer be repaired properly and can be demonstrated by PCR as so-called microsatellite instability (MSI). Since more than 90% of HNPCC associated and only about 15% of sporadic CRC show MSI, this test is a useful tool for HNPCC screening. In case of a negative result HNPCC is highly unlikely. In positive cases (with > or = 2 out of 5 unstable defined microsatellite markers) the definite molecular diagnosis can only be obtained by sequencing the mismatch repair genes from the patient's blood or normal DNA. As immunohistochemistry reveals loss of hMSH2 or hMLH1 expression in most MSI positive CRC, these data provide useful information for the sequencing strategy. Molecular tumor screening by MSI test and immunohistochemistry is recommended in patients i.) with a positive family history (acc. to the Amsterdam criteria), ii.) suffering from multiple HNPCC related carcinomas, iii.) with HNPCC related cancer before 45 ys of age, and iv.) with right-sided CRC exhibiting medullary, signet-ring or mucinous differentiation. Finally, these tests as well as genetic counseling and treatment of the patient need to be done by an interdisciplinary approach. Thereby, the pathologist can substantially contribute to identify HNPCC related carcinomas either by clinical or morphological criteria and to initiate the molecular screening test.
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PMID:[Molecular cancer disposition diagnosis exemplified by colorectal carcinoma. What is the contribution of pathology?]. 974 11

Germline mutations of the hMLH1 gene are estimated to account for a large fraction of kindreds affected by hereditary non-polyposis colorectal cancer (HNPCC). In a significant number of cases, hMLH1 mutations result in the expression of truncated proteins. We report here two novel alternatively spliced forms of hMLH1 mRNA in normal lymphocytes. One of these novel isoforms lacks the coding region of the gene between codons 557 and 578, corresponding to the entire exon 15. The deletion introduces a frameshift that results in a premature stop signal. The other isoform is characterised by an in-frame deletion spanning codons 578-632, corresponding to loss of the entire exon 16. Further studies are necessary to establish the biological significance of these alternative splicings. The presence of alternatively spliced hMLH1 transcripts that mimic pathogenic mutations should be taken into account in the mutational screening of the hMLH1 gene by reverse transcription-polymerase chain reaction methodologies.
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PMID:Transcripts with splicings of exons 15 and 16 of the hMLH1 gene in normal lymphocytes: implications in RNA-based mutation screening of hereditary non-polyposis colorectal cancer. 979 9

Patients affected by squamous cell carcinoma of the head and neck (HNSCC) show frequent occurrence of multiple cancers and widespread precancerous lesions in the mucosa of the upper respiratory tract, a phenomenon known as field cancerization. In this study, we investigated the role of genetic instability in the development of HNSCC and in particular in tumour multiplicity phenomena of the upper respiratory tract. For this purpose, we analysed microsatellite instability (MI) and loss of heterozygosity (LOH) at 20 loci mapping on five chromosomal arms in 67 HNSCC patients, 45 of whom had a single cancer and 22 had multiple primary tumours. The possible involvement of the hMLH1 gene in genetic instability and as a potential target of 3p21 deletion phenomena in head and neck cancers was also investigated. Our data indicate that mismatch repair-related genetic instability plays a minor role in the carcinogenesis of HNSCC and in tumour multiplicity of the head and neck region. Moreover, our results exclude a role for the hMLH1 gene as a determinant of MI and as a specific gene target of deletion at 3p21 in HNSCC. We conclude that presumably other genetic mechanisms, such as those hypothesized for MI-negative hereditary non-polyposis colorectal cancer patients, may play a major role in the carcinogenesis of the mucosa of the upper respiratory tract.
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PMID:Microsatellite instability in squamous cell carcinomas of the head and neck related to field cancerization phenomena. 982 Jan 70

A 53-yr-old man, a member of a hereditary nonpolyposis colorectal cancer (HNPCC) family, with previous colonoscopic polypectomies, presented for persisting vomiting and marked signs of dehydration. Previous radiological and endoscopic examinations of the upper digestive tract were negative, with the exception of the presence of a duodenal adenomatous polyp. Enteroclysis led to a diagnosis of obstruction at the Treitz angle due to a moderately differentiated adenocarcinoma. Microsatellite instability was demonstrated in the DNA extracted from the tumor. The patient was the carrier of a mutation in the intron 13 of the hMLH1 gene, one of the four mismatch repair genes known to be responsible for HNPCC.
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PMID:Small bowel carcinoma in hereditary nonpolyposis colorectal cancer. 982 Apr

At least four genes involved in DNA mismatch repair (MMR), hMSH2, hMLH1, hPMS1 and hPMS2, have been cloned and characterized. These genes have been demonstrated to be altered in the germline of patients with hereditary non-polyposis colorectal cancer (HNPCC). HNPCC is an autosomal dominant disease characterized by a preponderance of proximal colon, young age of onset, increased multiplicity, and improved stage-specific survival. In this study, we examined the expression of hMSH2 protein in sporadic colorectal cancer (CRC). As a result, the frequency of right-sided CRC and multiple CRCs were significantly higher in the patients with hMSH2-negative CRC than in those with hMSH2-positive CRC. The rate of p53 positivity was significantly lower in the hMSH2-negative tumours than that in the hMSH2-positive tumours. The disease-free survival rate tended to be higher in the patients with hMSH2-negative CRC than in the patients with hMSH2-positive CRC. Our findings suggest that both the clinicopathological and biological features of hMSH2-negative sporadic CRC seemed to be similar to those of HNPCC. To clarify the mechanism of carcinogenesis in HNPCC and sporadic CRC, further investigations of genetic alterations caused by MMR genes will be needed.
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PMID:Expression of the mismatch repair gene hMSH2 in sporadic colorectal cancer. 982 23

We describe a French Canadian hereditary non-polyposis colorectal cancer (HNPCC) kindred which carries a novel truncating mutation in hMLH1. Interestingly, the I1307K APC polymorphism, associated with an increased risk of colorectal cancer, is also present in this family. The I1307K polymorphism has previously only been identified in individuals of self-reported Ashkenazi Jewish origins. In addition, in this family, there appears to be no relationship between the I1307K polymorphism and the presence or absence of cancer.
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PMID:I1307K APC and hMLH1 mutations in a non-Jewish family with hereditary non-polyposis colorectal cancer. 983 55

Normal and tumor DNA samples of 35 patients with sporadic colorectal carcinoma were analyzed for microsatellite alterations at 12 markers linked to mismatch repair loci: hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2. Remarkably, no correlation was observed between the replication error phenotype (RER+) and allelic losses at these loci. Hemizygous deletions, seen in 6/35 (17%) informative cases at hMLH1, 4/27 (15%) at hMSH2/hMSH6 and 6/34 (18%) at hMSH3, were rarely found in RER+ tumors. Since mismatch repair protein components act in molecular complexes of defined stoichiometry we propose that hemizygous deletion of the corresponding loci may be involved in colorectal tumorigenesis through defects in cellular functions other than replication error correction. The analysis of the methylation status of the promoter region of hMLH1 revealed that methylation might be an important mechanism of this locus inactivation in RER+ sporadic colorectal cancer.
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PMID:Allelic losses and DNA methylation at DNA mismatch repair loci in sporadic colorectal cancer. 985 4


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