Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary nonpolyposis colorectal cancer (HNPCC) is a multi-organ cancer syndrome associated with heritable mutations in DNA mismatch repair genes, particularly MLH1 (MutL Homologue 1) and MSH2 (MutS Homologue 2). We took advantage of the unique characteristics of the Finnish HNPCC families to assess genotype- phenotype correlations in this disorder. We studied 295 mutation carriers (10 mutations in MLH1 and 3 in MSH2) segregating in 55 families. In addition to the comparison of families with different mutations, the enrichment of two MLH1 mutations, one affecting exon 16 (29 families, 186 individuals) and another one affecting exon 6 (10 families, 45 individuals) allowed the comparison of kindreds with identical predisposing mutations. Extracolonic cancers were more common in MSH2 than MLH1 mutation carriers, with the ratios of 0.48 and 0.64, respectively, of colorectal cancer to all cancers (P = 0.076). Within MLH1, two mutations affecting only the amino terminal portion showed a significant association with late onset of cancer as compared to the remaining mutations. Importantly, families with the MLH1 exon 16 mutation displayed significant variation (P = 0.012) in the age at onset of colon cancer, despite shared predisposition. We conclude that even though characteristics of the inherited mutations may explain part of the observed clinical variation, other factors have a significant impact on HNPCC phenotype determination.
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PMID:Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different vs. shared predisposing mutations. 1457 10

We sought to determine whether rare cancers indicate an increased risk of inherited cancer susceptibility. We ascertained 77 individuals with rare cancers which occur with increased relative risk in carriers of germline BRCA1/BRCA2 (fallopian, young-onset pancreatic) or HNPCC (biliary, small intestinal, urothelial, gallbladder, young-onset pancreatic) mutations. Individuals with two primary neoplasms (7), or with a first- or two second-degree relatives with breast/ovarian cancer were tested for BRCA1/BRCA2 mutations (18); those with two primary HNPCC cancers or one first degree relative with an HNPCC-related cancer were tested for mutations in MLH1/MSH2 (19). Of these 77 individuals with cancer (19 fallopian, 8 gallbladder, 17 biliary, 17 pancreatic, 11 urothelial, 5 small intestinal), 39 (50.6%) had at least one first degree relative with cancer (excluding lung and skin); two conformed to Bethesda HNPCC criteria. No definitely pathogenic germline MLH1 and MSH2 mutations were found in 19 individuals, although 2 MSH2 variants were detected. A family history of breast/ovarian, HNPCC or colon cancer in a first degree relative was found in 40% of fallopian, 20% of biliary, 35% of pancreatic, 27% of urothelial and 20% of small bowel cancer patients. A BRCA1 frameshift mutation was detected in a woman with fallopian (54 y) and breast (39 y) cancers, and a BRCA2 nonsense mutation in a woman with biliary (48 y) and breast (45 y) cancers. This study supports the premise that the occurrence of rare (especially double primary) cancers does indicate an increased cancer susceptibility, although the numbers of cases ascertained were too small to draw firm conclusions.
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PMID:Does the occurrence of certain rare cancers indicate an inherited cancer susceptibility? 1457 63

Colorectal cancer affected approximately 135,000 people in the United States in 2001, resulting in 57,000 deaths. At the cellular level, colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelial cells to colon adenocarcinoma cells. The loss of genomic stability appears to be a key molecular and pathogenetic step that occurs early in the tumorigenesis process and serves to create a permissive environment for the occurrence of alterations in tumor suppressor genes and oncogenes. At least three forms of genomic instability have been identified in colon cancer: (1) microsatellite instability (MSI), (2) chromosome instability (i.e. aneusomy, gains and losses of chromosomal regions) (CIN), and (3) chromosomal translocations. Microsatellite instability occurs in approximately 15% of colon cancers and results from inactivation of the mutation mismatch repair (MMR) system by either MMR gene mutations or hypermethylation of the MLH1 promoter. MSI promotes tumorigenesis through generating mutations in target genes that possess coding microsatellite repeats, such as TGFBR2 and BAX. CIN is found in the majority of colon cancers and leads to a different pattern of gene alterations that contribute to tumor formation. CIN appears to result primarily from deregulation of the DNA replication checkpoints and mitotic-spindle checkpoints. The mechanisms that induce and influence genomic instability in cancer in general and more specifically in colon cancer are only partly understood and are consequently under intense investigation. These studies have revealed mutation of the mitotic checkpoint regulators BUB1 and BUBR1 and amplification of STK15 in a subset of CIN colon cancers. The etiology of CIN in the other unexplained cases of colon cancer remains to be determined. Hopefully, discovery of the cause and specific role of genomic instability in colon cancer will yield more effective chemotherapy strategies that take advantage of this unique characteristic of cancer cells.
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PMID:Genomic instability and colon cancer. 1500 Jan 46

It is important to evaluate the effects of proposed interventions to reduce the risk of disease among carriers of a highly penetrant mutation, such as the mutations in BRCA1 and BRCA2 for breast and ovarian cancers or in APC and MLH1 or MSH2 for colon cancer. However, some studies that evaluate the effects of interventions designed to reduce risk in mutation carriers may be susceptible to a serious selection bias when they are based in clinics that care for persons at high risk for the disease. A study design in which a large fraction of the case patients were diagnosed before being seen at the clinic and all control subjects are persons previously seen at the clinic can create a false impression of intervention efficacy if, as is likely, mutation carriers seen at the clinic were more likely to receive the intervention than mutation carriers in the general population.
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PMID:Bias in intervention studies that enroll patients from high-risk clinics. 1531 55

A prospective study of psychosocial consequences following predictive testing for inherited mutations in breast/ovarian and colon cancer susceptibility genes BRCA1, BRCA2, MLH1, and MSH2 was performed. Eighty-seven healthy women were tested for known family mutations and self-assessment scales were used to evaluate anxiety, depression and quality of life. Extensive pre- and post-test information was given. Questionnaires were responded before testing and four times after during the following year. A statistically significant decrease in anxiety mean scores over time was observed among the studied participants. The levels of depression in cancer genes carriers decreased over time while, surprisingly the levels in non-carriers increased. Compared to a normative Swedish sample all women tested showed similar levels of anxiety but women tested for breast cancer genes showed statistically lower levels of depression. Vitality dropped initially after disclosure of the testing of colon cancer genes carriers, followed by increasing levels. No change in vitality or in other quality of life parameters was seen in the other groups and the levels were similar to Swedish norm data. Most tested individuals were satisfied with the testing procedure including genetic counselling and testing and all of them but one would redo the testing. Healthy self-referred women going through predictive breast/ovarian or colon cancer gene testing, including extensive pre- and post-test information and support, in general, will not experience adverse psychological consequences.
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PMID:Evaluation of psychosocial effects of pre-symptomatic testing for breast/ovarian and colon cancer pre-disposing genes: a 12-month follow-up. 1534 Feb 61

Hereditary non-polyposis colorectal cancer (HNPCC), the most common hereditary colon cancer syndrome, is a dominant disorder caused by germline defects in mismatch repair (MMR) genes. Identification of MMR gene mutations can have direct clinical implications in counseling and management of HNPCC families. We screened 44 HNPCC and 97 suspected HNPCC Korean families for germline mutations in three MMR genes: MLH1, MSH2 and MSH6. We identified twelve novel mutations: nine in MLH1(c.632_633insT, c.808_811delACTT, c.845C>G, c.1625A>C, c.1730+1delG, c.1907T>C, c.1918C>T, c.2104-2A>G and c.2170T>A), two in MSH2 (c.1886A>G, c.1316_1318delCCT) and one in MSH6 (c.3488A>T). In addition, two statically significant cSNPs in MLH1: c.1128T>C ( p=0.008 in HNPCC and p=0.037 in early-onset CRC) and c.2168C>A ( p<0.001 in HNPCC). Interestingly, the most frequent mutation, c.1757_1758insC in MLH1, was a founder mutation inherited from a common Korean ancestor.
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PMID:Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. 1536 95

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary colon cancer syndrome and is responsible for as many as 10% of all colorectal cancers. Hereditary nonpolyposis colorectal cancer is autosomally dominant with a prevalence of 1 in 200-2000 and exhibits incomplete penetrance. Affected individuals have an approximately 70% lifetime risk of colon cancer with a mean age of onset of 44 years and an approximately 40% lifetime risk of endometrial cancer. At least 5 mismatch repair genes (MLH1, MSH2, MSH6, PMS1, PMS2) have been implicated in HNPCC; however, no predominant mutations were found in these genes. Mutation detection by direct sequencing has proven to be the most sensitive method. We have developed high-throughput full-length sequencing assays of the MLH1, MSH2, and MSH6 genes. These 3 genes account for approximately 90% of all germline mutations found in HNPCC. In our assays, 19 exons of MLH1, 16 exons of MSH2, 10 exons of MSH6, and the adjacent splice sites were amplified using polymerase chain reaction and loaded onto a capillary sequencing machine. Results were analyzed using sequence analysis software and stored in a relational database. Our assay method was validated using 15 affected patients and normal controls. It is anticipated that our high-throughput assay technique will provide accurate diagnoses for patients at risk for HNPCC and thereby facilitate early curative intervention.
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PMID:High-throughput gene sequencing assay development for hereditary nonpolyposis colon cancer. 1555 11

Most hereditary nonpolyposis colorectal cancer (HNPCC) cases are caused by germline mutations of mismatch repair (MMR) genes (i.e., MLH1, MSH2, or MSH6). Here we describe six novel mutations in patients referred for genetic assessment. All of these mutations lead to premature translation termination. Five single base pair deletions lead to frameshift (MLH1: g.38-39insCCCA, g.1971del.T; MSH2: g.163del.C, g.746del.A; MSH6: g.3320del.A) and one nonsense mutation in MSH2 g.1030C>T leads to a stop codon: p.Q344X. In one patient, the previously described MLH1 nonsense mutation g.806C>G was found in a homozygous state. In this patient, the familial histories of both the mother and father suggested HNPCC syndrome. This patient developed colon cancer at 22 years of age, suggesting a more aggressive phenotype. The results of our study provide further insight into the mutational spectrum of MMR genes in HNPCC families.
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PMID:Six novel heterozygous MLH1, MSH2, and MSH6 and one homozygous MLH1 germline mutations in hereditary nonpolyposis colorectal cancer. 1557 1

An important anticarcinogenic function of the mismatch repair (MMR) system is its role in preventing recombination between similar, but nonidentical (homeologous) sequences, thus preventing chromosomal rearrangements. We recently identified a novel chromosomal instability (CIN) phenotype in an MMR defective colon cancer cell line (HCA7) characterized by an ongoing tendency to multiple reciprocal chromosomal translocations. To analyse the relation between MMR and chromosomal changes more closely, the HCA7 stem clone was divided into three stocks. The first was stably transfected with MLH1 expression plasmid, the second was regularly exposed to the demethylating agent 5-azacytidin to re-express the hypermethylated MLH1 gene, and the third was an unmanipulated control stock. All stocks were propagated in vitro for 55-80 passages and, furthermore, some of the early passages were irradiated to induce DNA double-strand breaks. Multiplex-fluorescent in situ hybridization (M-FISH) analysis showed that all three stocks acquired varying numbers of reciprocal translocations and other structural changes at some point. Interestingly, the control stock, which is MMR defective, maintained its numerical chromosomal stability, while some of the MMR-proficient clones showed additional numerical instability. Although the control stock was less sensitive to irradiation, its surviving clones showed marked stability of chromosome structure and number compared to the MMR-competent stocks. These results show that restoring MMR does not prevent the development of reciprocal translocations but rather predisposes cells to numerical CIN after irradiation. Thus, the accumulating data suggest that MMR defect may not be necessary for the development of reciprocal chromosomal translocations but might be permissive.
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PMID:Restoring mismatch repair does not stop the formation of reciprocal translocations in the colon cancer cell line HCA7 but further destabilizes chromosome number. 1558 Mar 8

Previous studies from our laboratory indicated that expression of the MLH1 DNA mismatch repair (MMR) gene was necessary to restore cytotoxicity and an efficient G(2) arrest in HCT116 human colon cancer cells, as well as Mlh1(-/-) murine embryonic fibroblasts, after treatment with 5-fluoro-2'-deoxyuridine (FdUrd). Here, we show that an identical phenomenon occurred when expression of MSH2, the other major MMR gene, was restored in HEC59 human endometrial carcinoma cells or was present in adenovirus E1A-immortalized Msh2(+/+) (compared with isogenic Msh2(-/-)) murine embryonic stem cells. Because MMR status had little effect on cellular responses (i.e. G(2) arrest and lethality) to the thymidylate synthase inhibitor, Tomudex, and a greater level of [(3)H]FdUrd incorporation into DNA was found in MMR-deficient cells, we concluded that the differential FdUrd cytotoxicity between MMR-competent and MMR-deficient cells was mediated at the level of DNA incorporation. Analyses of ATPase activation suggested that the hMSH2-hMSH6 heterodimer only recognized FdUrd moieties (as the base 5-fluorouracil (FU) in DNA) when mispaired with guanine, but not paired with adenine. Furthermore, analyses of incorporated FdUrd using methyl-CpG-binding domain 4 glycosylase indicated that there was more misincorporated FU:Gua in the DNA of MMR-deficient HCT116 cells. Our data provide the first demonstration that MMR specifically detects FU:Gua (in the first round of DNA replication), signaling a sustained G(2) arrest and lethality.
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PMID:DNA mismatch repair-dependent response to fluoropyrimidine-generated damage. 1561 Oct 52


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