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W F Bodmer

Publications and source records attributed to W F Bodmer.

At least 73 records · Page 4Linked to original sources
PubMed1997

Exclusion of PTEN and 10q22-24 as the susceptibility locus for juvenile polyposis syndrome.

Juvenile polyposis syndrome (JPS; MIM 174900) is an autosomal dominant condition with incomplete penetrance characterized by hamartomatous polyps of the gastrointestinal tract and a risk of gastrointestinal cancer. Gastrointestinal hamartomatous polyps are also present in Cowden syndrome (CS; MIM 158350) and Bannayan-Zonana syndrome (BZS; also called Ruvalcaba-Myhre-Smith syndrome; MIM 153480). The susceptibility locus for both CS and BZS has recently been identified as the novel tumor suppressor gene PTEN, encoding a dual specificity phosphatase, located at 10q23.3. A putative JPS locus, JP1, which most likely functions as a tumor suppressor, had previously been mapped to 10q22-24 in both familial and sporadic juvenile polyps. Given the shared clinical features of gastrointestinal hamartomatous polyps among the three syndromes and the coincident mapping of JP1 to the region of PTEN, we sought to determine whether JPS was allelic to CS and BZS by mutation analysis of PTEN and linkage approaches. Microsatellite markers spanning the CS/BZS locus (D10S219, D10S551, D10S579, and D10S541) were used to compute multipoint lod scores in eight informative families with JPS. Lod scores of < -2.0 were generated for the entire region, thus excluding PTEN and any genes within the flanking 20-cM interval as candidate loci for familial JPS under our statistical models. In addition, analysis of PTEN using a combination of denaturing gradient gel electrophoresis and direct sequencing was unable to identify a germline mutation in 14 families with JPS and 11 sporadic cases. Therefore, at least a proportion of JPS cases are not caused by germline PTEN alteration or by an alternative locus at 10q22-24.

Chromosomes, Human, Pair 10↗
PubMed1997

Beta-catenin mutations in cell lines established from human colorectal cancers.

beta-catenin has functions as both an adhesion and a signaling molecule. Disruption of these functions through mutations of the beta-catenin gene (CTNNB1) may be important in the development of colorectal tumors. We examined the entire coding sequence of beta-catenin by reverse transcriptase-PCR (RT-PCR) and direct sequencing of 23 human colorectal cancer cell lines from 21 patients. In two cell lines, there was apparent instability of the beta-catenin mRNA. Five different mutations (26%) were found in the remaining 21cell lines (from 19 patients). A three-base deletion (codon 45) was identified in the cell line HCT 116, whereas cell lines SW 48, HCA 46, CACO 2, and Colo 201 each contained single-base missense mutations (codons 33, 183, 245, and 287, respectively). All 23 cell lines had full-length beta-catenin protein that was detectable by Western blotting and that coprecipitated with E-cadherin. In three of the cell lines with CTNNB1 mutations, complexes of beta-catenin with alpha-catenin and APC were detectable. In SW48 and HCA 46, however, we did not detect complexes of beta-catenin protein with alpha-catenin and APC, respectively. These results show that selection of CTNNB1 mutations occurs in up to 26% of colorectal cancers from which cell lines are derived. In these cases, mutation selection is probably for altered beta-catenin function, which may significantly alter intracellular signaling and intercellular adhesion and may serve as a complement to APC mutations in the early stages of tumorigenesis.

Amino Acid Sequence↗
PubMed1997

Genetic diversity and disease susceptibility.

The range of genetic diversity within human populations is enormous. Genetic susceptibility to common chronic disease is a significant part of this genetic diversity, which also includes a variety of rare clear-cut inherited diseases. Modern DNA-based genomic analysis can now routinely lead to the identification of genes involved in disease susceptibility, provides the basis for genetic counselling in affected families, and more widely for a genetically targeted approach to disease prevention. This naturally raises problems concerning the use of information on an individual's decisions, but for employment, and health and life insurance.

Genetic Diseases, Inborn↗
PubMed1997

Dietary fat influences on polyp phenotype in multiple intestinal neoplasia mice.

Significant differences in colon cancer incidence worldwide have led to the hypothesis that this variation can be explained largely by environmental, notably dietary influences. Although a positive correlation between dietary fat intake and incidence is suggested from some human epidemiological and rodent carcinogenesis studies, a direct association remains contentious. Using a spontaneous mouse tumor model of multiple intestinal neoplasia, we demonstrate that there is a generalized increase in tumor counts, in both the large and small bowel with higher dietary fat [standard (3%) fat versus high (15%) fat diet (mean +/- SD) 1.59 +/- 1.46 vs. 3.85 +/- 2.37 P < 0.001 and 21.36 +/- 7.4 vs. 31.3 +/- 9.7, respectively, P < 0.001]. Increasing dietary fat also increases polyp size in the small bowel. These changes appear independent of total calorific intake as assessed by body weights. Halving the crude fiber intake together with an increase in dietary fat from 3% to 10% did not have as marked an effect on tumor counts as an increase of fat alone to 15%, which also decreased survival (P < 0.05). These results demonstrate that increasing dietary fat intake from weaning can have a significant adverse effect on polyp numbers in mice genetically predisposed to intestinal tumor development. A further understanding of the biology of this interaction may provide novel strategies aimed at both colonic polyp prevention and treatment.

Animals↗
PubMed1997

DNA mismatch repair in lymphoblastoid cells from hereditary non-polyposis colorectal cancer (HNPCC) patients is normal under conditions of rapid cell division and increased mutational load.

Patients with hereditary non-polyposis colorectal cancer (HNPCC) have germ-line mutations in one of four DNA mismatch repair genes (hMSH2, hMLH1, hPMS1 and hPMS2). It is supposed that a single functional copy of these genes is sufficient for normal mismatch repair, but it is not certain that this is the case under abnormal conditions such as rapid cell division or an increased tendency to DNA replication errors (RERs). We have analysed mismatch repair by examining replication errors in immortalised lymphoblastoid cells derived from two HNPCC patients heterozygous for mismatch repair defects (one hMSH2 mutant and one hMLH1 mutant), and from control individuals. Three conditions of cell culture have been used: (i) relatively slow cell growth and division; (ii) relatively fast growth and division; and (iii) chronic perturbation of the intracellular dNTP pool to promote a increased frequency of replication errors. No significant differences in microsatellite instability were found between HNPCC patients and controls in any of these environments. Lymphoblastoid cells from hMSH2 and hMLH1 mutant/wild-type heterozygotes appear, therefore, to have normal levels of mismatch repair, even under conditions that increase the requirement for repair. The pool bias cultures from the HNPCC patients and controls did, however, show similar, increased frequencies of RERs, suggesting that the mismatch repair capacity of the cells had been overloaded, but that the number of normal HNPCC alleles was not the limiting factor.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Introduction of a myc reporter tag to improve the quality of mutation detection using the protein truncation test.

The protein truncation test is a useful method for identifying frameshift and nonsense mutations. The interpretation of real results is often made difficult by the presence of internally translated protein products and other nonspecific bands. To overcome these problems, the technique has been modified to include a myc reporter tag in the 5' primer used to amplify the genomic region of interest. The myc tag is recognised by a monoclonal antibody, which can be used to manipulate the products of the protein truncation test using immunoprecipitation techniques. The presence of the myc tag also introduces a mechanism whereby the use of radioisotopes can be avoided, relying instead on the identification of newly synthesised proteins using Western blot technology. The myc-tag modification can be integrated into all protein truncation tests, regardless of the gene being examined, with only one monoclonal antibody required for the immunoprecipitation purification and Western blotting.

Antibodies, Monoclonal↗
PubMed1997

Clinical features and molecular analysis of a family with multiple colon tumours and reduced plasminogen activator activity.

A family is reported in which a pair of brothers has developed recurrent venous thromboses, which have been shown in one brother (the proband) to result from a reduced level of tissue plasminogen activator (t-PA) activity. Both brothers have also developed multiple synchronous and metachronous colorectal adenomas. Other pedigree members have developed colon cancers, but not multiple colonic tumours. We have shown that HNPCC and FAP/AAPC are unlikely causes of the family's phenotypes. Previous studies have found low levels of t-PA in sporadic colon tumours. In this family, mutations in the t-PA gene, at a linked locus, or at a locus controlling t-PA activity/release may modify the colon tumour phenotype to cause multiple lesions.

Adenoma↗
PubMed1997

Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteria.

Hereditary non-polyposis colorectal cancer (HNPCC) is a clinical syndrome characterised by an inherited predisposition to early onset colorectal and uterine cancers and an increased incidence of other cancers. It is caused by germline defects in the human mismatch repair genes. Defects in two of the known mismatch repair genes (namely hMSH2 and hMLH1) account for over 90% of mutations found in HNPCC families. In this study we have identified 14 families that fulfilled the clinical criteria for HNPCC and screened the hMSH2 and hMLH1 genes for germline mutations using single-strand conformational polymorphism (SSCP) analysis and DNA sequencing. Seven mutations were identified. Of these, there were five frameshifts, one missense mutation and a further novel mutation that involved separate transition and transversion changes in successive amino acid residues. Three of the mutations were in hMSH2 and four in hMLH1. The identification of germ-line mutations in an HNPCC family enables targeted surveillance and the possibility of early curative intervention. SSCP is a simple and effective method for identifying most mutations in the human mismatch repair genes using DNA from fresh, frozen or archival material.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Allele loss in colorectal cancer at the Cowden disease/juvenile polyposis locus on 10q.

The genes that are mutated in inherited cancer syndromes are often involved in the pathogenesis of sporadic cancers of the types that characterize those syndromes. In colorectal cancer such loci include the familial adenomatous polyposis (APC) gene and the hereditary nonpolyposis colorectal cancer (DNA mismatch repair) genes. Juvenile hamartomatous polyposis syndromes, which include Juvenile Polyposis and Cowden disease, also predispose to colorectal cancer. The gene for Cowden disease has recently been localized to chromosome 10q22-q23, and a juvenile polyposis locus, JP1, has been reported as mapping to the same location. We have studied up to 70 cases of sporadic colorectal cancer for allele loss at markers predominantly on the long arm of chromosome 10, including loci flanking the putative Cowden Disease/JP1 locus. Frequencies of allele loss of about 35% were found close to this locus, whereas low frequencies of allele loss were found elsewhere on 10q. Mutations at the putative Cowden Disease/JP1 locus may therefore be important in sporadic colorectal cancer and fine mapping of allele loss on 10q in sporadic colon cancers may help to refine the position of this gene.

Adenomatous Polyposis Coli↗
PubMed1997

Modelling the consequences of interactions between tumour cells.

Classical models of tumorigenesis assume that the mutations which cause tumours to grow act in a cell-autonomous fashion. This is not necessarily true. Sometimes tumour cells may adopt genetic strategies that boost their own replication and which also influence other cells in the tumour, whether directly or as a side-effect. Tumour growth as a whole might be enhanced or retarded. We have used mathematical models to study two non-autonomous strategies that tumour cells may use. First, we have considered the production by tumour cells of an angiogenesis growth factor that benefits both the cell from which it originates and neighbouring cells. Second, we have analysed a situation in which tumour cells produce autocrine-only or paracrine-only growth factors to prevent programmed cell death. In the angiogenesis model, stable genetic polymorphisms are likely to occur between cells producing and not producing the growth factor. In the programmed cell death model, cells with autocrine growth factor production can spread throughout the tumour. Production of paracrine-only growth factor is never selected because it is 'altruistic' (that is of no benefit to the cell that makes the growth factor), despite being potentially beneficial to tumour growth as a whole. No polymorphisms can occur in the programmed cell death model. Production of angiogenesis and other growth factors in tumours may be under stable genetic, rather than epigenetic, control, with implications for therapies aimed at such targets. Many of the mutations observed in tumours may have non-autonomous effects.

Animals↗
PubMed1997

Clinical and molecular features of the hereditary mixed polyposis syndrome.

BACKGROUND & AIMS: Various inherited syndromes predispose to the development of colonic juvenile polyps and colorectal cancer, with potential importance for sporadic tumorigenesis. This study describes features of a possibly new syndrome of atypical juvenile polyps and other colonic tumors and compares these features with those of known gastrointestinal tumor syndromes. METHODS: A large family, St. Mark's family 96, with a tendency to develop colonic polyps of mixed histological types is described. Genetic linkage to known polyposis syndromes has been tested. RESULTS: Adenomatous and hyperplastic polyps occur in affected members of the family, although the characteristic lesion is an atypical juvenile polyp. Some affected individuals have developed polyps of more than one type, and individual polyps may contain features of more than one histological type. Polyps can undergo malignant change. Typically, fewer than 15 polyps are found at colonoscopy and there is no extracolonic disease associated with the development of polyps. The family's polyps seem to be inherited in an autosomal-dominant fashion, but the disease is probably unlinked to candidate loci with importance in colorectal tumorigenesis, such as APC, hMSH2, and hMLH1. CONCLUSIONS: We term this family's disease hereditary mixed polyposis syndrome (HMPS). Although mutations in the putative HMPS gene may be responsible for syndromes such as juvenile and Peutz-Jeghers polyposes, HMPS may also be a distinct disease.

Adenomatous Polyposis Coli↗
PubMed1997

Allele loss, replication errors and loss of expression of E-cadherin in colorectal cancers.

BACKGROUND: Loss of E-cadherin expression has been implicated in the development of invasive characteristics in colorectal carcinomas. Failure to express E-cadherin may result from mutations of the E-cadherin gene (HSECAD). AIMS: To examine the correlation between E-cadherin expression and genetic changes at HSECAD; and to examine differences in E-cadherin expression and genetic changes at HSECAD between three different groups of colorectal cancer--replication error positive (RER+) sporadic cancers, RER--sporadic cancers and ulcerative colitis associated cancers. SUBJECTS AND METHODS: Sixty eight colorectal cancers (22 RER+ sporadic cancers, 32 RER- sporadic cancers and 14 ulcerative colitis associated cancers) were studied using immunohistochemistry and for allele loss at the HSECAD locus. Exon 16 of HSECAD contains several mononucleotide repeat tracts which are very similar to microsatellite repeats and which may be susceptible to replication errors (manifest as new alleles). All cases were also examined for new alleles in exon 16. RESULTS: Absent or decreased E-cadherin protein expression was found in 27 (38%) of 68 colorectal cancers and the pattern of expression did not differ significantly among the three tumour groups. Allele loss occurred at HSECAD in four (10%) of 40 informative cancers and there were no differences between the three subgroups. New alleles at exon 16 were detected in three (14%) of 22 RER+ tumours; no new alleles were detected in RER- or ulcerative colitis associated cancers. Overall, there was no correlation between allelic loss or exon 16 replication errors and immunohistochemical E-cadherin expression. CONCLUSIONS: (1) Loss of E-cadherin expression probably does not occur as a result of mutation at the HSECAD locus in colorectal cancers. (2) There is no difference in the frequency of loss of heterozygosity at HSECAD among RER+, RER- and ulcerative colitis associated colorectal cancers.

Alleles↗
PubMed1997

Frequency of germline hereditary non-polyposis colorectal cancer gene mutations in patients with multiple or early onset colorectal adenomas.

BACKGROUND: The hereditary non-polyposis colorectal cancer (HNPCC) syndrome is caused by germline mutations in mismatch repair genes and predisposes individuals to cancers of the colon and other specific sites. On theoretical grounds, it is expected that patients with HNPCC also develop more colorectal adenomas than the general population. In essence, if the mutation rate is raised owing to mutations at a mismatch repair locus, more mutations are expected at loci such as APC (adenomatous polyposis coli) and more adenomas will start to grow. Not all data support this expectation, however. AIM: To search for germline mutations at HNPCC loci in patients with multiple adenomas. SUBJECTS: Twenty five patients (without known APC mutations) who have developed colorectal adenomas in unusually large numbers and, in some cases, at an early age. METHODS: Germline APC mutations were excluded using the protein truction test for exon 15 and mismatch chemical cleavage analysis for remaining exons. Germline HNPCC mutations were detected by using PCR and single strand conformation polymorphism analysis. RESULTS: Just one germline HNPCC mutation was found (4% of cases) and this was of uncertain functional effect. CONCLUSIONS: In general, germline HNPCC mutations are not responsible for the phenotype of patients with multiple colonic adenomas. It is possible that patients with HNPCC tend to develop adenomas more frequently and earlier than the general population, but that this effect is relatively subtle. These results suggest that individuals with colorectal adenomas only should not strictly be classified as "affected" in HNPCC families (although they should certainly not be classified as "unaffected" either and may warrant intensive screening). In the absence of a personal or strong family history of colorectal cancer, it is probably not worthwhile performing diagnostic or predictive genetic testing for HNPCC mutations in subjects with colorectal adenomas. Although undetected APC mutations may be responsible for some of the phenotypes in this sample, as yet uncharacterised adenoma predisposing genes probably exist.

Adenoma↗
PubMed1997

Germline HNPCC gene variants have little influence on the risk for sporadic colorectal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) is a syndrome of inherited bowel and other cancers that has been said to account for up to 15% of all colorectal carcinomas (CRCs). HNPCC can now be diagnosed at the molecular level by detecting germline mutations in genes involved in mismatch repair. A current problem is to determine the prevalence of HNPCC mutations in colon cancer patients with limited or no family history, especially in cases of early onset. We have identified 50 cases of non-polyposis colorectal cancer without a family history of CRC or any other HNPCC cancer, who presented under the age of 45 years. Germline HNPCC variants (at the hMSH2 or hMLH1 loci) were detected in a small minority of cases (6%). The variants that we have found may be new or low penetrance mutations, or even polymorphisms. It remains possible that some of our sample have an inherited predisposition to CRC that is not caused by HNPCC mutations or by known polyposis syndromes. Our data suggest that most HNPCC mutations occur in families and have high or moderate penetrance. New or low penetrance HNPCC mutations probably do not contribute significantly to the risk of colorectal cancer in the general population and probably account for much fewer than 15% of all CRCs. Our results question whether mass population genetic screening programmes are worthwhile for diseases such as HNPCC using current technology.

Adolescent↗
PubMed1997

Genetic testing is important in families with a history suggestive of hereditary non-polyposis colorectal cancer even if the Amsterdam criteria are not fulfilled.

BACKGROUND: Clinical screening is still the first-line approach to identification of families with hereditary non-polyposis colorectal cancer (HNPCC). The need for uniformity of diagnosis of the syndrome, particularly in multicentre studies, led to the establishment of a set of minimum diagnostic criteria, the 'Amsterdam criteria'. It is now known that HNPCC is caused by germline defects in the human mismatch repair genes and DNA predictive testing is possible. Defects in two of the known mismatch repair genes, namely hMSH2 and hMLH1, account for over 90 per cent of mutations found in HNPCC families. METHODS: Ten families were identified with pedigrees suggestive of HNPCC (that is with a possible dominant inheritance of HNPCC), but in which the Amsterdam criteria were not fulfilled. Using the technique of single-strand conformational polymorphism analysis, samples were screened from an affected member of each of these ten kindreds for germline mutations in the genes hMSH2 and hMLH1. RESULTS: Mutations were identified in six families. Of these, there were three missense, one nonsense, one frameshift and one putative splice-site mutation. Three of the mutations were in hMSH2 and three in hMLH1. CONCLUSION: This study demonstrates that all families with a pedigree suggestive of HNPCC should be referred to a geneticist even if the Amsterdam criteria are not fulfilled. A knowledge of the gene carrier status enables targeted surveillance and the possibility of early surgical intervention that could be curative.

Colorectal Neoplasms↗