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Biomedical subjects

W F Bodmer

Publications and source records attributed to W F Bodmer.

At least 127 records · Page 7Linked to original sources
PubMed1994

Phenotypic expression in familial adenomatous polyposis: partial prediction by mutation analysis.

The phenotypic expression in familial adenomatous polyposis (FAP) is variable. This study compares the phenotype of 27 patients with an identical 5 base pair (bp) deletion at codon 1309 with a group of 61 matched patients with FAP where knowledge of specific mutations is not available and with seven other different mutations in 24 subjects. Patients with the codon 1309 deletion have significantly more colorectal polyps at the time of colectomy than age and sex matched FAP controls (p = 0.0001). The median number of polyps in colectomy specimens of patients with the deletion at codon 1309 was 4000 (interquartile (IQ) range 3000-4875), compared with 600 (IQ range 488-1400) in the matched controls. Mutations at codon 1323, 1407, and 233 were also associated with large numbers of polyps. Desmoid disease and extracolonic cancers were more common with the mutation at codon 1309 (p = 0.003). In conclusion, there may be a correlation between a specific germline mutation and the number of large bowel polyps. There is residual heterogeneity in phenotypic expression, however, and this may result from the influence of other genes, specific environmental factors or chance.

Adenomatous Polyposis Coli↗
PubMed1993

Mutation of p53 in primary biopsy material and cell lines from Hodgkin disease.

The p53 tumor-suppressor gene encodes a nuclear phosphoprotein that arrests cell cycle progress at G1. It may facilitate DNA damage repair and is frequently mutated in many human tumors. Hodgkin disease, a malignant condition of the lymphoid system, is characterized by the presence of Reed-Sternberg cells and mononuclear variants (Hodgkin cells), whose etiology remains unknown. The large multinucleated Reed-Sternberg cells often comprise < 1% of the total cell population within a biopsy specimen and are thought to be the neoplastic component in an admixture of reactive cells. It has been shown in the large majority of cases that up to 60% of these multinucleated cells react with CM-1, an anti-p53 antibody. However, whether this "overexpression" of p53 protein reflects abnormality at the DNA level can no longer be assumed by immunocytochemistry alone. p53 from six Hodgkin disease-derived cell lines was examined by immunoprecipitation, polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis, and sequencing. In one cell line, point mutations were identified in exons 5 and 8 of p53. Sequencing of cloned PCR products confirmed the mutations to be on different alleles. A strategy involving extraction of nuclei followed by enrichment by flow cytometry was used to determine whether p53 overexpression in the Reed-Sternberg cells from patient biopsy material was due to mutations in this gene. Single-strand conformation polymorphism revealed additional bands in the polyploid nuclear preparations, suggesting abnormalities, and sequence analysis confirmed the presence of point mutations.

Base Sequence↗
PubMed1993

Tissue typing the HLA-A locus from genomic DNA by sequence-specific PCR: comparison of HLA genotype and surface expression on colorectal tumor cell lines.

A system devised for tissue typing the HLA-A locus by PCR from genomic DNA has been used to investigate abnormalities of HLA expression in a panel of 30 colorectal tumor cell lines, by comparing the HLA-A locus genotype with surface expression of HLA. Three cell lines showed complete lack of HLA expression associated with failure to express beta 2-microglobulin. In two other cell lines, loss of expression of HLA-A2 was observed, in spite of the presence of the gene in genomic DNA. Eleven cell lines gave a single HLA-A locus specificity on PCR typing. In one of these cell lines we have demonstrated the loss of an HLA-A locus gene in the tumor cell by comparison with DNA from a lymphoblastoid B-cell line derived from the same patient. These data indicate that at least three independent mechanisms were involved in the loss of HLA expression on the colorectal tumor cell lines.

Base Sequence↗
PubMed1993

A long-range restriction map of human chromosome 5q21-q23.

A long-range restriction map encompassing the APC (adenomatous polyposis coli) gene has been constructed. The map includes 35 DNA markers and consists of two segments of 10 and 2.5 Mb. Published genetic markers have been connected using additional, nonpolymorphic DNA probes. The map clarifies marker order and allows comparison of physical and genetic data.

Adenomatous Polyposis Coli↗
PubMed1993

New vector for transfer of yeast artificial chromosomes to mammalian cells.

A modification vector has been constructed to facilitate the transfer of yeast artificial chromosomes (YACs) to mammalian cells in culture by targeting a dominant selectable marker (G418 resistance) to the right arm of pYAC4 clones. The ADE2 gene is used for yeast selection with consequent disruption of the URA3 gene, allowing direct modification of YACs within the common host strain AB1380, and providing a simple test for correct targeting. This vector has been tested by modification of a 550-kb YAC containing part of the human MHC class II region and transfer to CHO cells by protoplast fusion. Analysis of 15 independent G418-resistant CHO lines obtained following fusion suggests the majority contain a complete YAC with moderate amplification in some lines.

Animals↗
PubMed1993

Loss of human leukocyte antigen expression on colorectal tumor cell lines: implications for anti-tumor immunity and immunotherapy.

A system devised for tissue typing the human leukocyte antigen-A (HLA-A) locus from genomic DNA by the polymerase chain reaction (PCR) has been used to investigate abnormalities of HLA expression in a panel of 30 cell lines derived from colorectal adenocarcinomas, by comparison of the HLA-A locus genotype with surface expression of HLA. Eleven cell lines gave single HLA-A locus specificity on PCR typing, suggesting that loss of HLA alleles is a common abnormality. In one of these cell lines the loss of an HLA-A locus allele was confirmed by comparison with DNA from a lymphoblastoid B cell line derived from the same patient. In three cell lines, loss of expression of an HLA-A locus determinant was observed in spite of the presence of the relevant allele in genomic DNA. Three cell lines showed absent HLA expression associated with failure to express beta 2-microglobulin. These data indicate that at least three independent mechanisms were involved in the loss of HLA expression on the colorectal tumor cell lines.

Antigens, Surface↗
PubMed1992

Molecular analysis of APC mutations in familial adenomatous polyposis and sporadic colon carcinomas.

Mutations in the APC gene give rise to familial adenomatous polyposis (FAP) and also occur in many, perhaps most, sporadic colon cancers. By screening with single-strand conformation polymorphism analysis we identified several mutations in a small region of the APC gene in both FAP and sporadic cancers. These mutations were either point mutations or small deletions or insertions causing frameshifts, and all generated stop codons. One 5 base-pair deletion was found in a sporadic colon tumour, a colorectal cancer cell line derived from a sporadic colon tumour, and in four unrelated FAP patients. This mutation produces distinctive heteroduplex bands, which can be detected with a simple non-radioactive assay. Our findings suggest that highly localised short sequences, essentially runs that code for adenine and thymine, may account for up to 20% of all observed APC mutations.

Adenomatous Polyposis Coli↗
PubMed1992

Loss of HLA class-I alleles, heavy chains and beta 2-microglobulin in colorectal cancer.

Using immunohistochemical methods, we have analysed colorectal biopsies of normal mucosa, metaplastic polyps (5 cases), adenomas (15 cases) and adenocarcinomas (70 cases) with 13 monoclonal antibodies (MAbs) to allelic products of the HLA-A, B, C loci. Nine of the 70 carcinomas showed total loss of HLA Class-I molecules due to an underlying defect regarding not only the expression of beta 2-microglobulin (beta 2-m), but also the heavy chains of HLA A, B and C loci, or both. Much commoner was a loss of one or more Class-I alleles as follows: A1/Aw36 (completely lost in 4 of 29 cases and focally lost in another 2), A2 (in 1 of 37 cases), A3 (in 2 of 14 cases), A1 1/28/31/33 (in 3 of 11 cases), B7 (in 3 of 13 and focally in 1 other case), B17 (in 1 case), Bw4 (in 8 of 45 and focally in another 6), Bw6 (in 9 of 62 and focally in another 3). Focal selective loss (Bw6 and a combined A1-Bw6), was observed in 2 adenomas. Normal colonic mucosa, as well as stromal and lymphoid cells present between the neoplastic glands, were studied in each case as a control. A particular allele was only considered to be lost by the malignant cells if it was still expressed on these adjacent tissues.

Alleles↗
PubMed1992

Cloning and characterization of a gene that regulates cell adhesion.

Molecules of the cadherin and integrin families involved in cell-cell and cell-matrix adhesion have been implicated in epithelial differentiation, carcinogenesis and metastasis. Having observed that a colon cancer cell line bound avidly to collagen type I, inducing integrin-triggered glandular differentiation, we investigated the regulation of integrin function in these cells. We modified a mammalian expression cloning system that used monoclonal antibody selection to clone cell surface molecules. Using attachment to collagen type I to select for adhesive phenotype, we isolated a complementary DNA clone that increases cell adhesion to components of the extracellular matrix. The corresponding gene (cell adhesion regulator, CAR) is located on the long arm of chromosome 16 (16q) and encodes a protein of 142 amino acids, which has an N-terminal myristoylation motif and a consensus tyrosine-kinase phosphorylation site at the C terminus. Removal of this tyrosine residue abolishes enhancement of cell-matrix adhesion. This gene may encode an adhesion signal transduction molecule that functions in the suppression of tumour invasion.

Amino Acid Sequence↗
PubMed1992

Over-expression of p53 nuclear oncoprotein in colorectal adenomas.

p53 is a nuclear phosphoprotein which controls normal cell growth. Normal p53 protein is undetectable by standard immunohistochemical staining and the over-expression found in neoplastic cells correlates with the presence of point mutations of evolutionary conserved regions of the p53 gene. We examined the expression of p53 protein in a series of 36 colorectal adenomas (13 tubular, 17 tubulovillous, 6 villous) showing different degrees of dysplasia (11 mild, 19 moderate, 6 severe), 11 moderately differentiated adenocarcinomas (6 Duke's A, 4 Duke's B, 1 Duke's C) and 5 metaplastic polyps using the polyclonal antibody CM1 which recognises p53 protein in conventionally fixed and processed histological material. We found that 15 out of 36 colorectal adenomas showed p53 immunoreactivity, although in 4 positive cases (26%) the staining was very focal (less than 0.1% positive cells). More than 80% of severely dysplastic adenomas showed strong p53 immunoreactivity and this over-expression was correlated with increased cell proliferative rate as detected by the proliferating-cell-nuclear-antigen (PCNA) staining. p53 nuclear staining was also seen in 8 out of 11 (65%) colorectal adenocarcinomas as previously shown. Our data suggest that the p53 gene mutation, with the subsequent over-expression of the protein, occurs in colorectal adenomas and may therefore be a fundamental genetic event underlying the dysplasia and loss of proliferative control that are characteristic of adenomas with malignant potential.

Adenoma↗