The p53 gene in human cancer.
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Genes, Dominant↗
Biomedical subjects
M R Stratton
Publications and source records attributed to M R Stratton.
A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome.
Breast cancer in men is rare--among the risk factors that have been identified are a family history of breast cancer and evidence of androgen insufficiency. We report a family in which two brothers who both developed breast cancer had clinical and endocrinological evidence of androgen resistance. Sequence analysis revealed a mutation in the androgen receptor gene on the X chromosome, within the region encoding the DNA binding domain. This is the first report of a germline mutation in a member of the steroid/thyroid hormone receptor superfamily associated with the development of cancer.
Aged↗
Molecular genetic study showing that the IN/157 'oligodendroglioma' cell line has been contaminated by rhabdomyosarcoma (RD) cells.
The IN/157 cell line was originally isolated from a human oligodendroglioma biopsy and has been used in recent years to study aspects of glioma cell biology. We established that IN/157 cells carry a relatively infrequent mutation at position three of codon 61 of the N-ras gene, suggesting that such a mutation may have contributed towards the genesis of the original tumour. However, the mutation was not detectable within the original paraffin-embedded glioma biopsy from which the cell line was supposedly derived. We thus considered the possibility that the cells had been contaminated by another cell line and, by means of DNA fingerprinting, have demonstrated that the contaminating cell line is the rhabdomyosarcoma line RD. We feel that this study makes several important points regarding experiments which make use of cell lines. We discuss the possible implications of contamination events with regard to erroneous conclusions about the biology of the cell lines and tumour types from which they supposedly derive. We also suggest ways in which future contamination-related errors can be minimized.
Base Sequence↗
A case of cerebellar medulloblastoma with a single chromosome abnormality.
In the few published karyotypes of human medulloblastoma, multiple chromosome abnormalities have usually been demonstrated. We report a case of medulloblastoma in which only a single structural alteration was observed, namely an unbalanced translocation between chromosomes 1 and 6 resulting in partial 1q trisomy and partial 6q mónosomy. This finding may help define genomic regions that are of importance in development of medulloblastoma.
Cerebellar Neoplasms↗
Soft tissue tumours: the genetic basis of development.
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Animals↗
Detection of transforming genes by transfection of DNA from primary soft-tissue tumours.
A series of adult soft-tissue tumours were screened for the presence of activated oncogenes by transfecting tumour DNA into NIH3T3 mouse fibroblasts. In these studies an activated K-ras gene that contained a mutation at the second position of codon 12 (GGT----GAT) was found in a leiomyosarcoma. In addition, following transfection of DNA from a liposarcoma, we identified an activated gene that failed to hybridize to probes prepared from 10 known human oncogenes (K-ras, H-ras, N-ras, ret, met, trk, mas, dbl, raf and hst) that have previously been detected in DNA transfection experiments. BamHI-BamHI fragments of this activated gene of 3.5 and 8.5 kb were cloned from NIH3T3 secondary transfectants using a probe that detects the human alu family of highly repetitive DNA sequences. Repeat-free subclones of these BamHI fragments were used to map this gene to human chromosome 19 (p13.2-q13.3). Our studies also demonstrate that a subclone from one of the BamHI fragments detects a 3.0 kb transcript in primary and secondary transfectants.
3T3 Cells↗
Dinucleotide repeat polymorphism at the SIS locus.
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Base Sequence↗
Mutation of the p53 gene in human soft tissue sarcomas: association with abnormalities of the RB1 gene.
Soft tissue sarcomas have been examined for alterations in the p53 gene. In six sarcomas, loss or rearrangement of both alleles of this gene was detected while in a further seven sarcomas, point mutation or absence of transcription of the p53 gene was observed. Abnormalities of the p53 gene were found in several classes of soft tissue sarcoma, including leiomyosarcomas, rhabdomyosarcomas and malignant fibrous histiocytomas. Our studies also show that abnormalities of the RB1 suppressor gene and of the p53 gene frequently occur together. These results are consistent with the idea that the p53 gene is a tumour suppressor gene and indicate that coincident inactivation of more than one tumour suppressor gene may, in some cases, be required for tumour development.
Base Sequence↗
Detection of point mutations in N-ras and K-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain reaction.
Previous studies have demonstrated that genes of the ras family (H, K, and N) can be activated by point mutations at codons 12, 13, and 61. In the present study we have used oligonucleotide probes corresponding to these regions to assess the role of ras gene mutations in the genesis of human rhabdomyosarcoma. To increase the sensitivity of this method the appropriate regions of the three ras genes were first amplified using the polymerase chain reaction. The results show that 35% (5/14) embryonal rhabdomyosarcomas investigated contain mutations in the N-ras or K-ras genes. Thus ras gene mutation is implicated in the development of mesenchymal and embryonal tumors in addition to its previously documented role in epithelial and hematological neoplasia.
Adolescent↗
Cytogenetic abnormalities in human ependymomas.
The karyotypes of 4 human ependymomas have been determined. In one ependymoma, translocations involving chromosomes 9, 17 and 22 were observed together with the loss of the normal chromosome 17. A second ependymoma had many chromosomal alterations that included a translocation between chromosomes 1 and 2 and re-arrangements involving chromosome 17. No major consistent alterations were detected in the remaining 2 cases. Our karyotypes do not resemble the few previously published karyotypes of ependymomas, but had features, such as the alterations involving chromosome 17, that were similar to those of other brain tumours in children.
Brain Neoplasms↗
Structural alterations of the RB1 gene in human soft tissue tumours.
Sixty-nine primary soft tissue tumours were examined for alterations of the RB1 gene which has previously been implicated in the genesis of retinoblastoma. In three tumours loss of both alleles of this gene (homozygous deletion) was detected. Two of these, both leiomyosarcomas, contained a chromosomal breakpoint within the RB1 gene, while in the third tumour, a radiation induced sarcoma, complete deletion was observed. Using a probe that detects a polymorphic locus within the RB1 gene we found loss of only one allele (heterozygous deletion) in 33% of soft tissue sarcomas examined, including two leiomyosarcomas, a malignant peripheral nerve sheath tumour, a rhabdomyosarcoma and a chondrosarcoma. When taken together our results suggest that alterations of the RB1 locus may play an important part in the pathogenesis of soft tissue tumours and particularly in leiomyosarcomas which accounted for four of the eight RB1 alterations observed in this study.
Alleles↗
Characterization of the human cell line TE671.
The cell line TE671 has been widely used as a model of human medulloblastoma. In the present study we have demonstrated that transfection of DNA from this cell line into NIH 3T3 cells reveals the presence of an activated N-ras gene. Using oligonucleotide probes we have shown that the N-ras gene is activated by a point mutation at the third base of codon 61 resulting in the substitution of histidine for glutamine in the p21 ras gene product. We noted that this relatively uncommon activating mutation is also present in the human rhabdomyosarcoma cell line RD. Based on this finding and on the observation that several of the phenotypic characteristics of TE671, such as the presence of muscle-type nicotinic acetylcholine receptors and the intermediate filament protein desmin, are suggestive of myoid origin we investigated the possible identity of these two cell lines. Cytogenetic analysis revealed the presence of marker chromosomes common to both TE671 and RD. DNA fingerprinting using both locus specific and multilocus core probes showed indistinguishable band patterns in the two cell lines. Taken together our data show that TE671 and RD are derivatives of the same cell line and we conclude that the properties of the TE671 line should be ascribed to rhabdomyosarcoma rather than medulloblastoma cells.
Animals↗
Structure of the met protein and variation of met protein kinase activity among human tumour cell lines.
An in vitro autophosphorylation assay has been used to demonstrate that there is considerable variation in met associated protein kinase among human tumour cell lines. Of particular note was the very high level of autophosphorylation of the 140 kD met protein (p140met) in experiments with A431 human cervical carcinoma cells. In contrast in experiments with Daoy human medulloblastoma cells we failed to detect phosphorylation of p140met; instead a high level of phosphorylation of a 132 kD protein was observed. To help understand the basis for the variation in kinase activity and to learn more about the structure of the mature met protein we have analysed p140met in SDS-polyacrylamide gels under non-reducing conditions. Under these conditions the met protein had an apparent molecular weight of 165,000 indicating that the mature met protein may exist as an alpha beta complex in which p140met (designated the beta subunit) is joined by disulphide bonds to a smaller, 25 kD, alpha-chain. We have identified a potential proteolytic cleavage site with the sequence Lys-Arg-Lys-Lys-Arg-Ser at amino acids 303-308 in the human met protein that may account for cleavage of the met protein into alpha and beta subunits.
Amino Acid Sequence↗
Co-secretion of calcitonin gene-related peptide, gastrin-releasing peptide and ACTH by a carcinoid tumour metastasizing to the cerebellum.
A carcinoid tumour presenting as Cushing's syndrome is reported. Although no tumour mass could be initially identified the patient returned with first a liver and subsequently a cerebellar mass both of which were resected. Only at post-mortem was the lung primary discovered. ACTH, gastrin-releasing peptide (GRP) and calcitonin gene-related peptide were elevated in plasma before resection of the hepatic tumour. These peptides were demonstrated in both the hepatic and cerebellar tumours by immunocytochemistry and radioimmunoassay. This case illustrates the occasional tendency of primary lung carcinoids to remain small and clinically undetectable while generating secondary tumours which are symptomatic. It is suggested that immunological demonstration of GRP may be diagnostically helpful in directing attention to the lung as a primary site in neuroendocrine tumours which present in this fashion.
Adrenocorticotropic Hormone↗
The effects of interferon on glial cells.
The effects of a partially purified rat interferon (RIF) on cell lines cloned from a chemically induced rat glioma (A15A5) and normal rat brain (ARBOC9) were investigated. Interferon treatment reduced the rate of exponential growth and saturation density of both cell lines, but induced contrasting morphological changes. A15A5 cells became bipolar, developed longer processes and produced less extracellular fibronectin, whereas ARBOC9 cells became enlarged, showed increased multinuclearity, expressed more fibronectin and contained actin-like cytoplasmic filaments. These findings demonstrate that RIF has an antiproliferative activity in vitro on both neoplastic and non-neoplastic astrocytes, but that morphological and immunocytochemical responses differ.
Animals↗