Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.796384
Title: Molecular genetic changes during tumour progression in mouse skin
Author: Bremner, Rod
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1990
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Abstract:
This thesis describes the development of a model to analyse the genetic changes associated with tumour progression in mouse skin. Tumours were induced in F1 hybrid mice, thereby permitting the use of heterozygous DNA markers (restriction fragment length polymorphisms) to determine the role of allele loss in papilloma and carcinoma development. Frequently, initiation of mouse skin carcinogenesis involves H-ras activation. This gene is located on mouse chromosome 7. The F1 hybrid tumour model was used to demonstrate that tumours with this mutation also show loss of heterozygosity (LOH) or imbalance of alleles on chromosome 7 at a very high frequency. Thus LOH may indicate the presence of an oncogene, although it is often equated with tumour suppressor gene loss. Most frequently the alterations involved non-disjunction, but in some cases mitotic recombination or deletion was detected. These gross chromosome changes were not observed in mouse skin tumours lacking activated H-ras. Thus, it is clear that the initiation event can influence the type of alterations which occur at later stages of tumour progression. In the majority of cases, gross chromosome 7 changes result in an increased copy number of mutant H-ras and under-representation or loss of the normal allele, indicating that mutant H-ras is involved in both the initiation and progression of mouse skin tumours. It may be that elevation of the mutant signal is required to overcome a suppressive effect of the normal allele. In addition, because elevation of mutant H-ras gene copy number occurs by gross chromosomal mechanisms, it is possible that another chromosome 7 gene is also involved in tumour progression. In support of this, mitotic recombination or deletion was detected distal to H-ras in 4/26 of the chemically induced tumours with activated H-ras. In addition, a chromosome 7 alteration was detected in a v-H-ras initiated tumour, further evidence that a gene other than H-ras on this chromosome is involved in tumour progression. Human tumours frequently demonstrate LOH at the chromosomal region 11p 15.5, which is syntenic with the part of mouse chromosome 7 that encompasses the H-ras locus. Thus, the homologue of a tumour suppressor gene in this region of human chromosome 11 may be involved in mouse skin tumour development. The Wilms' tumour locus, also on human 11p, is on mouse chromosome 2. RFLP analyses provided no evidence that this gene has a role in mouse skin tumorigenesis. The non-random nature of chromosome 7 changes was supported by the low frequency of alterations on chromosomes 2 and 11. Two carcinomas did show LOH of a marker on the latter. Interestingly, this chromosome contains a region homologous to human chromosome 17p, which is involved in colorectal cancer. Minisatellite analysis also supported the non-random nature of chromosome 7 changes. Loss or rearrangement of minisatellite bands tended to involve hypervariable loci, suggesting that these were random rearrangements at unstable loci. In some human cancers genomic imprinting influences the direction of allele loss on 11p. However, this did not appear to be the case with LOH on chromosome 7 in mouse skin carcinomas. The parental strain also did not influence which alleles were under-represented in these tumours. Some important differences were detected between the genetic changes associated with carcinomas induced by initiation/promotion and those seen in carcinomas obtained by repeated carcinogen treatment. A similar proportion of MNNG/TPA and MNNG/MNNG carcinomas were positive for mutant H-ras. However, whereas non-disjunction of chromosome 7 had also occurred in the former, no chromosome 7 changes were detected in carcinomas induced by repeated MNNG treatment. This carcinogen may remove the need for additional chromosome 7 changes by mutating the gene(s) affected by these events in TPA-promoted tumours, or by altering entirely separate loci. In contrast, tumours induced with repeated DMBA treatment which were positive for activated H-ras also had chromosome 7 changes. However, the frequency of events such as mitotic recombination or deletion was much higher in these tumours than in carcinomas induced by an initiation/promotion regime. The major difference between DMBA/DMBA carcinomas and DMBA/TPA carcinomas was that the latter contained a much higher proportion of tumours which lacked activated H-ras. Thus it appears that repeated DMBA treatment stimulates the growth of initiated cells which are insensitive to TPA. Analysis of papillomas showed that gross chromosome 7 changes occur at a premalignant stage of tumorigenesis. This may suggest a tumour promoter-related genetic effect.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.796384  DOI: Not available
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