Thomas, Huw Jeremy Wyndham; (1991) Molecular analysis of the adenomatous polyposis coli gene region. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The adenomatous polyposis coli (APC) gene has been mapped to the the long arm of human chromosome 5. Mutations of the APC gene are responsible for familial adenomatous polyposis (PAP); a dominantly inherited predisposition to colorectal cancer. In order to isolate DNA probes in the APC gene region human:hamster somatic cell hybrids were made in which human chromosome 5 is retained. These were derived from three individuals: one patient with PAP and an interstitial deletion of chromosome 5, one patient with an interstitial deletion of chromosome 5 of unknown PAP status and a patient with PAP and mental retardation with no visible karyotypic abnormality. The two human chromosome 5s were segregated in these hybrids and they have been used to construct a mapping panel. A panel of 150 radiation hybrids was made from somatic cell hybrid PN/TS-1, in which the only human genetic material is chromosome 5. These hybrids were used to order probes from the APC gene region. A lambda library was constructed from a radiation hybrid retaining genetic material in the APC gene region and the human clones mapped on the chromosome 5 deletion hybrid panel. The retinoblastoma model suggests that inherited cancer genes may also be involved in the development of sporadic tumours. This hypothesis is supported by the loss of genetic material on chromosome 5 in sporadic, non-familial, colorectal cancer. As the majority of colorectal carcinomas are thought to arise from preexisting adenomatous polyps studies of loss of heterozygosity for markers on chromosome 5 were extended to sporadic colorectal adenomas and carcinomas. Loss of genetic material on chromosome 5 appears to be a frequent early event in colorectal tumourigenesis.

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