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Modifier genes of familial adenomatous polyposis

Crabtree, Michael David; (2003) Modifier genes of familial adenomatous polyposis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Familial adenomatous polyposis (FAP) is a mendelian cancer syndrome caused by mutations in the APC gene. It is an excellent model for sporadic colorectal cancer (CRC), a common disease that also has a heritable risk component. Variation in FAP severity occurs between individuals and also within families. Epidemiological analysis indicated that close relatives with FAP had more similar types colonic adenoma number than did distant relatives. The observed pattern of variation may plausibly have been caused by modifier genes. A segregation analysis suggested that the pattern of variation could be attributed to the action of additional genetic loci, mirroring published evidence from animal models of the disease. Theoretically, modifier genes are likely to be common genetic variants that also alter the risk of sporadic colorectal cancer. Putative CRC risk genes were assessed for their association with colonic FAP disease severity. Two genes (NAT2 and GSTμ) were found to be associated with an approximately two fold increase in colonic adenoma number in FAP patients after correction for germline APC mutation effects. Variation was also seen in the pattern of somatic APC mutation clustering in polyps from FAP patients suggesting that modifier genes may affect carcinogenic pathways early on in the development of colonic adenomas. Assessment of variation in adenoma number in FAP patients demonstrated that change in the total size of the adenoma population was real rather than apparent. Indicating that modifier effects may exert their action at the time of adenoma initiation. Collectively the data support the hypothesis that modifier genes alter the severity of human colonic FAP.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Modifier genes of familial adenomatous polyposis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Familial adenomatous polyposis
URI: https://discovery.ucl.ac.uk/id/eprint/10100620
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