Graham, T.A.; (2009) The expansion of mutant clones in tumorigenesis. Doctoral thesis , UCL (University College London).

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Abstract

The formation of a cancer is an evolutionary process. A somatic cell may acquire an (epi)-mutation that gives it a growth advantage relative to its neighbours. Progression to cancer occurs as cells in the resulting mutant clone acquire additional mutations, which may also confer a selective advantage. This thesis investigated the expansion of mutant clones both prior to, and during, tumour growth. First, the clonal expansion of a mutant lineage within a stem cell niche was considered. The behaviour of mutant germline stem cells in the Drosophila testis, a remarkably well-characterised niche, was investigated. A model was developed which identified stem cell phenotypes that were selectively advantageous in the niche. Crypt fission is thought to be the primary mechanism of clonal expansion in the gut. A model of crypt fission was developed, which was used to estimate the frequency of fission events in the normal human colon. Crypts were found to divide infrequently, and fission was predicted to decrease the likelihood that a mutant clone would be lost from the gut. Next, the expansion of mutant clones during the initial growth of colorectal adenomas was considered. Individual crypts were micro-dissected from small adenomas, and the mutation status of the APC and K-ras genes in each crypt was determined. Combining this information revealed how the adenoma had formed. It was found that K-ras mutations may have occurred earlier in tumorigenesis than had been previously established. Last, the effect of clonal expansion on the genetic heterogeneity in a cancer was examined. A model of microsatellite slippage during cancer growth was developed. The model showed that clonal expansion during cancer growth, coupled with a low rate of somatic mutation, can generate non-negligible amounts of genetic diversity. This suggested that there was little evidence for a low-level microsatellite mutator phenotype in colorectal cancers.

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