The Initiation and Progression of Neoplasia in Inherited and Sporadic Colorectal Cancer.
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This dissertation describes investigations into aspects of neoplastic initiation and
progression in the gut, in the context of inherited and sporadic gastrointestinal
cancer.
In familial adenomatous polyposis, there is marked locoregional variation in
polyp density. This work investigated the relationship between gut location and
somatic inactivation of APC. It demonstrated that the frequency of APC loss
of heterozygosity (LOR) varied along the colon, suggesting a colonic gradient
in "just right" signalling. It investigated adenomas of the ileoanal pouch, where
small bowel functions as rectum. A longitudinal study revealed the largely indolent
natural history of these polyps, while mutational analysis demonstrated
that they differed from polyps arising in colon, by usually retaining 2-3 remaining
20-amino-acid repeats. A comparison of pouch and rectal polyps showed
differences in their histogenesis.
Neoplastic initiation was investigated arising in the context of a f!t' new phenotype
of young-onset colorectal cancer, with multiple adenomas and neurological
deficit. A novel homozygous mutation involving PMS2 and FSCJV was found.
Although neoplastic lesions showed nuclear beta-catenin expression, no mutated
wnt pathway genes were identified. No evidence was found that PMS2 or FSCN
mutation was causative in other patients with related multiple adenoma or neurological
phenotypes.
Key stepwise events in the adenoma-carcinoma sequence were investigated in
sporadically occurring adenomas with contiguous carcinoma. Laser microdissection
allowed crypt-by-crypt analysis of APC, TP53, KRAS2, and LOR at
17p and 18q, in order to establish the presence of cryptal heterogeneity and
the inferred order of genetic alterations. Using similar contiguous paired lesions,
a further study investigated neoplastic aneuploidy using image cytometry~
genome-wide LOR analysis and individual SNP analysis for LOR 5q, 17p, and
18q. Aneuploidy did not cluster as tetraploidy. The degree of aneuploidy correlated
well with the degree of LOR ascertained by genome-wide analysis, with
LOR at 17p and 18q (but not 5q), and with nuclear beta-catenin accumulation.
Authors
Will, Olivia Constance ClaireCollections
- Theses [3919]