The Initiation and Progression of Neoplasia in Inherited and Sporadic Colorectal Cancer.

Abstract

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.