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Title: Intratumoral genetic heterogeneity in sporadic colorectal cancer and its association with underlying genomic instability
Author: Georgiades, Izabela Bozena
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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This study has identified the presence of genetic intratumoral heterogeneity in sporadic colorectal cancer. It has shown that the RER+ phenotype is characteristic of a proportion of sporadic colorectal cancer and confirmed that a single sample analysis is sufficient for determining RER+ phenotype in these tumours. The analysis of chromosome copy number changes in the RER- and RER+ groups of sporadic colorectal cancers confirmed previously reported higher incidence of chromosomal abnormalities occurring in RER- cancers. Different patterns of chromosomal changes were found to occur in RER- and RER+ tumours. In this study the most frequently detected chromosomal abnormalities in RER- and RER+ cancers were 20q+, 18q+, 13q+, 8p-, 1p-, 8q+ and 1p-, 19del respectively. The most important finding of this study is the identification of a novel group of sporadic colorectal cancers which do not display instability of either chromosomes or microsatellites (called non-MIN, non-CIN cancers). These tumours do not show any striking differences in clinical and pathological features compared with RER- tumours exhibiting high levels of chromosomal instability, but may harbour fewer abnormalities of p53. It is likely that non-MIN, non-CIN colorectal cancers represent a distinct entity in sporadic colorectal cancer and, based on this data, their prevalence might be as high as 35% of RER- colorectal cancers or 25% of sporadic colorectal cancers in total. The analysis of colorectal cancer xenografts established from samples collected from multiple sites from primary tumours showed that a xenograft established from a single sample is in general representative of its tumour of origin, despite the presence of genetic heterogeneity within primary tumours. This applies firstly to the preservation of the RER+ and RER- phenotype and secondly to specific chromosomal abnormalities being retained in RER- colorectal cancer xenografts. The study also showed that p53 status of the primary tumour is unchanged in a corresponding xenograft and that the DNA ploidy closely resembles that of the sample of origin. Preservation of all these important genetic features in colorectal cancer xenografts makes them a valuable model for investigating the genetics of the disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available