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An investigation into the genetic pathways of colorectal cancer. / Susannah Ruth Fradley

Swansea University Author: Susannah Ruth Fradley

Abstract

The mortality associated with colorectal cancer is extremely high, however if the disease IS caught at the earliest stage then there is a 95% 5 year survival. An improved screening technique which is less invasive than current methods may increase uptake by the public. Also, an increase in knowledge...

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Published: 2006
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42566
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Abstract: The mortality associated with colorectal cancer is extremely high, however if the disease IS caught at the earliest stage then there is a 95% 5 year survival. An improved screening technique which is less invasive than current methods may increase uptake by the public. Also, an increase in knowledge of the different genetic pathways of colorectal carcinogenesis may help to tailor treatments to individual patients. The experiments in this thesis address these aims by searching for possible biomarkers which may be detectable in stool samples and by looking for early genetic alterations at the molecular, gene expression and chromosomal levels. This thesis also explored various different techniques such as single stranded conformation polymorphism, fragment analysis, sequencing, cDNA arrays and fluorescent in situ hybridisation (FISH). The findings of these experiments include mitochondrial DNA mutations occurring frequently in late stage colorectal carcinogenesis. These mutations predominantly occurred in microsatellites within the mitochondrial genome. Nuclear microsatellite instability (MSI) levels within the South Wales population studied are within the levels found in the rest of the Western world. There was no correlation found between mitochondrial and nuclear MSI suggesting the presence of separate mismatch repair systems. Various genes were found down-regulated in the early stages of colorectal cancer, including PTEN, TGF-BRII and p21. These genes may be key to the early stage development of a significant proportion of colorectal cancers. I developed a FISH probe for p21 which was simple to make and apply, as well as being cost effective. Chromosome 6 aberrations were detected in an increasing frequency in samples with increasingly developed tumours. A large variation was found in chromosome 6 copy number within different regions of an individual tumour. This variation shows how essential it is that research and diagnostic tests are based on either large portions of a tumour or from multiple smaller biopsies.
Keywords: Genetics.;Oncology.
College: Faculty of Science and Engineering

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