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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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first_indexed 2018-08-02T18:55:01Z
last_indexed 2018-08-03T10:10:29Z
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spelling 2018-08-02T16:24:29.6809968 v2 42566 2018-08-02 An investigation into the genetic pathways of colorectal cancer. 87d2015455021f3f126564dea558d28d NULL Susannah Ruth Fradley Susannah Ruth Fradley true true 2018-08-02 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. E-Thesis Genetics.;Oncology. 31 12 2006 2006-12-31 COLLEGE NANME Biosciences COLLEGE CODE Swansea University Doctoral Ph.D 2018-08-02T16:24:29.6809968 2018-08-02T16:24:29.6809968 Faculty of Science and Engineering School of Biosciences, Geography and Physics - Biosciences Susannah Ruth Fradley NULL 1 0042566-02082018162504.pdf 10805315.pdf 2018-08-02T16:25:04.5800000 Output 20964181 application/pdf E-Thesis true 2018-08-02T16:25:04.5800000 false
title An investigation into the genetic pathways of colorectal cancer.
spellingShingle An investigation into the genetic pathways of colorectal cancer.
Susannah Ruth Fradley
title_short An investigation into the genetic pathways of colorectal cancer.
title_full An investigation into the genetic pathways of colorectal cancer.
title_fullStr An investigation into the genetic pathways of colorectal cancer.
title_full_unstemmed An investigation into the genetic pathways of colorectal cancer.
title_sort An investigation into the genetic pathways of colorectal cancer.
author_id_str_mv 87d2015455021f3f126564dea558d28d
author_id_fullname_str_mv 87d2015455021f3f126564dea558d28d_***_Susannah Ruth Fradley
author Susannah Ruth Fradley
author2 Susannah Ruth Fradley
format E-Thesis
publishDate 2006
institution Swansea University
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Biosciences, Geography and Physics - Biosciences{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Biosciences, Geography and Physics - Biosciences
document_store_str 1
active_str 0
description 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.
published_date 2006-12-31T03:53:13Z
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score 11.035786

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