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An Investigation into the Significance of Mucin Pools following Chemoradiotherapy for Locally Advanced Rectal Cancer and an Exploration of the Molecular Basis Underlying the Resistance to Chemotherapy and Radiotherapy in Mucinous Adenocarcinoma of the Colon and Rectum

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posted on 15.02.2022, 12:23 by Ian Reynolds
Mucin production can occur through one of several mechanisms in colorectal cancer. In this PhD we describe the association between mucin production following neoadjuvant chemoradiotherapy for rectal cancer and clinicopathological outcomes. We do this in both our own cohort of patients from Beaumont Hospital and then through a systematic review and meta-analysis of published studies. We conclude that mucin pool production should be viewed only as a morphological response to treatment and should not be used to determine prognosis or likely response to adjuvant chemotherapy.

The second component of the thesis defines the genomic landscape of mucinous colorectal cancer. This is done firstly through meta-analytical techniques and the findings of this are then verified and expanded on using data from The Cancer Genome Atlas. Mucinous colorectal cancer is associated with microsatellite instability high tumours, BRAF mutations, KRAS mutations and the CpG island methylator phenotype. The fifth publication gives a description of some of the differences in somatic mutations and copy number variation in genes responsible for drug resistance and metabolism between mucinous colorectal cancer and adenocarcinoma not otherwise specified (NOS) and highlights some of the potential reasons why mucinous tumours might be chemoresistant.

Papers 6 and 7 focus solely on the genomic basis of mucinous rectal cancer. These papers help to define the genomic landscape of this disease and highlight the similarities and differences found between mucinous rectal cancer and rectal adenocarcinoma NOS. Paper 7 describes mutational signatures for 10 cases of mucinous rectal cancer and demonstrates an association between the cases and Fusobacterium.

The final paper summarises the available evidence on the role of mucin glycoproteins in epithelial derived cancers. They appear to act through diverse mechanisms to inhibit apoptosis and promote cancer cell survival.

Funding

Beaumont Hospital Colorectal Research Fund

HSE Spark Innovation Programme

History

Associated research data files

Data is deposited at the European Genome-phenome Archive (EGA: https://ega-archive.org/). Data will be available on request upon publication from the EGA database by contacting the data access committee (Genomic Oncology Research Group DAC: EGAC00001001585) assigned for this project.

First Supervisor

Prof. Jochen H.M. Prehn

Second Supervisor

Mr John P. Burke

Third Supervisor

Dr Simon J. Furney

Comments

Submitted for the Award of Doctor of Philosophy to the Royal College of Surgeons in Ireland, 2020

Published Citation

Reynolds I,. An Investigation into the Significance of Mucin Pools following Chemoradiotherapy for Locally Advanced Rectal Cancer and an Exploration of the Molecular Basis Underlying the Resistance to Chemotherapy and Radiotherapy in Mucinous Adenocarcinoma of the Colon and Rectum [PhD Thesis] Dublin: Royal College of Surgeons in Ireland; 2020

Degree Name

Doctor of Philosophy (PhD)

Date of award

30/11/2020

Programme

  • Doctor of Philosophy (PhD)

Research Area

  • Cancer