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Mechanisms of Chemotherapy Resistance in Mucinous Colorectal Cancer

thesis
posted on 23.06.2022, 11:25 by Emer O'ConnellEmer O'Connell

Aims: To investigate differences in expression of chemoresistance and cell death mediators between mucinous and non-mucinous CRC. 

Methods: Expression of chemotherapy resistance, cell death signalling and immune checkpoint genes was compared in mucinous and non-mucinous CRC in an open-access genetics database. A meta-analysis was performed measuring tumour response to neoadjuvant chemoradiotherapy according to expression of the fluorouracil target thymidylate synthase and the expression of thymidylate synthase was determined in an in-vitro model of mucinous rectal cancer. Cell death signalling proteins were analysed in mucinous versus non-mucinous cancer in an in-vitro model and in a tumour microarray.  

Results: Significant differences were observed in the expression of chemotherapy resistance genes between mucinous and non-mucinous CRC. SRPK1 was identified as a prognostic marker in rectal cancer. Significantly higher gene expression of immune checkpoints PD-L1 and TIM-3 was observed in mucinous CRC with mucinous status predicting expression of TIM-3. Low expression of the 5-FU target thymidylate synthase was associated with tumour response in a meta-analysis of neoadjuvant chemoradiotherapy for rectal cancer. Amplification of thymidylate synthase in response to fluorouracil was observed in a mucinous rectal cancer cell line. Significant differences in the expression of apoptotic and necroptotic proteins was observed between mucinous and non-mucinous cancer in a rectal cancer microarray and in a cell line model. 

Conclusion: Mucinous CRC is a distinct CRC subtype with molecular characteristics permitting chemotherapy resistance. These findings may inform investigation of targeted treatment in a therapeutically challenging cancer subtype. 

Funding

Beaumont Hospital Colorectal Research Trust

Bons Secours Hospital Dublin through the RCSI Strategic Academic Recruitment programme

History

First Supervisor

Prof. John. P Burke

Second Supervisor

Prof. Deborah A. McNamara

Third Supervisor

Prof. Jochen H.M. Prehn

Comments

Submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2021

Published Citation

O'Connell E,. Mechanisms of Chemotherapy Resistance in Mucinous Colorectal Cancer [MD Thesis] Dublin: Royal College of Surgeons in Ireland; 2021

Degree Name

Doctor of Medicine (MD)

Date of award

30/11/2021

Programme

  • Doctor of Medicine (MD)