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Title: Expression and DNA methylation of TNF, IFNG and FOXP3 in colorectal cancer, and association with clinico-pathological features
Author: Ganapathi , Senthil Kumar
ISNI:       0000 0004 5372 4248
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2014
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Colorectal cancer (CRC) progression is associated with suppression of host cell mediated immunity (CMI) and local immune escape mechanisms. Suppression of CMI associated cytokines (IFN-y & TNF-a) has been demonstrated in CRC. Immunosuppressive effect of T regulatory cells in solid cancers has been demonstrated with FOXP3 being identified as the most specific T regulatory cell marker. To assess the impact of immunological function upon survival in CRC and investigate the expression of TNF, IFNG & FOXP3 and their epigenetic regulation in CRC. Methods Sixty patients with CRC were recruited. TaqMan quantitative PCR (qRT-PCR) was performed for relative quantitation of expression of TNF, IFNG and FOXP3 in the PBMC and tumour samples. Methylation specific PCR (MSPCR) was performed to determine the DNA methylation status. Survival analysis was performed using Kaplan-Meier method and Cox regression models. Results TNF was suppressed in tumour tissue and IFNG was suppressed in the PBMC of patients with CRC. IFNG suppression in PBMC was significant in recurrent CRC. Tumour tissue showed enhanced expression of FOXP3 and had a positive correlation with tumour size. Methylated TNFprom0 ter, TNFexonl and FOXP3cpg correlated significantly with suppression of TNF and FOXP3 respectively. Significant TNF suppression was noted in the PBMC of patients with MSI. A suppressed FOXP3 in PBMC was associated with poor overall survival. Tumour vascular invasion (VI) was associated with enhanced expression of TNF. While VI is associated with adverse prognosis in CRC, its presence is an independent predictor of poor survival in younger patients. Conclusion Specific patterns of TNF, IFNG and FOXP3 expression correlate with tumour progression. DNA methylation appears to influence the expression of TNF and FOXP3. Further quantitative analyses are needed to confirm the findings. We have detected changes in the immunomodulatory genes that could act as biomarkers for prognosis and future immunotherapeutic strategies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available