CONTRIBUTIONS OF VIRAL AND CELLULAR GENE PRODUCTS TO THE PATHOGENESIS AND PROGNOSIS OF AGGRESSIVE LYMPHOMAS

A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of PhilosophyHigh grade aggressive lymphomas have high mortality. By their nature, more than 40% of patients die from these diseases even with the improved treatment strategies currently available for oncology patients. The characteristic feature is that they are functionally heterogeneous and therefore have different biological and molecular signatures which make it difficult for all groups to respond to same line of treatment. Based on the above, I set out to look at the impact of viral and cellular gene products on these groups of diseases: In chapter 3 I developed monoclonal antibodies against HERV‐K10. I subsequently investigated their expressions in aggressive lymphomas including Diffuse Large B‐cell lymphoma, Hodgkin’s lymphoma and Primary CNS lymphomas. I showed HERV‐K10 is expressed in cell lines of aggressive lymphomas, but not in paraffin‐embedded tissues. In chapter 4 I showed that the expression of ATM using immune‐histochemistry techniques in aggressive lymphomas does offer a guide to prognosis and treatment. Nearly 30% of Diffuse Large B‐cell lymphomas express ATM, 55% of Hodgkin’s lymphomas and more than 80% of Primary CNS lymphomas. I also showed there is a correlation of ATM expression and EBV‐driven aggressive lymphomas and that this has a poor prognostic significance. Chapter 5 analysed the results obtained by generating, validating and evaluating data base of DLBCL and PCNSL from a retrospective cohort over a 17‐year period. The results confirmed that prognostic indicators including ATM, S1PR2, Autotaxin and EBV using immuno‐histochemistry techniques help with categorising aggressive lymphomas into different prognostic groups and does influence future management. In summary, my results showed there is a critical place for immuno‐histochemistry techniques in convincingly helping understand the expressions of viral and cellular gene products in aggressive lymphomas and in contributing positively to their management.Cancer Studies, University of Birmingha