Telomere dynamics in children undergoing cancer treatment and the relationship between telomere length and treatment outcome

Abstract

Telomeres are specialised DNA structures that protect the ends of linear chromosomes, and their length is important for cell viability. Telomere length declines with age, and there is a large variability seen within the general population. Patients with short telomere disorders (STD) suffer increased toxicity from chemotherapy given for haematopoietic stem cell transplant (HSCT), however little is known of the relationship between telomere length, outcome and toxicity in the general population undergoing chemotherapy. This thesis shows that patients with STDs have poor short- and long-term outcomes following HSCT with mortality mostly due to pulmonary disease or infections. To define the relationship between telomere length and outcome in patients receiving therapy for cancer, we undertook retrospective analysis of outcome and telomere dynamics in children who had undergone HSCT, treatment for childhood acute lymphoblastic leukaemia (ALL) and who were long term survivors of childhood cancer. Children undergoing cancer treatment have an acute decline in telomere length at the time of cancer therapy, however there is no evidence that this telomere attrition continues in the long term, with the exception of patients with some cancer types, and who received certain specific chemotherapy agents. Patients undergoing HSCT or treatment for ALL with shorter telomere length have higher rates of specific organ toxicity and certain infections. However there does not appear to be any relationship between telomere length and significant late effects from childhood cancer, aside from avascular necrosis. These findings highlight the complex relationship between telomere length and cancer therapy. They require further confirmation in prospective clinical trials, and in a wider population with differing initial malignancies, and undergoing different chemotherapy regimes in order to better define the complex relationship between telomere length, chemotherapy and outcome.