DNA methylation, cell differentiation and genetic factors involved in radiosensitivity

• Main Author: Giotopoulos, George
• Other Authors: Dubrova, Yuri
• Published: University of Leicester 2009
• Subjects: 616.9940642
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492789

Despite its benefits in cancer treatment, ionising radiation (IR) can induce a series of adverse acute and/or long term effects. Studies on A-bomb survivors and radiotherapy patients have shown that acute whole-body exposure results in an increased risk for radiation-induced Acute Myeloid Leukaemia (r-AML), a bone marrow (BM) malignancy; whereas local-radiotherapy patients run the risk of developing acute and/or long term normal tissue reactions. Irradiated BM cells manifest persistent radiation-induced genomic instability. BM is one of the most susceptible tissues to radiation-induced cancer and one of the most radiosensitive tissues, which proposes a link between cancer susceptibility, genomic instability and radiosensitivity. The exact mechanism by which exposure of BM cells to IR leads to malignant transformation is still unclear, but the non-targeted nature of radiation-induced damage and genomic instability could suggest that an epigenetic mechanism is also involved; and DNA methylation is a good candidate. This thesis investigated genetic and epigenetic factors that may be involved in biological responses to ionising radiation exposure. Stem cell frequency is genetically determined in mouse haemopoiesis and is possibly part of the equation that defines cancer risk. Global DNA methylation levels were assessed in control haemopoietic tissues and radiation-induced leukaemias. The methylation status of haemopoietic malignancies reflects that of their untransformed tissue. Additionally, DNA methylation levels of untransformed haemopoietic tissues were found to correlate with their relative radiosensitivity in vivo. In vivo responses to ionising radiation were found to be under the influence of both genetic and epigenetic factors, highlighting the complexity of such biological reactions.