Primary content

Metabolic complications in childhood cancer survivors

Authors

D Simar (Lead)

S Eslami

R J Cohn

K Johnston

R Barres

Aims

We aimed to investigate the mechanisms responsible for the development of metabolic complications in childhood cancer survivors treated using radiotherapy.

Method

We recruited 78 childhood cancer survivors, who were 16 years or older and who had been in full remission for at least 5 years. Participants were grouped based on the use of total body irradiation (TBI) as a treatment or no irradiation (non-IRR). Anthropometric data and blood samples were collected. Lipid and glucose profiles were established and the level of insulin resistance was calculated. Circulating levels of pro and anti inflammatory cytokines were measured using a multiplex assay. Peripheral blood mononuclear cells (PBMCs) polarised activation was assessed using flow cytometry, as well as intracellular signalling activation upon mitogen activation. Global DNA methylation was measured in different PBMCs sub-types using flow cytometry.

Results

The TBI group was characterised by impaired glucose metabolism and increased prevalence of insulin resistance. The same group also showed increased circulating levels of pro-inflammatory cytokines. PBMCs from the TBI group showed a preferential Th1 polarised activation upon mitogen stimulation which was linked to increased activation of both the mitogen activation protein kinase p38, as well as mammalian target of rapamycin complex 1. We further identified that the over activation of those two signalling pathways was not due to a direct action of irradiation but rather a bystander effect. We further identified a very specific epigenetic signature in T helper and T cytotoxic cells in survivors treated using irradiation.

Implications

Our results suggest that metabolic complications in childhood cancer survivors treated using total body irradiation are linked to a systemic and long-lasting inflammation, potentially due to the hyper-activation of intracellular signalling pathways in those cells. This long-term memory effect of irradiation could be explained by epigenetic changes. These alterations could represent useful markers to support early identification of survivors at risk of developing metabolic complications.