Identifying Epigenetic Precursors Of Childhood Cancer And Associated Early - Life Exposure Factors

Akram GHANTOUS, International Agency for Research on Cancer, France
DWYER T. 1 , CROS M. 2 , DURAND G. 3 , LE CALVEZ-KELM F. 3 , HÅBERG S. 4 , CHENG MUNTHE-KAAS M. 5 , HERNANDEZ-VARGAS H. 2 , HERCEG Z. 2

1 The George Institute for Global Health, University of Oxford, Oxford, UK
2 Epigenetics Group, International Agency for Research on Cancer, Lyon, France
3 Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France
4 Norwegian Institute of Public Health, Oslo, Norway
5 Department of Paediatrics, Oslo University Hospital, Oslo, Norway

Childhood cancer, though rare, remains the first cause of disease-related death in children, with increasing incidence worldwide. Its risk factors are largely unidentified but could be predetermined during in utero development. During embryogenesis, a global redistribution of DNA methylation occurs to enable tissue differentiation. Hence, DNA methylation is a potential sensor of environmental exposures during development and may persist later in life. We profiled the genome-wide methylation levels in cord blood samples from the International Childhood Cancer Cohort Consortium (I4C), the largest mother/child birth cohort of childhood cancer.
Starting with one of the largest I4C cohorts, the Norwegian Mother and Child Cohort (MoBa), DNA methylation levels of more than 450,000 cytosines were compared (using HM450-BeadChip) between nested cases of childhood cancer (n=80, representing similar proportions of leukemias, central nervous system tumors and other tumors) and control subjects followed-up for the same time period (n=160). We identified a differentially methylated 200-bp region in leukemias relative to controls (FDR<0.05). A mean difference of 5-10% methylation was consistently found across 8 CpG sites in this region and was validated using bisulfite pyrosequencing. The observed association was not influenced by covariates such as blood cell subtype distribution, gender or birth weight. This potential epigenetic signature of childhood leukemia is currently being replicated and analyzed in relevance to early-life exposure factors in other I4C cohorts, in neonatal blood spots from a Californian birth cohort focusing on leukemia, and in the Pregnancy And Childhood Epigenetics consortium. Preliminary findings suggest a role for early-life infection, maternal smoking during pregnancy and maternal use of hormone contraception preceding pregnancy.
These findings may place DNA methylation in the causal pathways linking early-life exposures and childhood leukemia and may contribute to a ‘leap forward’ in deciphering mechanistic precursors of childhood cancer. [Acknowledgement: INSERM/INCA grant and the IARC Postdoctoral Fellowship-Marie-Curie-Actions-People-COFUND].