INTRODUCTION
Cancer is the leading cause of death in children and adolescents worldwide . Every year, just above 150,000 children are diagnosed with cancer . Since a large proportion of childhood cancers in low- and middle-income countries are never diagnosed, the more realistic annual number is estimated to be at least twice as high, i.e. above 360,000 children . Given these caveats, the age-standardized incidence (ASR) of the disease, estimated at 140.6 per million person-years in children aged 0-14 years, is increasing with leukemia being the most common cancer type (ASR: 46.4) followed by central nervous system (CNS) tumors (ASR: 28.2) and lymphomas (ASR: 15.2) . Due to striking diagnostic and therapeutic advances, the number of deaths from childhood cancer has decreased by more than 50% between 1975 and 2017. Despite the high cure rates, current therapeutic modalities remain traumatic for young patients and their families with significant long-term complications. The question at stake is to what extent childhood cancer is a preventable disease that can be spearheaded as an utmost priority .
Current etiological speculations on childhood cancer involve a complex interplay between genetic factors, epigenetics and environmental influences , but there is so far little to no evidence of it. Among environmental factors, adaptation to westernized lifestyle patterns could, among others, explain the increasing prevalence of childhood cancer . There is a wealth of studies examining environmental and other non-genetic factors in relation to childhood cancer risk; yet, aside from the 10-15% of children with high-penetrance germline variation, the causes of the disease are not definitively known . Evidence is mainly compromised by specificity of exposure measurements, underpowered original research, selection bias in participation-based case-control studies, residual confounding and selective reporting of positive results, whereas systematic reviews and meta-analyses are often hampered by significant between-study heterogeneity . Thus, though some reported associations may be causal for some exposure measures, they are flawed owing to inherent biases that exaggerate their effect on cancer incidence.
Umbrella reviews have recently come to be conducted with the aim of systematic appraisal of the evidence on an entire topic across many meta-analyses of multiple putative risk factors on multiple outcomes . To our knowledge, no umbrella review has been published so far to summarize the existing evidence, appraise its quality and provide decision makers with the available, highest level of evidence relevant to the association of environmental influences on childhood cancer risk. Specifically, we performed an umbrella review of systematic reviews and meta-analyses that investigated the association between a series of environmental risk factors and the development of different types of childhood cancer aiming to explore the validity and strength of evidence, as well as potential biases and limitations of published literature.