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.