4. DISCUSSION
Childhood cancers are a multifactorial group of disease that have both
genetic and environmental causes. Many studies on the causes of
childhood cancers have limitations due to the rare occurrence of these
cancers, reliance on retrospective evaluation based on parental
statements, which can lead to biases in recalling and reporting, and
inability to design appropriate studies due to the presence of multiple
factors in the cancer mechanism 6,7. For this reason,
there are studies in the literature containing many different results on
risk factors that may play a role in the etiology of childhood cancers6-10. Therefore, we aimed to account for as many
confounding factors as possible in order to evaluate the effect of ETS
exposure on childhood cancers in details.
In our study, we observed that a positive family history of malignancy
was present in 51% of the case group while 36.4% of the control group
(p < 0.05). Among the cancer patients 9.1% of individuals
with malignancy were first-degree relatives, whereas 90.8% were
second-degree or more distant relatives. In contrast, all individuals
with malignancy in the control group were second degree or more
distantly related. Considering that environmental and hereditary factors
play a role in the etiology of cancer, it was an expected finding that
the rate of relatives with malignancy in cancer patients was
significantly higher.
Greaves and Kinlen suggested that early exposure to infection,
especially during and before infancy, reduces the risk of developing
leukemia 8. They stated that children who attend
kindergarten and have an older sibling are more likely to encounter such
infectious agents at an earlier and more frequently, and this will
reduce the risk of developing leukemia. Although there are both
supportive and contradictory findings regarding this claim. In our
study, revealed a significant disparity between the case and control
groups with regard to the proportion of children who had at least one
older sibling, it was significantly higher in case group(59.6%; n=59)
than the children in the control group (36.7%; n=36) (p <
0.05).
This finding does not support Greaves and Kinlen’s hypothesis. Present
study showed that a significantly higher percentage of patients in the
case group (13%) resided in rural areas compared to those in the
control group (1%) (p < 0.05).This would be inconsistent with
Greaves and Kinlen’s hypothesis of early exposure to infection, assuming
that rural residents may be infected more frequently and earlier;
however, an increased risk of insecticide and pesticide exposure or
exposure to other pathological infectious agents may explain the higher
rate of rural living in cancer patients. The fact that many infectious
agents are no longer present and undetectable at the time of diagnosis
makes it very difficult to evaluate the cancer-infection relationship.
For this reason, it may be useful to question indirect indicators such
as birth order, whether he went to a kindergarten, a history of
infection requiring hospitalization, and where he lived.
The fact that cigarettes contain many carcinogenic and toxic substances
and that these substances are detected in fetal blood, placenta, and
urine of exposed children lead us to consider smoking as a possible risk
factor in the etiology of childhood cancers 2. The
most important source of children’s exposure to cigarette smoke is
parental smoking. For this reason, many studies on this subject focus on
smoking behaviors of parents 1,2,6,11-14. The fact
that smoking has been demonstrated to cause damage to almost every cell
and tissue by various mechanisms including DNA damage, epigenetic
changes, oxidative damage, inflammation among others, it is crucial to
evaluate the consequences of smoking from the prenatal stage. In our
study, pre-conceptional, during pregnancy and current smoking status of
the mother and father were examined in the case and control groups. In
the United Kingdom Childhood Cancer Study, the pre-conceptional period
was considered as the one-year period before the pregnancy of the index
case and was accepted as such in our study 2. For this
reason, parents were also asked whether they smoked regularly at any
time in their lives, and their smoking behaviors outside of these three
periods were also taken into account.
In a retrospective cohort study published by Kessous et al. in 2019, an
increased risk of benign neoplasm (hemangioma, thyroid cyst, etc.) was
found in the children of mothers who smoked during pregnancy; however,
no increased risk of malignant neoplasm was detected14. In a cohort study conducted in Canada between 2006
and 2016, children whose mothers’ used alcohol, drugs and cigarettes
during pregnancy were examined. Maternal smoking during pregnancy was
associated with the risk of AML and fibrosarcoma, and weakly associated
with neuroblastoma and renal tumors 11. A Danish study
found no association between maternal smoking during pregnancy and an
increased risk of childhood cancer 12. We found no
difference between the case and control groups in terms of
pre-conceptional, during pregnancy and current smoking behaviors of the
mother according to questionnaire (p > 0,05).
In our study, more than half of the fathers in the case and control
groups were smokers, and there was no significant difference between two
groups in this regard. All fathers who smoked during the
pre-conceptional period continued to smoke during pregnancy in both
groups. The rate of fathers who smoked in the pre-conceptional period
and during pregnancy in the control group (75.8%) was significantly
higher than the cancer group (61.7%) (p < 0.05). At the same
time, 81.8% of the fathers in the control group stated that they used
to smoke regularly in any period of their lives, and this rate was
significantly higher than the cancer group (68.1%) (p<0.05).
It would be wrong to interpret this situation as paternal smoking has a
protective effect on childhood cancers. As our objective measurement
findings show and we will talk about later, this may be a manifestation
of subjective methods such as surveys that can cause biases or a result
of our small sample size. Social desirability bias of cancer patients’
parents and socio-economic differences between two groups may also be a
reason.
Many methodological limitations make it difficult to establish a
relationship between childhood cancers and ETS exposure. Therefore, we
evaluated ETS exposure with the measurement of cotinine, which is an
objective marker. According to questionnaire data, the ETS exposure rate
of children with cancer (68.8%) was found to be significantly lower
than the rate of children in the control group (83.8%)
(p<0.05). Many studies define ETS exposure as ’cigarette
smoking in the child’s environment’ 15. The American
Academy of Pediatrics, on the other hand, defines a person’s exposure to
second-hand and/or third-hand cigarettes as ”involuntary exposure to
tobacco smoke” 16. As we mentioned before, the
children in the study were considered to have exposure to ETS in the
presence of at least one of the smoking conditions of their mother,
father, another individual in the house or another individual (friend,
etc.) whom they frequently encounter. However, the extent of exposure to
cigarette smoke depends on many factors such as the number of smokers,
the amount of cigarettes smoked, proximity to smokers, the size of the
environment and ventilation conditions, and the duration of exposure17. The fact that the definition of ETS exposure does
not cover these factors may be a reason for the higher ETS exposure in
the control group.
Cotinine is the primary metabolite of nicotine and is the most reliable
biomarker of tobacco smoke exposure according to Benowitz et al17. Cotinine levels can be measured from blood,
saliva, urine and hair. Plasma, saliva, and urine measurements cannot
detect long-term exposure due to their short half-lives, leading to
difficulties in sample storage. In contrast, hair cotinine analysis
allows for cross-sectional and long-term cumulative evaluation as
cotinine accumulates in the hair shaft as hair grows. While individual
differences such as age, gender and race may impact cotinine metabolism,
the meta-analysis of Florescu et al. aimed to determine the most
suitable hair cotinine threshold value for certain age groups and
pregnant women. The results of meta-analysis suggest that 0.2 ng/mg is
the most appropriate for distinguishing children exposed to ETS based on
its high sensitivity and specificity 5. The mean
cotinine value of the case group was found to be 0.224±0.088 ng/mg, and
the mean cotinine value of the control group was 0.136±0.048 ng/mg. Hair
cotinine levels were found to be significantly higher in children with
cancer (p<0.001). When the exposure to ETS was evaluated with
the hair cotinine analysis, 59.4% of the children with cancer and
14.1% of the children in the control group were found to be exposed to
cigarette smoke according to the threshold value. Cotinine analysis
shows that ETS exposure was significantly higher in cancer patients
(p<0.001). Our findings support the prediction that smoking
may be among the factors that cause childhood cancers.
In conclusion, in this study, which we evaluated the cigarette smoke
exposure of 104 children with cancer and 99 children without cancer
diagnosis, using a questionnaire and hair cotinine levels, supports the
idea that parental smoking may cause childhood cancer. As seen in this
study, the evaluation of cigarette smoke exposure by subjective methods
such as questionnaires can cause biases. Hair cotinine analysis is a
good test in the evaluation of cigarette smoke exposure, as it is an
easy to apply, non-invasive test and also shows cross-sectional and
long-term exposures. We believe that the use of hair cotinine analysis
together with valid and reliable questionnaires in studies aimed at
evaluating the effects of smoking on childhood cancers would prove
highly beneficial in preventing biases.