J Canep 2014 07 006

Review
Epidemiology of childhood leukemia in the presence and absence

of Down syndrome
Gabor Mezei
a,
*, Madhuri Sudan
b
, Shai Izraeli
c,d
, Leeka Kheifets
b
a
Exponent Health Sciences, 149 Commonwealth Drive, Menlo Park, CA 94025, United States
b
Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E. Young Drive South, Los Angeles, CA 90095, United States
c
Sheba Medical Center Tel-Hashomer, Ramat Gan 52621, Israel
d
Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel
1. Introduction
Leukemia is the most common cancer among children, and it
accounts for one-third of all childhood cancers [1,2]. Its reported
incidence has increased over the past several decades, and it is
hypothesized that changes in risk factors may play a role in this
increasing trend [3]. Childhood leukemia is mostly a develop-
mental accident during fetal hematopoiesis and may require
multiple prenatal and postnatal hits. Although some of these hits
may be related to environmental exposures, the only generally
accepted risk factor (ionizing radiation) explains only a small
fraction of childhood leukemia cases. Additional environmental
exposures, such as extremely low frequency (ELF) magnetic elds
[4] and chemical carcinogens [5], have also been extensively
investigated, but signicant uncertainty remains regarding the
causality of these associations. Most previously published epide-
miologic studies of childhood leukemia employed a casecontrol
design with inherent uncertainty due to the potential for selection
bias and, in many studies, recall bias and reverse causality [6,7]. To
gain further insight into the role of potential environmental
carcinogens in the development of childhood leukemia, new
approaches are needed. Due to the rarity of childhood leukemia
and rarity of high levels of many environmental exposures, cohort
studies in the general population remain unfeasible for most
exposures. A cohort study within a population of children with an
elevated risk of leukemia, however, could bypass the problem of
disease rarity and may be a feasible new approach [8]. Children
with Down syndrome (DS) may serve as a population for this type
of cohort study. DS is a common congenital anomaly, and affected
children are signicantly more likely to develop leukemia than
Cancer Epidemiology xxx (2014) xxxxxx
A R T I C L E I N F O
Article history:
Received 3 March 2014
Received in revised form 10 July 2014
Accepted 11 July 2014
Available online xxx
Keywords:
Acute leukemia
Down syndrome
Childhood leukemia
Etiology
Children
A B S T R A C T
Down syndrome (DS) is a common congenital anomaly, and children with DS have a substantially higher
risk of leukemia. Although understanding of genetic and epigenetic changes of childhood leukemia has
improved, the causes of childhood leukemia and the potential role of environmental exposures in
leukemogenesis remain largely unknown. Although many epidemiologic studies have examined a
variety of environmental exposures, ionizing radiation remains the only generally accepted
environmental risk factor for childhood leukemia. Among suspected risk factors, infections, exposure
to pesticides, and extremely low frequency magnetic elds are notable. While there are well-dened
differences between leukemia in children with and without DS, studies of risk factors for leukemia
among DS children are generally consistent with trends seen among non-DS (NDS) children.
We provide background on DS epidemiology and reviewthe similarities and differences in biological
and epidemiologic features of leukemia in children with and without DS. We propose that both acute
lymphoblastic and acute myeloblastic leukemia among DS children can serve as an informative model
for development of childhood leukemia. Further, the high rates of leukemia among DS children make it
possible to study this disease using a cohort approach, a powerful method that is unfeasible in the
general population due to the rarity of childhood leukemia.
2014 Elsevier Ltd. All rights reserved.
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia;
COG, Childrens Oncology Group; DS, Down syndrome; ELF, extremely low
frequency; ML-DS, myeloid leukemia subtype specic to Down syndrome; NDS,
non-Down syndrome; TAM, transient abnormal myelopoiesis; TMD, transient
myeloproliferative disorder.
* Corresponding author. Tel.: +1 650 688 7341.
E-mail address: gmezei@exponent.com (G. Mezei).
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CANEP-734; No. of Pages 11
Please cite this article in press as: Mezei G, et al. Epidemiology of childhood leukemia in the presence and absence of Down syndrome.
Cancer Epidemiology (2014), http://dx.doi.org/10.1016/j.canep.2014.07.006
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unaffected (NDS) children [9]. We provide background on DS
epidemiology and review the similarities and differences in
epidemiologic features of leukemia in children with DS (DS-
leukemia) and without DS (NDS-leukemia). This is a rst attempt
to evaluate whether ndings in a DS cohort could be extrapolated
to the general population of children to shed new light onto the risk
factors of childhood leukemia.
2. Epidemiology of Down syndrome
DS is caused by an extra copy of chromosome 21 (trisomy 21). In
most cases, trisomy 21 results from abnormal chromosome
segregation during gamete formation (meiotic nondisjunction).
Less than 5% of DS cases are due to chromosome 21 translocations,
and a small fraction is due to somatic mosaicism [10].
DS is generally characterized by decits in learning, memory,
and language leading to overall cognitive impairment [11]. DS
individuals also have elevated risks for a multitude of other health
problems including early-onset Alzheimers disease, ocular pa-
thology, congenital heart defects, neurological problems, infec-
tious diseases, thyroid disorders, ulcerative colitis, celiac disease,
type 1 diabetes mellitus, alopecia areata, hearing loss, and
leukemia [1114]. Mortality among individuals with DS is about
510 times higher than mortality in the general population [15,16].
The excess mortality shows a decreasing trend in more recent
decades. Hospitalization is estimated to be 23-fold higher among
DS individuals compared to the general population. Higher
hospitalization rates, particularly among those under 20 years of
age, are primarily for malformations, respiratory and nervous
system diseases. Hospitalization for neoplasms and musculoskel-
etal diseases are less frequent among adults with DS than in the
general populations.
The live birth prevalence of DS has increased around the
world in the past few decades. In the United States, the live
birth prevalence of DS rose from 9.2/10,000 live births during
19831990, to 12.94/10,000 live births during 19992001, and
to 13.56/10,000 live births by 20042006 [1719]. Similar
increasing trends have been seen in many countries including
Norway, Hungary, Canada, the UK, and Japan [2023].
The rising live-birth prevalence of DS is likely due, at least
partially, to the increasing number of women having children later
in life, as advanced maternal age is the most important risk factor
for having a child born with DS (Fig. 1) [2426]. Due to the
increased role of prenatal screening and selective termination of
affected pregnancies, the prevalence of DS at birth varies by
cultural factors, ethnic background, religious beliefs and socioeco-
nomic status (SES) of the mothers. In the United States, infants of
Hispanic mothers have higher live-birth prevalence of DS
compared to Whites and Blacks [18,27]. Women in lower SES
categories are also more likely to give birth to a child with DS [28].
Religious and cultural differences are also likely to play a role, as
exemplied by low rates of screening and elective terminations of
pregnancies in certain countries and communities [29,30].
3. Leukemia among children with Down syndrome
Prevalence of DS varies around 2% among cases of acute
lymphoblastic leukemia (ALL), and the prevalence of DS among
acute myeloid leukemia (AML) cases is even higher (214%) [31
33]. This is signicantly higher than the prevalence of DS (around
0.1%) at birth in the general population. Thus, DS is associated with
a relative risk of about 2040 for childhood leukemia. In contrast
to leukemia, children and adults with DS very rarely develop solid
tumors compared to the general population [34,35].
Trisomy 21 is the dening feature of DS. It may be assumed that
this trisomy may also play a role in leukemia development among
DS children. Yet the mechanisms by which constitutional trisomy
21 predisposes to leukemia are unclear. Interestingly, acquired
trisomy of chromosome 21 is also a common feature in many ALLs
of NDS children [1]. However, the myeloid and lymphoid
leukemias among DS children differ markedly in their clinical,
biological and genetic features as compared to leukemias among
Fig. 1. Down syndrome live births compared to percent of mothers 35 years or older at birth by year in the United States. Note: This gure was created using U.S. birth
certicate data from the National Vital Statistics System for 19902010 [177]. Many cases of DS in the U.S. are not recorded on birth certicates, and therefore these data do
not accurately reect the total live birth prevalence of DS. However, this gure provides a basis for evaluating the overall trend in DS live births relative to maternal age.
G. Mezei et al. / Cancer Epidemiology xxx (2014) xxxxxx 2
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NDS children. These leukemias arise on the background of altered
hematopoiesis in DS children, in particularly during fetal
development. Thus fetal liver hematopoiesis in DS is characterized
by enhanced mega-erythro-poiesis and a partial block in B cell
development [3638]. These abnormalities and the immunode-
ciency in children with DS may predispose them to leukemogenic
mutations.
DS children have substantially higher risk of a specic subtype
of myelodysplastic syndrome and acute megakaryocytic myeloid
leukemia for which studies have reported relative risks as high as
175600 [39,40]. Thus myeloid leukemia among DS children
received a unique classication by the WHO (ML-DS) [39]. ML-DS
evolves in two distinct clinical stages, a transient congenital
leukemic syndrome that is followed, in 20% of the children, by full-
blown leukemia by the age of four years [41]. Up to 10% of DS
neonates develop a pre-leukemic megakaryoblastic disorder
termed transient myeloproliferative disorder (TMD), or tran-
sient abnormal myelopoiesis (TAM) within the rst few weeks of
life. This is a transient phenomenon that lasts for up to three
months, although up to 15% of these neonates succumb to death,
mostly from liver failure. Uniquely in children with DS, these
megakaryoblasts carry somatic mutations in the megakaryocytic
X-linked transcription factor GATA1. TMD, therefore, results from
cooperation between the congenital trisomy 21 and an acquired
somatic mutation in GATA1 that occurs in utero in a hematopoietic
precursor cell in the fetal liver. This genetic collaboration leading to
a TMD-like syndrome has recently been modeled in transgenic
mice [42]. Remarkably, although the incidence of clinical TMD in
DS is 510%, acquired mutations can be detected in up to 30% of all
DS newborns [43]. Nothing is known today about any intrinsic or
environmental factors leading to the exceedingly high rate of these
mutations.
In one of every ve DS children with TMD, remission is
eventually followed by acute myeloid leukemia (ML-DS) before the
age of four years. This leukemia is of the megakaryocytic
phenotype and is often preceded by a prolonged phase of
myelodysplasia. The leukemia is associated with the acquisition
of many different somatic mutations, mainly in signaling and
epigenetic pathways [44]. Importantly, the pattern of myeloid
leukemia development in children with DS is reminiscent of the
model for pathogenesis of childhood ALL (and probably also of
childhood AML) (Fig. 2). This general model, conrmed by many
molecular studies [4551], assumes an initiating somatic hit
occurring in utero in a fetal hematopoietic cell that causes the
proliferation of a pre-leukemic clone. Unlike in DS-TMD, this pre-
leukemic clone in NDS ALL is not manifested clinically by
accumulation of blasts in the peripheral blood at birth, but can
be detected using molecular methods. A fraction of children born
with this abnormal clone of cells will develop ALL during childhood
due to the occurrence of additional genetic and epigenetic events
in the pre-leukemic cells. Thus, although the myeloid leukemias of
DS are unique, their two-stage pathogenesis is highly similar to the
pathogenesis of the most common childhood leukemias. Therefore,
in both types of leukemias environmental risk factors may impact
either the initiation of pre-leukemia in-utero or the progression to
leukemia after birth.
The relative risk of ALL among DS children (DS-ALL) is also
markedly increased and varies from 15 to 60 compared to NDS
children [14,40,52]. These leukemias are almost always of the B cell
phenotype (similar to the most common immunophenotype of
NDS-ALL). In contrast to the myeloid leukemias, DS-ALL is very
rarely seen in children before 1 year of age. The age distribution of
DS-ALL cases, however, appears to be comparable to NDS ALL cases,
peaking at about 5 years of age [14,40,52,53].
Genetically DS-ALLs are heterogeneous and consist of multiple
biological subtypes. The most common cytogenetic subtypes of
childhood ALL, ETV6-RUNX1 and high hyperdiploidy, together
account for 55% of sporadic childhood B cell precursor ALL among
NDS children, but are less prevalent in DS-ALL (15%) [53,54]. Yet,
given that the total risk for ALL in DS is substantially higher, there
seems to be an absolute increase in risk for these typical
cytogenetic groups of childhood ALL as well. On the other hand,
60% of DS-ALLs carry a submicroscopic genomic rearrangement
leading to expression of the cytokine receptor CRLF2. Often there
are additional mutations in cytokine receptors and in the
downstream JAKSTAT signaling pathway [5559]. The prevalence
of this CRLF2 subtype of childhood B cell precursor ALL in
children without DS is 610% [6063]. Thus the same cytogenetic
aberrations can be found in DS and NDS ALLs, although their
frequency differs.
The prognosis of DS-ALL is worse than NDS-ALL due to
increased risk of relapse and treatment-related mortality. Inter-
estingly, however, the prognostic factors, such as age, white cell
count at diagnosis, and specic cytogenetic subgroups are similar
in children with and without DS [53,6466].
4. Risk factors for leukemia among children with Down
syndrome
We identied all studies in the literature that examined risk
factors for leukemia specically among children with DS by
searching for publications in PubMed using search terms Down
syndrome or Trisomy 21 and leukemia or leukaemia. Only
twelve studies, conducted by two research teams, were identied
Fig. 2. Model of leukemogenesis in Down syndrome AML and non-down syndrome ALL.
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that examined risk factors for leukemia among children with DS.
Studies among NDS children that examined the same risk factors as
the DS studies were also identied in PubMed using search terms
leukemia or leukaemia and risk factors or etiology or
aetiology or specic risk factor categories (e.g., infection, birth
weight, pesticide, etc.). Our purpose is to compare risk factors
for childhood leukemia between children with DS and children
without DS. Therefore, only the studies among NDS children that
presented results for the same childhood leukemia risk factors as in
the DS studies were selected. All studies that satised the selection
criteria are reviewed here.
Eight publications were based on registration les of the
Childrens Oncology Group (COG) from 116 participating institu-
tions and included 210 DS leukemia patients living in North
America and diagnosed with acute leukemia before age 20 years.
Of these, maternal interviews were completed for 97 DS-ALL and
61 DS-AML cases. Controls were randomly selected from a roster of
DS children with no history of leukemia provided by primary care
clinics that treated the cases. Telephone interviews were
completed for 173 DS-control mothers [6774].
We identied four publications that ascertained DS-leukemia
cases from among the 9 public institutions in Mexico City that treat
children with cancer [7578]. DS controls were identied from
special education centers in Mexico City that work with children
with disabilities. The time periods, enrollment centers, and
inclusion criteria varied somewhat among the four publications.
The study populations, which likely overlapped between studies,
included 2797 DS-leukemia cases and 58222 DS-controls. In the
Mexico City publications, results for DS-AML were not presented
separately from DS-ALL. Where results from multiple studies were
reported for the same risk factor, we included the study with the
most complete information.
4.1. Reproductive factors
Two studies reported slightly elevated risks of NDS-ALL with
the use of oral contraceptives [79,80] (Table 1). One of these
investigations also examined a variety of other contraceptives and
observed no associations with most contraceptive methods, which
is in line with the results for DS-leukemia. The COG study found
that the use of most contraceptives did not alter the risk of DS-
leukemia, but there was a pattern of reduced risk for both DS-ALL
and DS-AML in relation to oral contraceptive use [68].
Pregnancy loss, difculty becoming pregnant, use of fertility
treatments or drugs to maintain pregnancy, and a long interval
since the last live birth all increased the risk of NDS-ALL in a
number of investigations [7987]. One study reported an increased
risk of acute leukemia with the use of hormonal fertility treatments
[83]. Other studies found no association with prior pregnancy loss
[83,86,88], and one reported a reduced risk of NDS-ALL in relation
to prior miscarriage [89]. The COG study observed associations
between various measures of reduced fertility and DS-leukemia
[68]. An earlier study from the COG reported similar unadjusted
results for DS-leukemia in relation to the mothers number of fetal
losses [71]. Associations between DS-leukemia and mothers live
birth interval were not apparent in the COG study [68].
Prenatal maternal health factors, such as hypertension, urinary
tract infections, gestational diabetes, and amniocentesis, have
Table 1
Reproductive risk factors for childhood leukemia comparing studies among NDS and DS children.
Relative risk estimates
d
Comments
ALL AML
NDS DS NDS DS
Contraception
a
1.11.3 0.51.7 0.61.2 Oral contraceptives are associated with a slight increase in risk of
NDS-ALL, but this trend is not seen for DS-ALL. Range of point
estimates for overall contraception is similar between NDS-ALL
and DS-ALL. No NDS-AML studies are available for comparison.
Fertility/reproduction
b
0.62.6 0.82.2 1.02.3 1.42.8 There is some indication that difculty becoming pregnant,
maintaining pregnancy, infertility treatment, and long live birth
interval may be associated with an increased risk of NDS-ALL.
There is not enough information to conrm this trend in DS-ALL
studies, although mothers who had more than one previous fetal
loss or tried for longer periods to become pregnant tended to be
more likely to have a child with DS-ALL. There is a trend of
increased AML-risk in association with these factors for both NDS
and DS.
Prenatal conditions/procedures
c
0.61.3 0.40.9 0.82.2 0.52.1 No apparent pattern in associations for NDS or DS leukemia and
prenatal health conditions/procedures.
Older maternal age 0.81.3 1.24.5
e
0.91.2 2.12.6 Older maternal age is not clearly associated with NDS-ALL or NDS-
AML, but studies among DS children reported an increased risk of
DS-leukemia in relation to advanced maternal age (particularly
with DS-AML).
Birth weight 1.21.7 0.92.5
e
1.21.5 2.53.1 Higher birth weight is associated with an increased risk of NDS-
ALL and NDS-AML across several studies. The pattern is similar in
studies among children with DS.
Congenital abnormality 1.11.4 0.8 2.3 1.2 NDS-AML is associated with congenital abnormalities based on 1
study (others included DS children). Some evidence for possible
association between congenital abnormalities and NDS-ALL, but
the number of studies is limited. Additional congenital
abnormalities do not appear to increase the risk of DS-ALL or DS-
AML.
a
Includes oral, implant, and injectable contraceptives, barrier method, rhythm method, spermicides, and other contraceptives.
b
Includes failed pregnancy, fertility treatment and infertility, and live birth interval.
c
Includes prenatal hypertension/preeclampsia, prenatal UTI/bladder infection, gestational diabetes, amniocentesis, and prenatal vaginal bleeding.
d
Range of relative risk estimates across studies.
e
Includes results from Mexico City studies that presented point estimates for DS-ALL and DS-AML combined, but greater than 80% of cases were DS-ALL.
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been examined by several studies in relation to childhood
leukemia. No associations were detected among NDS children or
DS children [70,86,88,9092].
Advanced maternal age at birth is of interest in relation to
childhood leukemia, but ndings from NDS studies have been
inconsistent for ALL [79,82,8890,9396]. The results are just as
inconsistent for other types of NDS-leukemia in children
[86,90,9294,96].
On the other hand, most studies among DS children suggest a
trend of increasing leukemia risk with older maternal age at birth,
particularly for DS-AML [68,75]. Several other studies reported
unadjusted results relating maternal age to childhood leukemia
[67,69,71,73,76,77], and two of these investigations found an
increased risk of DS-AML with older maternal age, but no clear
association with DS-ALL [67,69].
High birth weight and large size for gestational age are
associated with increased risks for both ALL and AML in children
based on several NDS studies, including two meta-analyses [97
101]. Most investigations among DS children reported unadjusted
results for birth weight that are consistent with the NDS ndings
[67,69,76,77].
Increased risks for both ALL and AML in children have been seen
in many studies in relation to congenital malformations [40,85,102
109]. Most of these studies did not exclude children with DS, and
therefore much of the risk increase could be attributed to trisomy 21.
However, some authors noted that excluding children with DS did
not remove the associations [85,103,107109]. Linabery et al.
concluded that, among DS children, other congenital malformations
contributed no additional risk for childhood leukemia beyond the
risk attributable to trisomy 21 [74].
4.2. Immune system/infections
Various forms of infection and the bodys response to infection
are hypothesized to play a role in childhood leukemia etiology
(Table 2). Two main hypotheses were proposed to explain the
potential role of infection in childhood leukemia development.
According to the population mixing hypothesis put forth by
Kinlen [110], childhood leukemia may develop as a rare response
to a relatively common infection when new infections are
introduced by inux of new residents to a previously isolated
population. According to the delayed infection hypothesis
proposed by Greaves [111], infections in early childhood enable
the normal development of the immune system. Relative lack of
early infections in modern societies may predispose the immune
system for aberrant reaction when the infection occurs later in life.
Resistance to growth inhibitory cytokines (e.g., TGF beta or
Interferon) is suggested to give a growth advantage to existing pre-
leukemic clones predisposing to progression to frank leukemia
[112,113]. This hypothesis may be particularly relevant to the
evolvement of DS-ALL since the immunodeciency in DS was
reported to be associated with increased sensitivity to interferon
[114116].
Several studies have suggested that infections in childhood
could play a protective role against the development of childhood
leukemia [88,117120], whereas others reported the opposite
[121123] or produced a wide range of results that have tended to
be imprecise and uninformative on their own [87,124128].
However, a recent meta-analysis found that day-care attendance,
which is thought to be associated with earlier and more frequent
common infections in early childhood, appeared to reduce the rate
of childhood leukemia [129]. In the COG, children who had
infections early in life had lower odds of developing DS-ALL and
DS-AML [73]. This is in contrast to one study from Mexico City that
reported elevated odds of DS-ALL and DS-leukemia in general
among children who were hospitalized for infection, or had any
infection, during their rst year of life [77]. A more recent study
from Mexico City found no association of DS-ALL or DS-leukemia in
general with this risk factor [78].
The association between birth order (a potential indicator of
early infections) and leukemia also remains unclear. Most studies
reported reduced risks of NDS-ALL with higher birth order and
increased maternal parity, although some results were imprecise
[8183,85,93,94,124,130132]. Other investigations reported an
increase in ALL risk [79,86,91,117] and a potential increase in AML
risk with higher birth order [90,92,93,130]. The picture for DS-
leukemia is similar. The COG investigations did not observe
associations with birth order [6769,73], but studies from Mexico
City reported a pattern of increased risk of DS-leukemia (mostly
ALL) with increased birth order [75,77,78].
Breastfeeding is known to protect against some early-life
infections, and evidence from several studies suggests a protective
Table 2
Immune system and infection-related risk factors for childhood leukemia comparing studies among NDS and DS children.
b
Comments
ALL AML
NDS DS NDS DS
Infections 0.43.9 0.53.5 0.46.0 0.6 Most studies indicate a reduced risk of NDS-ALL with exposure to
early-life infections, while no pattern emerges for DS-ALL. Point
estimates for NDS-AML are mixed, and information for DS-AML is
limited.
Asthma/allergies 0.51.7 0.34.2
c
0.61.1 Most studies reported a reduced risk of NDS-ALL in relation to
asthma and allergies. Studies of DS-ALL also tend to report a
reduced risk in relation to allergies. No clear pattern emerged for
NDS-AML, and no studies reported results for DS-AML in relation
to allergies and asthma.
Higher birth order
a
0.62.0 0.73.1
c
0.82.5 0.51.0 Point estimates for NDS-ALL varied across studies, but most
reported negative trends with higher birth order associated with
lower risk of NDS-ALL. No clear pattern emerged for DS-ALL, NDS-
AML or DS-AML.
Breastfeeding 0.61.5 0.71.3
c
0.71.3 0.7 Most studies indicate a reduced risk of NDS-ALL and NDS-AML
with increased breastfeeding. Information for DS-ALL and DS-AML
is limited, but not inconsistent with the results for the general
population.
a
Combines point estimates for >1st born, >2nd born, and >3rd born.
b
c
Includes results from Mexico City studies that presented point estimates for DS-ALL and DS-AML combined, but greater than 80% of cases were DS-ALL.
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effect of breastfeeding against childhood leukemia. Two meta-
analyses on this subject reported reduced risks of NDS-ALL and
NDS-leukemia with longer duration of breastfeeding [133,134].
Recent studies, however, showed mixed results [120,122,135].
Breastfeeding was associated with reduced DS-ALL risks in the COG
studies [67,73], but mixed results were reported from the Mexico
City study [78].
Various allergic conditions, including asthma, potentially result
from anomalous development of the immune system, and are also
of interest in relation to childhood leukemia. A few investigations,
including two meta-analyses, reported reduced risks of NDS-ALL in
relation to asthma and allergies, while no association with AML
was detected [120,136,137] (Table 2). However, Chang et al.
reported increased risks of ALL in relation to any allergies, urticaria,
and atopic dermatitis [138]. Bronchial asthma was found to be
associated with an increased risk of DS-ALL, but skin allergies were
associated with a reduced risk, and no association was detected for
allergies overall in the Mexico City study [78]. An earlier paper
from the same study reported no association between allergies and
DS-leukemia in their unadjusted results either [77]. Interestingly
the most common subtype of ALL in DS is associated with the
aberrant expression of CRLF2 and response to thymic stormal
lymphopoietin, the cytokine that is associated with asthma and
allergic disorders [139].
4.3. Environmental exposures
Ionizing radiation is a known risk factor for leukemia [140],
including relatively low prenatal exposure as a risk factor for
childhood leukemia [80,88,141] (Table 3). There is also some
Table 3
Environmental risk factors for childhood leukemia comparing studies among NDS and DS children.
a
Comments
ALL AML
NDS DS NDS DS
Medical ionizing radiation 0.57.2 0.72.0 0.92.4 0.71.4 Parental exposure to diagnostic ionizing radiation before
pregnancy is not clearly associated with NDS-ALL or NDS-AML, but
there is limited evidence of increased risk in relation to prenatal in
utero exposure and some evidence of increased risk with exposure
during childhood. No associations were detected for DS-ALL or DS-
AML.
ELF magnetic elds 1.42.1
b
3.7
c
Residential ELF magnetic eld exposure is consistently associated
with an increased risk of NDS-ALL in pooled analyses. One study
looked at this association for DS, and reported a highly elevated
risk of DS-ALL among children exposed to high level of ELF
magnetic elds.
Vitamin use 0.81.7 0.51.7 0.92.6 Studies suggest a reduced risk of NDS-ALL with maternal vitamin
use during pregnancy. Only one study looked at this risk factor for
DS-ALL and reported a reduced risk with periconceptional vitamin
use, but not with vitamin use only after knowledge of the
pregnancy. Childhood vitamin use was associated with an
increased risk of NDS-ALL in one study, while information on this
association for DS-ALL is limited. No studies of vitamin use in
relation to NDS-AML were found.
(Alcohol) prenatal/pre-pregnancy 0.53.0 0.43.9
c
0.81.8 No clear pattern for paternal alcohol use during or before
pregnancy in relation to NDS-ALL or DS-ALL. Some studies suggest
that maternal alcohol use during pregnancy may increase the risk
of NDS-AML, but there are no comparable studies for DS-AML.
Smoking
Prenatal/pre-pregnancy 0.62.1 0.94.2
c
0.23.8 Overall, no clear trend was observed for maternal smoking before
or during pregnancy in relation to either NDS-ALL or DS-ALL.
However, there is evidence of an increased risk of NDS-ALL in
relation to paternal smoking prior to pregnancy; One study looked
at this risk factor for DS-ALL and reported a strong increase in risk
of DS-ALL with paternal smoking prior to pregnancy. Results for
NDS-AML are mixed and there are no comparable results for
DS-AML.
Childs exposure 1.01.8 3.4
c
0.21.5 There is evidence for slight increase in risk of NDS-ALL in relation
to parental smoking after the childs birth in some studies, and
evidence for a large increase in risk of DS-ALL in relation to infant
smoke exposure (based on a single DS study). A trend for NDS-AML
is less apparent, and there no available data for DS-AML in relation
to this risk factor.
Chemicals
Pesticides 1.42.6 1.22.3 1.42.6 0.51.1 Prenatal exposure to pesticides is associated with increased risks
of ALL in both NDS and DS studies. The trend is similar but not as
strong for postnatal pesticide exposure of the child and NDS-ALL
and DS-ALL. Associations between pesticide exposure, both
prenatal and postnatal, tend to suggest an increase in risk of NDS-
AML with exposure, while the results for DS-AML inconsistent.
Petroleum, paints, stains,
lacquers
1.02.0 1.11.2 1.21.3 Most studies indicate an increase in risk of NDS-ALL with exposure
to petroleum products, solvents, paints, stains, and lacquers.
Results for DS-ALL are limited but indicate a similar trend. Results
for DS-AML also show a similar trend, but there are no comparable
studies for NDS-AML.
a
b
Includes results from pooled analyses that presented point estimates for ALL and AML combined, but most cases were ALL.
c
Result from Mexico City studies that presented point estimates for DS-ALL and DS-AML combined, but greater than 80% of cases were DS-ALL.
G Model
evidence to suggest that exposure of the child to diagnostic
ionizing radiation increases leukemia risk [141143]. Only one
study has examined ionizing radiation as a risk factor for DS-
leukemia, and no association was seen with pre-conception, in
utero, or postnatal medical test irradiation among DS children [69].
Pooled analyses of residential exposure to ELF magnetic elds
and childhood leukemia reported a roughly twofold increase in
leukemia risk for children with average exposures of 0.304 mT
and above [144146]. One study from Mexico City reported highly
elevated odds of DS-leukemia among children with exposure of at
least 0.6 mT, but observed no doseresponse trend [76].
A meta-analysis found a reduced risk of NDS-ALL among
children whose mothers used vitamins during pregnancy, but
found no association with vitamin use before pregnancy [147].
Among DS children, maternal peri-conceptional vitamin use was
associated with a reduced risk of DS-ALL in the COG study, while
vitamin use only after knowledge of the pregnancy appeared to
increase the risk of DS-ALL and DS-AML [71]. NDS children who
ever used vitamin supplements had increased risks of NDS-ALL and
leukemia overall in one study [128]. A study of DS children
reported similar results for DS-AML for children who used vitamins
for more than 50% of their lives prior to diagnosis, but did not
detect an association for DS-ALL [67]. While vitamins are a very
diverse group of chemicals, the DS studies dened vitamin use very
broadly, therefore, we cannot compare the roles of specic
vitamins as risk factors or protective factors for childhood
leukemia between DS and NDS children.
A meta-analysis reported increased odds of NDS-AML in
relation to maternal prenatal alcohol use [148], while other
studies in the general population have produced a range of modest
results in relation to both maternal and paternal (pre-pregnancy)
alcohol use [149154]. Results for DS-children are also varied.
Findings from Mexico City indicate a pattern of increased leukemia
risk among DS children whose fathers consumed alcohol prior to
pregnancy [75,77], but maternal alcohol consumption during
pregnancy was related to a reduced risk (Flores-Lujano, 2009). On
the other hand, two studies in the COG did not detect any risk
increases for DS-leukemia with maternal alcohol use [71,73].
Findings from three meta-analyses suggest that paternal
smoking before and around the time of conception increases the
risk of NDS-ALL [155157], while ndings for AML are less
consistent [83,152,158160]. In contrast, maternal pre-pregnancy
or prenatal smoking has not been shown to increase the risk of
NDS-ALL. Findings among DS-children are generally consistent
with the general population. Mejia-Arangure et al. reported an
increased risk of DS-leukemia among children whose fathers
smoked before pregnancy, but no increase among children whose
mothers smoked before or during pregnancy [75]. Likewise, other
investigations found no increase in risk of DS-leukemia in relation
to maternal smoking during pregnancy [71,73,77].
Passive childhood smoke exposure was examined in many
studies as a risk factor for leukemia, and three of these reported
positive associations [156158,160164]. Two meta-analyses,
however, did not detect associations between postnatal exposure
to smoking and childhood leukemia [156,157]. Studies did not
exclude smoking before the childs birth, and therefore, the results
may not reect effects of postnatal smoke exposure alone. One
study found highly elevated odds of leukemia among DS children
exposed to passive smoke from greater than 10 cigarettes per day
in infancy [75].
Several meta-analyses and casecontrol studies have reported
increased risks of ALL, AML, and leukemia in relation to maternal
exposure to pesticides and chemicals (petroleum products,
solvents, paints, stains, and lacquers) [165175]. Similarly, a
COG study found that maternal exposure to residential pesticides,
professional pest exterminations, or any household chemicals
around the time of pregnancy was associated with increases in the
risk of DS-ALL [72]. No increases in the risk of DS-AML were
observed. Postnatal childhood exposure to these substances may
also be associated with leukemia in the general population [165
167,170172], and with DS-leukemia, although results from DS
studies are limited [72,76]. Pesticides and chemical exposures
include a wide variety of individual chemical substances. However,
the DS studies dened these exposures broadly, thus, we cannot
compare the impact of specic chemicals and pesticides between
DS and NDS children.
5. Discussion
Although our understanding of genetic and epigenetic changes
in childhood leukemia has signicantly improved in past decades,
the causes of childhood leukemia and, particularly, the potential
role of environmental exposures in leukemogenesis remain largely
unknown. Ionizing radiation remains the only conrmed and
generally accepted environmental risk factor for childhood
leukemia, in spite of the large number of epidemiologic studies
that have looked at a variety of exposures in the general
population. Among suspected environmental risk factors, infec-
tions, pesticides and ELF magnetic elds could be mentioned.
However, for these exposures, the evidence remains less than
convincing for a causal relationship. While casecontrol epidemi-
ologic studies have provided a substantial contribution to our
understanding of leukemia etiology, additional studies of this type
may not be able to further our understanding about the role of
environmental exposures due to their inherent limitations, such as
the potential for selection bias. The cohort approach has fewer
opportunities for certain epidemiologic biases but remains
prohibitively large and expensive for rare outcomes such as
childhood leukemia. Children with DS, a common congenital
anomaly that substantially increases the risk of leukemia, may
represent a population in which a cohort study for childhood
leukemia and environmental exposures is feasible.
There are well-dened differences in the incidence patterns and
cytogenetics of leukemia observed among children with and
without DS. Children with DS are much less likely to develop ALL in
their infancy compared to NDS children, and the ratio of ALL to
AML is closer to 1:1 as opposed to 4:1 among NDS children. This
reects the much greater increase in risk of AML, compared to the
already increased risk of ALL, among children with DS. AMLs with
the characteristic mutation in the megakaryocytic X-linked
transcription factor GATA 1 and with the transient myeloprolifera-
tive disorder are unique among children with DS. However, the
pattern of development through ontogeny is reminiscent of the
pattern observed in all childhood leukemias, including NDS ALL.
For lymphoid leukemia, the same cytogenetic subgroups are
present in DS-ALL and NDS ALL, although their distribution is
markedly different in the two groups (e.g., lower relative
prevalence of ETV6-RUNX1 and higher prevalence of CRLF2
subtype among DS children). Nevertheless, from a biological
standpoint, studies of the pathogenesis of leukemia in DS may be of
relevance to childhood leukemia in general.
To further assess the similarities in pathogenesis of ALL
between DS and NDS children and to assess the potential role of
congenital trisomy 21 in leukemogenesis, the expansion of the
pool of preleukemic cells with certain genetic changes (e.g., ETV6-
RUN1 translocation or changes leading to CRLF2 expression) could
be examined among DS children as compared to NDS children. For
example, if DS children have an increase in the number of CRLF2
cells in their cord blood at birth compared to NDS children, then
that may be at least partially responsible for the increased
leukemia risk among DS children.
G Model
Epidemiologic studies of risk factors for leukemia among
children with DS are limited in number and sample size. Only two
study groups have conducted casecontrol epidemiologic studies
of environmental exposures and childhood leukemia, and only one
of them analyzed the data separately for ALL and AML. One
research group reported substantially higher odds ratios for many
of the risk factors examined, which may be an indication of some
bias in that study. Nevertheless, the results of the two groups,
which reported associations for several of the investigated
exposures (maternal age, vitamin use, parental smoking during
pregnancy, birth weight, some allergic conditions and ELF
magnetic elds), although typically imprecise, are not inconsistent
with each other and with patterns seen in the general population.
Studies of leukemia among children with DS are fraught with
unique challenges, including a higher potential for bias due to
confounding. For example, immunodeciency is common in
children with DS, and therefore, they have higher risks of infection
and different immune responses to infection compared to children
without DS. Studies of maternal age and birth order may also be
prone to confounding, as these are strong risk factors for DS, as
well. The required size of the cohort also represents signicant
challenges. Although the lifetime incidence of childhood leukemia
is signicantly higher among DS children (1%) than among NDS
children (1 in 2000), still a large cohort (15,000) of DS children
would be required to accumulate 150 cases of leukemia during
their rst 15 years of life. While it would represent a major
undertaking, it would still be in the realm of feasibility as the
examples of successful enrollment and follow up of several large
cohorts of children worldwide indicate [176].
6. Conclusions
Despite difculties in the conduct and interpretation of the
studies, currently there is no evidence to suggest that potential
environmental risk factors for childhood leukemia in the general
population have different effects among children with DS. This
observation, along with similarities in the biological features of
leukemia development in the two groups (multistage development
of leukemia including the occurrence of a prenatal preleukemic
clone and postnatal progression of the disease and the similar role
of prognostic factors among DS and NDS ALL, despite the different
prevalence of specic cytogenetic subtypes), suggest that studying
environmental risk factors and leukemia development among
children with DS may greatly contribute to our understanding of
childhood leukemia in the general population, as well.
We propose that both ALL and AML in DS children can serve as a
useful model for childhood leukemia. Further, high rates of
leukemia in DS children make it feasible to study risk factors
using a cohort approach. By overcoming numerous methodological
limitations of casecontrol studies, such a cohort has the potential
to be a powerful tool for generating new scientic knowledge
about the causes of childhood leukemia. By enrolling children with
DS at or shortly after birth and following them long-term, the rst
large-scale prospective cohort of DS individuals could be
established. Data collection on various environmental expo-
sures suspected as risk factors for leukemia in such a cohort may
provide a unique opportunity to further our understanding of
their etiologic role. Such a cohort study may also provide an
excellent opportunity to study other health conditions that are
common among DS individuals (e.g., cardiovascular conditions,
developmental disabilities, infections, Alzheimer disease).
Knowledge to be gained from this work is much needed and
could potentially lead to prevention of disease, including
lowering the rates of childhood leukemia overall and in children
with DS.
Conict of interest statement
The authors have no conicts of interest to report.
Authorship contribution
All authors contributed equally to the attached manuscript. GM
developed the initial concept and completed initial literature
search, MS drafted the initial manuscript, SI contributed to the
biological sections, LK oversaw the entire project and the
development of the manuscript. All authors reviewed and
approved the nal version of the manuscript.
Acknowledgments
This work was supported by a grant from the Electric Power
Research Institute, Palo Alto, CA, USA (P42127/C18416). All authors
contributed to the designing, writing, and revising this manuscript
in its entirety, and all authors approved of the nal submitted
version. GM conceived the original idea for this manuscript and led
its development; MS compiled the background literature and
wrote the rst draft of the manuscript; SI contributed invaluable
expertise on leukemia biology; LK oversaw the overall project and
brought this team of authors together.
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