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Pediatr Clin North Am. 2015 February ; 62(1): 11–25. doi:10.1016/j.pcl.2014.09.013.

Genetic and nongenetic risk factors for childhood cancer

Logan G. Spector, Ph.D. [Associate Professor],
Division of Epidemiology/Clinical Research Department of Pediatrics University of Minnesota 420
Delaware Street, SE, MMC 715 Minneapolis, MN 55455

Nathan Pankratz, Ph.D. [Assistant Professor], and

Department of Lab Medicine and Pathology University of Minnesota
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Erin L. Marcotte, Ph.D. [Postdoctoral Fellow]

Division of Epidemiology/Clinical Research Department of Pediatrics University of Minnesota

Summary
The causes of childhood cancer have been systematically studied for several decades, but apart
from high-dose radiation and prior chemotherapy there are few or no strong external risk factors.
On the other hand, inherent risk factors including birth weight, parental age, and congenital
anomalies are consistently associated with most types of pediatric cancer. Rare, highly-penetrant
syndromes have long been known to cause a small proportion of cancers but recently the
contribution of common genetic variation to etiology has come into focus through genome wide
association studies. These have highlighted genes not previously implicated in childhood cancers
and, surprisingly, have suggested that common variation explains a larger proportion of childhood
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cancers than adult. Rare variation and non-Mendelian inheritance, such as through maternal
genetic effects or de novo germline mutations, may also contribute to childhood cancer risk but
have not been widely examined to date.

Keywords
Epidemiology; etiology; genome-wide association studies; case-control studies; pediatric cancer

Introduction
The causes of childhood cancer have been systematically studied for several decades. The
incidence of all cancers occurring in children under 20 years of age is about 175 cases per
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million in the United States (1), with the incidence of many individual types [typically
grouped by the International Classification of Childhood Cancer (ICCC) schema(2)], in the
low dozens (Figure 1). Rarity is thus a central fact which dictates the quality and quantity of
evidence for causal associations between putative risk factors and childhood cancers. Most
etiologic investigations of childhood cancer have thus of necessity used the case-control
study design (3), in which the characteristics of patients with a disease are compared to
those of a carefully selected group of disease-free controls. When they require participant

(corresponding author) 612-624-3912 [email protected].

 Spector et al. Page 2

involvement, as in the many studies of childhood cancer which have collected exposure
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information through parental interview, case-control studies are susceptible to both recall
and selection biases.

Given the milieu for childhood cancer epidemiology, evidence regarding causal associations
has accumulated slowly. However, for the most common types of cancer, particularly acute
lymphoblastic leukemia (ALL), the body of literature is now sufficiently large to allow data
synthesis through meta-analyses and data pooling. This review will only briefly discuss such
analyses of external, or environmental, risk factors, as they have mainly demonstrated weak
or null associations. In contrast, intrinsic characteristics or conditions of childhood cancer
patients have shown stronger, more consistent associations and in the last half-decade the
application of genome wide single nucleotide variant (SNV) arrays to several childhood
cancers has generated surprising insights into their biology. Hence, the majority of this
review for the general pediatrician will cover these topics in a broad overview to reflect their
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increased importance in the current understanding of childhood cancer etiology.

Demographic risk factors

Childhood cancer incidence has long been noted to vary by age, sex, and race/ethnicity.
Overall incidence is highest in infancy at about 240 cases per million per year. This rate
drops to a nadir of 128 cases per million at 5-9 years of age before rising to 220 cases per
million at 15-19 years of age (1). Grouped incidence however obscures interesting patterns
among individual cancers (Figure 1). For instance, all the embryonal tumors
(neuroblastoma, Wilm's tumor, retinoblastoma, etc.) share a downward sloping incidence
which starts high at birth and dissipates after about 5 years of age. ALL is notable for the
incidence peak which occurs between 2 to 5 years of age, while bone sarcoma incidence
peaks sharply around the time of the pubertal growth spurt in early-tomid adolescence.
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For most childhood cancers there is a slight male preponderance (Figure 2). The male-to-
female ratio ranges from 1.04 to 1.64 in neuroblastoma and germ cell tumors, respectively,
in cases 0-19 years of age but varies considerably by age group and more specific diagnosis.
Wilm's tumor is notable for being the one major childhood cancer which is more common in
females.

Childhood cancer risk also differs by race/ethnicity (Figure 3). Relative to white children in
the United States the incidence of most types of cancer is lower in black, Asian, and
Hispanic children. In some cases, such as the near complete lack of Ewing sarcoma among
black and Asian children, the disparity is rather dramatic. In a few notable instances cancer
incidence is higher in other groups compared to white children. That acute leukemia
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incidence is about 10% higher in Hispanic children compared to white children is

particularly notable. The extent to which racial/ethnic differences are attributable to genetic
versus environmental differences has yet to be determined but will surely come into focus as
the genetic architecture of childhood cancer continues to be elucidated.

Environmental risk factors

High dose ionizing radiation and prior chemotherapy are accepted causes of childhood
cancers, each raising risk several fold (4-7). No other environmental risk factors, by which

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 Spector et al. Page 3

we mean any exposure which originates outside the body, have emerged as definitively
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causal for childhood cancer.

Measurement of environmental exposures poses a challenge in elucidating their effects on

childhood cancer risk. Prospective studies would require hundreds of thousands, if not
millions, of children to identify enough cases to generate statistically meaningful results.
Thus most childhood cancer studies must rely on the case-control design, which is
particularly problematic for evaluating certain types of exposures. Demographic and
intrinsic factors are unambiguous, relatively easy to obtain via questionnaire, and, in such
cases as parental age, race/ethnicity, and birth defects, generally not subject to recall error.
In contrast, environmental factors such as parental diet, maternal medication, caffeine, and
alcohol use, and pesticide and air pollution exposure, among others, are very difficult to
measure accurately in a retrospective design. Although use of registries, birth and medical
records and other data sources reduces some sources of bias, accurate exposure assessment
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remains a major barrier to determining the causal impact of environmental factors on

childhood cancer risk.

For many childhood cancers findings are inconsistent or studies too few to conduct meta-
analysis; moreover synthesis is hampered by the need to separately examine exposures
during the preconceptional, pregnancy, and postnatal periods and the progressively finer
classifications of tumors. ALL, being the most common childhood cancer, has however been
the subject of several meta-analyses of putative environmental risk factors (Table 1)(8-15).

Exposure to infections has been one of the most commonly examined environmental
exposures in relation to ALL risk, and there are two main hypotheses regarding the nature of
this relationship. Kinlen proposes that previously isolated, and therefore immunologically
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naïve, populations are susceptible when exposed to specific infectious agents due to
population mixing (16). A recent meta-analysis estimated an increased risk of ALL in rural
settings of population mixing (17). Greaves’ hypothesized that an immature and
unchallenged immune system, resulting from delayed exposure to common infections,
produces an unregulated immune response and leads to ALL in the presence of susceptible
cells (18, 19). While direct measurement of exposure to infections and the resulting immune
response is generally not feasible, several proxies have been employed, including birth
order(20-22), daycare attendance(23, 24), breastfeeding(25), infectious illness histories(26),
and vaccinations(27). Meta-analyses have shown protective effects for both breastfeeding
(28) and daycare attendance (13), although because these are indirect exposure measures, it
is unclear whether infection exposure or some other factor is driving these associations.

Several recent meta-analyses have identified increased risk for both residential (29, 30) and
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maternal occupational (14) exposure to pesticides. Studies of residential pesticide exposure

have generally relied on self-report, which is subject to recall bias that may inflate risk
estimates. Some recent studies have used residential proximity to pesticide applications
(31-33), a method which is less prone to bias but still prone to measurement error which
may attenuate risk estimates (34). Occupational studies typically rely on either self-report or
record data. While an association between pesticide exposure and ALL is supported by the
available meta-analytic data, it is difficult to estimate the true magnitude of effect, if there is

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indeed a causal relationship, given the varying exposure assessment methods and the
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inherent biases and measurement errors therein.

Associations for other exposures examined using meta-analyses, including maternal

alcohol(11), coffee(35), and vitamin use(9), and both paternal (12) and maternal (10)
smoking have yielded mostly null (10, 11) or slightly elevated (12, 35) results. Maternal
prenatal vitamin use was associated with a decreased risk of ALL in offspring, although the
meta-analysis was based on only three studies (9). . While a causal role for these risk factors
is possible, observational epidemiology is not conclusive in these circumstances. High-
quality studies with a focus on accurate exposure assessment are necessary to evaluate
environmental risk factors for childhood cancer.

Intrinsic risk factors

Several intrinsic characteristics of children or their parents have been consistently associated
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with childhood cancers. Risk of ALL(36), central nervous system tumors(37),

neuroblastoma(38), and Wilm's tumor(39), among others, rises as a linear function of birth
weight, to varying degrees, and recent analyses that have used alternate measures of birth
size (e.g. size for gestational age, percent of optimal birth weight) have found similar results
(40). Risk of acute myeloid leukemia is elevated with both low and high birth weight(41),
while risk of hepatoblastoma is inversely related to birth weight and strikingly elevated
among the smallest infants (42). The reasons behind the association of higher birth weight
with childhood cancers have not been explored in detail, but may include prenatal growth
hormone exposure (43), the underlying genetics of birth weight (44), and the greater number
of cells at risk for carcinogenic transformation. The strong inverse association of
hepatoblastoma with birth weight has been thought to be related to neonatal treatment, but
no culprit exposure has been identified to date(45).
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Advanced parental age has also been associated with most childhood cancers. A large
pooled analysis of population-based record-linkage studies found significant positive linear
trends in leukemia, lymphoma, brain tumor, neuroblastoma, Wilm's tumor, bone tumors, and
soft tissue sarcomas with 6-15% increased risk per five years of maternal age(46). Paternal
age was not associated with these cancers after adjustment for maternal age, however since
the two are highly correlated it is not clear that maternal age was solely responsible. As with
birth weight, the reasons behind these findings are unclear, but may include genetic or
epigenetic mutations associated with advanced parental age (47).

Structural birth defects have consistently been found to increase the risk of childhood
cancers, as a group, about threefold (48-50) although due to the rarity of both individual
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birth defects and individual childhood cancers more specific associations have not been
reported to date. Undoubtedly some of this association is explained by underlying genetic
causes, but as most birth defects appear sporadic(51) genetics are not likely the sole
explanation for cooccurrence.

Genetic risk factors

Inherited syndromes, caused by high-penetrance germline DNA mutations(52, 53),
chromosomal aneuploidy(54), or epigenetic disorders(55), are known to cause a minority of

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childhood cancers. Although the proportion attributable to syndromes has rarely been
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precisely quantified for common childhood cancers the estimate is typically 5-10%. For
especially rare cancers, such as pediatric adrenocortical carcinoma, the proportion can be
much higher (56). Specific syndromes predisposing to particular childhood cancers are
covered elsewhere in this issue.

Genome wide association studies (GWAS) compare the frequency of hundreds of thousands
of common SNV's in those with a disease to those without(57). Due to the large number of
comparisons made in GWAS a SNV-disease association must reach a high degree of
statistical significance (generally p < 5 × 10−8) to be convincing. This requires large sample
sizes not readily achievable for rare diseases. Yet, despite the a priori presumption that the
GWAS design could not be successfully applied to childhood cancers investigations of
ALL(58-64), neuroblastoma(65-74), Wilm's tumor(75), osteosarcoma(76), and Ewing's
sarcoma (77), each have identified multiple variants associated with each disease (Table 2).
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The unexpected success of GWAS to studies of these rare cancers appears to be due to the
larger magnitude of SNV-disease association among young onset cancers compared to those
with adult onset, which was recently formally quantified (Figure 4) (78). An implication of
this finding, besides reaffirming the applicability of GWAS to other childhood cancers not
yet studied thusly, is that common genetic variation explains a greater proportion of the
population attributable risk for childhood than adult cancers.

The GWAS and replication studies of ALL and neuroblastoma include diverse populations
and subtype-specific analyses, giving a more mature picture of the genetic architecture of
each disease than is available for those with a single GWAS to date. Two recent GWAS of
ALL conducted with African-American and Hispanic cases and controls replicated many of
the SNV's first identified in studies of subjects with European ancestry; SNV's in ARID5B,
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IKZF1, and PIP4K2A were associated with ALL in both ethnicities, and CEBPE as well in
Hispanics (60). OR's per allele were similar in each group, in line with the generally high
trans-ethnic replicability of GWAS results (79), however frequencies varied in directions
that suggest several SNVs may explain a substantial proportion of lower incidence of ALL
in African-Americans and the higher one in Hispanics compared to Europeans. ARID5B
rs10821936 was present in 33% of Europeans, 24% of African-Americans, and 47% of
Hispanics; the equivalent numbers for IKZF1 rs11978267 were 28%, 19%, and 26%. CEBP
rs4982731 was present in 28% of Europeans and 39% of Hispanics, as well as 38% of
African-Americans in which this SNV did not replicate. Similarly, SNVs in BARD1
replicated in a GWAS of neuroblastoma among African-Americans, while no others did,
possibly due to small sample size (71).
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Several SNVs in both diseases show far stronger OR's with specific subtypes, demonstrating
that lumping disparate cases can dilute associations. In ALL, ARID5B SNVs have been more
strongly associated with hyperdiploid disease(59, 80, 81) and GATA3 SNV's with leukemias
displaying a Philadelphia-chromosome-like expression pattern (63); the latter is an
especially dramatic instance, with subtype-specific ORs per allele of about 3.5 versus 1.3 in
total ALL. BARD1 and LMO1 SNVs are associated with aggressive disease in
neuroblastoma (66, 67, 73), and SNVs in or near DUSP12, DDX4, IL31RA, and HSD17B12
with low-risk disease (73). It seems reasonable to speculate that similarly specific

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 Spector et al. Page 6

associations with subtypes of other childhood cancers will emerge as the GWAS literature
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expands.

Although the progress in identifying common variants associated with several childhood
cancers in the past several years has been remarkable, a large portion of heritability remains
unexplained. For instance, estimates indicate that about 25% of genetic variation in ALL
risk was due to common variants identified by GWAS available in 2012 (82). The remainder
of genetic risk may be attributable to several other plausible mechanisms which will more
often be evaluated as next-generation sequencing and the inclusion of parental samples are
adopted by the field. Rare variation is generally defined as that with a population allele
frequency of <0.01. A recent exome-sequencing study of infant leukemia, among the first of
its kind, identified compound heterozygosity for rare pathogenic variants in the MLL3 gene
as risk factors (83). Sequencing of parents and children and comparing exomes or genomes
can identify de novo mutations which will not be apparent by other technologies(47). Lastly,
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since many childhood cancers are presumed to initiate in utero(84), maternal genetic effects
may be relevant(85), but have only been examined in a candidate gene rather than genome
wide context to date (86, 87).

Conclusion
The rarity of childhood cancer slows the search for their causes, but the accumulation of
case-control studies and advancement of genomic technology have improved our knowledge
in recent years. Few environmental risk factors for childhood cancer have been identified
that exceed the capacity of observational epidemiology to distinguish causal associations
from those due to bias. Inherent risk factors such as birth weight, parental age, and birth
defects- as well as common genetic variation- are on the other hand consistently associated
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with childhood cancers.

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Key Points
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- Apart from high-dose radiation and prior chemotherapy there are few or no strong
external risk factors with relative risks >2.

- Inherent risk factors including birth weight, parental age, and congenital anomalies
are consistently associated with most types of pediatric cancer.

- Common genetic variation has been associated with several childhood cancers in
genome wide association studies, often with subtype-specificity, and explains a
larger proportion of childhood than adult cancers.
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Fig. 1.
Incidence rate per million for International Classification of Childhood Cancer (ICCC)
categories by 5-year age groups
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Fig. 2.
Incidence rates per million for International Classification of Childhood Cancer (ICCC)
categories by sex.
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Fig. 3.
Incidence rates per million for International Classification of Childhood Cancer (ICCC)
categories by race/ethnicity. AI/AN, American Indian/Alaska Native; As/Pacl, Asian/Pacific
Islander.
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Fig. 4.
Boxplot of SNV odds ratios from GWAS of cancer by age group. Dark horizontal lines
represent the median and the box represents the 25th and 75th percentiles. (From Raynor
LA, Pankratz N, Spector LG, et al. An analysis of measures of effect size by age of onset in
cancer genomewide association studies. Genes Chromosomes Cancer 2013;52(9): 857; with
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permission.)
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Table 1

Results of selected meta-analyses of environmental risk factors and childhood ALL.

Exposure Time period N studies Findings Ref

Spector et al.

Maternal alcohol use Pregnancy 10 * (11)

No association of any alcohol use during pregnancy with ALL [mOR = 1.10 (0.93-1.29)

Maternal coffee use Pregnancy 5 Small association of any coffee consumption during pregnancy with ALL [mOR = 1.16 (1.00-1.34)] (8)

Daycare attendance Postnatal 14 Small reduced risk of ALL associated with daycare attendance [mOR = 0.76 (0.67-0.87)] (13)

Electromagnetic field exposure Postnatal 9 No association of electromagnetic field exposure >=0.2 μT with ALL [mOR = 1.25 (0.97-1.60)] (15)

Occupational pesticide exposure Pregnancy 5 Strong association of maternal occupational exposure to pesticides during pregnancy and ALL [mOR = 2.64 (1.40-5.00)] (14)

Maternal prenatal vitamins Pregnancy 3 Small reduced risk of ALL associated with maternal prenatal vitamin consumption [mOR = 0.61 (0.50-0.74)] (9)

Paternal smoking Preconception 10 Small association of any paternal preconceptional smoking with ALL [mOR = 1.15 (1.06-1.24)] (12)

Maternal smoking Pregnancy 20 No association of any maternal smoking during pregnancy with ALL [mOR = 1.03 (0.95-1.12)] (10)

*
mOR = meta-analytic odds ratio

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Table 2

SNV's identified by GWAS of childhood cancers.

Cancer Gene SNV Population Subtype OR 95% CI P-value Ref

Spector et al.

ALL ARID5B rs10821936 European Total 1.91 1.6-2.2 1.4 × 10−15 (39)

ALL ARID5B rs10740055 European Total 1.53 1.4-1.6 5.35 × 10−14 (38)

ALL ARID5B rs10821936 African-American Total 1.52 1.1-2.0 0.004 (40)

ALL ARID5B rs10821936 Hispanic Total 1.95 1.6-2.4 3.78 × 10−11 (40)

ALL ARID5B rs10821936 European B-hyperdiploid 2.17 1.5-3.1 1.62 × 10−5 (39)

ALL CDK2NA rs3731217 European Total 0.71 0.6-0.8 3.01 × 10−11 (41)

ALL CDK2NA rs17756311 European Total 1.43 1.2-1.7 3.25 × 10−5 (40)

ALL CEPBE rs2239633 European Total 1.34 1.2-1.5 2.88 × 10−7 (38)

ALL CEBPE rs4982731 Hispanic Total 1.58 1.3-1.9 2.32 × 10−6 (40)

ALL COMMD3/BMI1 rs4266962 European Total 1.41 1.2-1.7 4.35 × 10−8 (40)

ALL GATA3 rs3824662 European Total 1.31 1.2-1.4 8.62 × 10−12 (44)

ALL GATA3 rs3824662 European Philadelphia-like 3.85 2.7-5.47 2.17 × 10−14 (43)

ALL IKZF1 rs11978267 European Total 1.69 1.4-1.9 8.8 × 10−11 (39)

ALL IKZF1 rs4132601 European Total 1.69 1.6-1.8 1.2 × 10−19 (38)

ALL PIP4K2A rs10828317 European Total 1.23 1.2-1.3 2.3 × 10−9 (44)

Ewing sarcoma TARDBP rs9430161 European Total 2.20 1.8-2.7 1.4 × 10−20 (57)

Ewing sarcoma EGR2 rs224278 European Total 1.66 1.4-1.9 4× 10−17 (57)

Neuroblastoma FLJ22536 rs6939340 European Total 1.40 1.3-1.6 5.82 × 10−8 (52)

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Neuroblastoma BARD1 rs6435862 European Total 1.64 1.4-1.9 3.19 × 10−9 (46)

Neuroblastoma BARD1 rs6435862 African-American Total 1.44 1.2-1.7 1.8 × 10−5 (46)

Neuroblastoma HACE1 rs4336470 European Total 1.26 1.2-1.4 2.7 × 10−11 (49)

Neuroblastoma LIN28B rs17065417 European Total 1.38 1.2-1.5 1.2 × 10−8 (49)

Neuroblastoma LMO1 rs110419 European Total 1.34 1.3-1.4 5.2 × 10−16 (54)

Osteosarcoma GRM4 rs1906953 European Total 1.57 1.4-1.8 8.0 × 10−9 (56)

Osteosarcoma Intergenic at 2p25.2 rs7591996 European Total 1.39 1.2-1.5 1.0 × 10−8 (56)
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Cancer Gene SNV Population Subtype OR 95% CI P-value Ref

Wilm's tumor Intergenic at 2p24 rs3755132 European Total 1.48 1.3-1.7 1.03 × 10−14 (55)

Wilm's tumor Intergenic at 11q14 rs790356 European Total 1.43 1.3-1.6 4.25 × 10−15 (55)I
Spector et al.

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