HLA MHC Inf & Imm Genetics Evolution Epidemiology Genetic Epidemiology Biostatistics Glossary Homepage
Childhood Leukemias
M. Tevfik Dorak, M.D., Ph.D.
Leukemia
is a malignancy of the hematopoietic system characterized by diffuse
replacement of the bone marrow by neoplastic cells. In acute leukemias, the
immature hematopoietic cells are increased in the blood, and chronic leukemias
are characterized by an excess of well-differentiated blood cells. In children,
the vast majority of leukemias are of the acute type, whereas in adults,
chronic leukemias are more common 1. Leukemias are the most common childhood malignancies, accounting for
just above 30% of all cancer diagnoses in children under 15 years of age 2-4. In this age group, approximately 75% of leukemias are classified as
acute lymphoblastic leukemia (ALL) 2; 4. The prefix 'acute' is superfluous but persists in the universal
acronym ALL. The second most frequent leukemia type in childhood is acute
myeloid leukemia (AML), and the second most common cancer in childhood is
central nervous system tumours 2; 4; 5.
Immature
hematopoietic cells giving rise to ALL are not easy to distinguish
morphologically. The modern classification of acute leukemias relies on the
changes in the expression of cell surface antigens as a precursor cell
differentiates. Using monoclonal antibodies, cell surface antigens (called
clusters of differentiation (CD)) can be identified in cell populations; leukemias
can be accurately classified by this means (immunophenotyping) 6; 7. By immunophenotyping, it is possible to classify ALL into the major
categories of 'common - CD10+ B-cell precursor' (around 50%), 'pre-B' (around
25%), 'T' (around 15%), 'null' (around 9%) and 'B' cell ALL (around 1%) 8. All forms other than T-ALL are considered to be derived from some
stage of B-precursor cell, and 'null' ALL is sometimes referred to as 'early
B-precursor' ALL. Etiology of childhood ALL is not known. The undisputed fact
is the multigenic, multifactorial and multistep nature of its development 9-11. A few recognized risk factors account for a small proportion of
cases. The genetic abnormalities associated with the disease and the recognized
epidemiological risk factors provide some clues to the etiology of childhood
ALL.
Genetic background
Childhood
ALL is not an inherited disease 12; 13. A genetic background in childhood ALL is, however, suggested by a
tendency to cluster in families that experience an excess incidence of leukemia
or cancer 13-17, increased risk for the siblings of a patients with childhood leukemia
(one in five siblings develop leukemia) 18; 19, and a high degree of concordance among twins 20-24, although not in all studies 25. There is, however, evidence for
intrauterine single cell origin, with twin-to-twin transmission, of concordant leukemia
in twins 22; 23; 26. This is a more likely cause for
concordance than genetic factors. It has recently been shown that leukemia may
indeed arise in utero 27-29. Several molecular studies found
the same clonotypical MLL or TEL rearrangement in patients' blood samples taken
at birth. This was shown for patients with infant leukemia and for those with
cALL. These results provide unequivocal evidence for prenatal
initiation of acute leukemia in most patients.
Acquired
genetic changes
Cytogenetic
or molecular biological techniques have revealed a number of clonal chromosomal
changes in childhood ALL 30-33. A major group of these changes consists of alterations in the number
of chromosomes as a feature of genomic instability as in any malignancy.
Alterations in ploidy is common in childhood ALL and have prognostic
significance, patients with hyperdiploidy having better prognosis 9; 33-36. Among the specific genetic changes, chromosomal translocations are
common in childhood ALL. The t(12;21) translocation,
barely detectable when searched by conventional cytogenetic techniques, is the
most frequent genetic lesion occurring in childhood ALL 37. Certain translocations have a negative influence on prognosis,
particularly in cases of t(9;22) or t(4;11); whereas, t(12;21) confers a better
prognosis 9; 31; 33; 36. During the production of a translocation, the chromosome is broken
and the gene at this site may be disrupted. The broken gene comes to lie
adjacent to another gene as the partner chromosomes fuse. This reorganization
can lead to the production of a fusion protein which can contribute to the
development of leukemia. An example of this is the TEL-AML1 fusion protein resulting from t(12;21) 9; 32; 37. Among infants with ALL, translocations involving 11q23 / MLL occur in about 85% of cases 10. Also more frequently detected by molecular analysis is deletions on
chromosome 6q 38; 39. This chromosomal change is present in 32% of (adult) ALL cases.
Inherited
genetic changes
In addition to the acquired genetic abnormalities, a
number of inherited genetic syndromes are associated with childhood leukemia,
although they lead to a small number of cases 3; 10; 40. The best-known ones causing ALL are Downs syndrome,
neurofibromatosis, Shwachman syndrome, Bloom syndrome and
ataxia-telangiectasia. Children with Downs syndrome are estimated to have an
approximate 10- to 15-fold increased risk for the development of acute leukemia
(ALL or AML), the most common subtype being M7 (megakaryoblastic) variant of
AML 41; 42. The familial occurrence of leukemia mentioned above also suggests a
genetic component in the etiology.
Childhood ALL is a heterogeneous disease. Significant
geographic variations in its incidence exist, with rates ranging from 9 to 47
per million 2. Rates are highest in Costa Rica, low among US blacks, and lowest in
Kuwait 2; 43. There are variations in the incidence among whites, with rates being
higher in New Zealand and Australia than in Europe. In England and Wales, there
seems to be geographical clustering 44; 45. This may be due to environmental exposures, infectious agents or
unknown factors. The incidence of childhood ALL (below the age of 15 years) is
approximately 30% higher among boys and male gender is a poor prognostic factor
36; 46-50. In the case of T-cell disease, the male:female ratio is nearly 4:1 51, and in infant leukemia there is a female predominance 3.
The
distribution of childhood ALL in age groups is not homogeneous. A peak in
incidence occurs between the ages of two and five years but only in common ALL 40; 43; 52; 53. The age peak is absent in many developing countries 3, leading some to postulate that it may reflect environmental exposures
associated with modernization 54. In Africa, ALL is relatively rare before the age of five years 3 although this may be due to under registration. The absence of the age
peak in other subtypes of childhood ALL underlines the importance of taking the
heterogeneity of the disease into account in epidemiological studies. A number
of epidemiological risk factors have been identified in childhood ALL (Table
1). Some of these are discussed below.
Table 1. Risk factors for childhood ALL identified in epidemiological studies
_______________________________________________________
Male
sex
Down's
syndrome and other genetic disorders
Sibling
with leukemia, brain tumour or Down's syndrome
Middle
and upper socioeconomic class
Miscarriage(s)
in the maternal reproductive history
Advanced
maternal and paternal age
Parental
smoking
Parental
or household exposure to pesticides
Parental
history of autoimmune disorders
High
birth weight
Being
the first-born or the only child
Delayed
exposure to common childhood infections
Prenatal
ionizing (diagnostic) radiation exposure
Nitrous
oxide administration during delivery
Post-natal
use of chloramphenicol
Electromagnetic field exposure (?)
__________________________________________________________
Data
compiled from Refs 3; 10; 55-57
See also the SEER
childhood leukemia report (Table I.5) and
Table
1 in Linet,
2003.
The
speculation that the peak incidence of ALL in early childhood may reflect
socio-economic factors prompted epidemiological studies to investigate this
possibility. The epidemiological data have generally shown a consistently increased
risk of ALL in children of the middle and upper socio-economic classes 58; 59but there is also evidence
against this 53; 60; 61. Although socio-economic status can be confounded with race, personal
habits, life style, access to medical care, maternal age, occupational
exposures and parental education, there are also several etiologic hypotheses
that attempt to explain this phenomenon, including delayed exposure to
infectious agents associated with smaller families, less crowding, and later
interaction with other children 3; 61-65.
Maternal reproductive history
Since
noted in the Oxford survey of childhood malignancies by Stewart et al in 1958 66, numerous studies have examined the association between miscarriages
in maternal reproductive history and childhood leukemia 61; 67-73. Prior fetal loss appears to be one of the most consistent risk
factors for childhood ALL in different populations such as UK 66, USA 68; 69; 73, Holland 70, and Germany 61. Only one study has found a lower risk associated with prior fetal
loss in a Chinese population 71. One study failed to find any association in ALL 74, and another one in infant leukemia 75. It is particularly important that the ongoing US Children's Cancer
Group case-control study has so far reported only the maternal history of fetal
loss as a risk factor for childhood ALL 73; 76. In that study, this association is
significant only for those patients diagnosed before four years of age and most
significant in those patients diagnosed before two years of age. In the latter
group, one previous fetal loss is associated with a five-fold increased risk (P
< 0.001), whereas, two or more fetal losses are associated with a relative
risk [RR] of 24.8 (P < 0.001) 73. About a third of patients
mothers have a history of spontaneous abortions. The same study reported a
similar association also for childhood AML diagnosed before two years of age 73.
The
connection between reproductive failure and childhood leukemia is further
supported by the reports that survivors of threatened abortions are at a higher
risk to develop childhood leukemia 66; 70. Prior fetal loss suggests a number of potential mechanisms, including
chronic environmental exposures and/or a genetic predisposition with varying
effects on the fetus ranging from nonviability to damage to a single cell
lineage. Several lines of evidence support the genetic theory: childhood
rhabdomyosarcoma and maternal reproductive history of stillbirth(s) show a
similar association 77; selective early mortality of twin fetuses or neonates who would
otherwise have developed a clinical cancer, an effect particularly notable in
males 78; increased incidence of cancer, leukemia and lymphoma in the families
of women experiencing spontaneous recurrent abortions 79; increased HLA-DR sharing between parents in both leukemia (ALL or
AML) 80-85and recurrent spontaneous
abortions 86-90or reproductive failure 91; 92; in rats the growth-retardation complex (grc) is involved in both
fetal development and susceptibility to post-natal malignancies 93-100. The grc complex is part of the rat major histocompatibility complex
(MHC).
Parental age
Advanced
maternal age has been associated with childhood ALL in a number of studies even
after adjustment for associations with Downs syndrome 48; 67; 69; 101; 102. The Chinese study which did disagree with other studies on the
association of recurrent fetal loss with childhood ALL, also disagreed about
the effect of the maternal age 71 together with a Swedish study 103. Advanced paternal age has been identified as a risk factor in some
studies 69, and as a possible risk factor in another 104.
Parental smoking
Maternal
smoking during pregnancy with the index child is associated with increased risk
in a dose-related manner 105-109. Others reported no elevated risk with maternal smoking 61; 70; 71; 110; 111. Recent progress in toxicology and molecular pharmacogenetics
suggested plausible mechanisms for the possible effect of smoking on the fetus.
Cigarette smoke contains many leukemogenic compounds including benzene 112 and animal experiments showed the carcinogenic effect of
transplacental cigarette smoke 113. The main carcinogens in cigarette smoke are polycyclic aromatic
hydrocarbons (PAHs) which are activated mainly by the xenobiotic enzyme CYP1A1 114. In experimental models, genetically-determined differences in CYP1A1
activity correlate with susceptibility to chemically-induced leukemia 115. This enzyme is present in the fetal liver and is activated by
maternal cigarette smoking in the placenta 114. Since smoking has a leukemogenic effect in adults 116, and the metabolic pathways involved in this process are active in the
fetus, maternal cigarette smoking may be a serious risk factor for childhood leukemia.
Paternal smoking before conception also increases the risk for childhood ALL
among offspring of non-smoking mothers 117.
Parental occupational exposures
Results
of animal studies support the hypothesis of a relation between a number of
chemical exposures and leukemia risk, particularly pesticides 118; 119. Many pesticides, including household insecticides and agricultural
herbicides and fungicides contain organophosphate 120. Household exposure to insecticides is associated with childhood leukemia
121. A significant association was also found
for pesticide use in gardens (odds ratio [OR] = 2.5) 122. One study which examined the
risk specifically for childhood ALL, found an increased risk associated with
maternal occupational exposure to pesticides (OR = 3.5) 71. There seems to be an agreement
in the overall results of pesticide association studies that they are a risk
factor for childhood leukemia 123. While the xenobiotic enzyme
CYP1A1 is involved in the activation of procarcinogens, GSTM1 and GSTT1
inactivate the carcinogens including those in cigarette smoke, pesticides and
solvents 124-126. It is important that a high frequency of combined
null genotype for GST-M1/T1 has been reported in black children with ALL 127. If lacking the enzymes inactivating the notorious chemicals is a risk
factor for childhood ALL, the epidemiological observations may soon be
confirmed by molecular studies specifically designed to investigate this
possibility. This finding, however, is restricted to the black patients with
childhood ALL at the moment and has not been confirmed by another study.
Parental history of autoimmune
disorders
A
possible link between leukemia, especially CLL, and autoimmune disorders has
been suspected for a long time 128; 129. History of autoimmunity in the family is increased in childhood ALL 130. More specifically, an increased co-occurrence of multiple sclerosis
and leukemia in families has been reported 131; 132. Maternal multiple sclerosis increases the RR four-fold for childhood
ALL, while paternal multiple sclerosis does not make a difference in the risk 132. In this context, it is important to note that leukemic cells in some
cases of virus-induced adult T-cell leukemia seem to have derived from T cells
autoreactive to HLA-DR / DQ molecules 133. Since many common viruses mimic common HLA epitopes as an immune
evasion mechanisms 134-137, similar virus-induced autoimmune reactions may be relevant in the
development of childhood ALL 138.
Birth weight and birth order
Like all other associations, there are
studies for and against the suggestion that high birth weight may be a risk
factor for childhood ALL. The majority of the studies have reported that there
is a higher risk for ALL in children who weigh more than 3,500 to 4,500 g
(depending on the study) at birth 69; 71; 75; 139-142. In a population-based cohort study, a steady increase with increasing
birth weight in ALL risk was noted 104. The same study showed that high birth weight increases the risk also
for childhood AML. The following biological scenario has been constructed to
explain this association 143. Birth weight is correlated positively with circulating
levels of insulin-like growth factor-1 (IGF-1). IGF-1 is important in blood
formation and regulation. It stimulates the growth of both myeloid and lymphoid
cells in culture. Since infants who develop leukemia are likely to have had at
least one transforming event occurred in
utero 62; 144, it has been hypothesized that
high levels of IGF-1 may produce a larger baby while contributing to leukemogenesis.
This hypothesis remains to be tested. (Note added in 2008: One
recent study on birth weight and childhood cancer association found that
heavier babies have higher risk for childhood ALL but in boys only in the North
of England (Dorak,
2007) but see also Milne,
2007 & McNally,
2007).
Being
firstborn or the only child was one of the first identified risk factors for
childhood leukemia 66; 67; 101; 145. Some of the later studies supported this earlier finding 146; 147, whereas some could not find evidence in favor of it 60; 71; 104; 140. Because of a negative confounding effect, when maternal age is taken
into account, the decreasing risk with increasing birth order 67; 101; 145becomes more accentuated 148. No association between birth order and infant leukemia risk was found
75. One study did not find any change in the risk for childhood ALL with
birth order but noted that larger intervals (greater
than five years) between the birth of the proband and the preceding sibling
conferred an increased risk (OR = 1.86) 69. It has been speculated that
birth order may be a surrogate measure for timing of exposure to infectious
agents 149. This suggests that increased
birth order reflects lower ages for exposure to infection 148 which would support the delayed
exposure to infection hypothesis of leukemia development.
There may be another explanation for these observations. The
strong association of childhood ALL with a history of abortion(s) may be a
confounding factor. It is not only being the first child but also being the
only child, which is associated with a high risk, and
longer than 5 years interval between the proband and the preceding sibling is
another risk factor. Thus, the firstborn association may be a reflection of the
most consistent risk factor identified so far, i.e., reproductive failure in
the same families. It is important that if reproductive failure is a
confounder, in those families experiencing fetal losses, the family size will
be small with one or two children. Childhood ALL is not the only cancer which
has an association with being firstborn or small family size. The same has been
observed in testis cancer and the increased risk for testicular cancer among
boys from small families could be explained by the association between family
size and birth order 150. Generally lacking distinction
between the firstborn and the only child in previous studies makes it difficult
to distinguish these possibilities using the available data. It would be
interesting to see if the birth order effect was the same if it was sought only
in the families with no reproductive problems.
Prenatal and postnatal radiation
Although
accounting for a small proportion of cases, prenatal (obstetric) exposures to
diagnostic radiation is considered to be a causal risk factor for childhood ALL
3; 10; 151. In general, the increase in the risk is in the range of 1.4 to 1.7 66; 67; 108; 151-157. In contrast to the increased risk related to diagnostic radiation, no
elevated risk of leukemia was observed in children exposed in utero to atomic bomb radiation 158. Further evidence supporting a leukemogenic effect of diagnostic
X-rays in utero is the increase in
the risk with the number of exposures 151.
Postnatal
diagnostic radiation is not a risk factor for childhood ALL 159. Therapeutic radiation for the treatment of both malignant and benign
conditions 160; 161and exposure to the atomic
blasts of children in Japan 162; 163are associated with elevated risk.
There have been inconsistent observations on the clusters of childhood leukemia
around nuclear power facilities, the most popular one being the Sellafield
report 164. A general consensus seems to have been reached that there is not firm
evidence to believe that the external doses are high enough to cause increases
in childhood ALL 165-168.
Electromagnetic fields
A
possible connection between non-ionizing radiation in the form of
electromagnetic field (EMF) exposure and childhood cancer, including ALL, was
first reported in 1979 169. The results of the following studies have been most inconsistent and
most of them suffered from small numbers of patients in different categories of
exposures. This issue is another one in the epidemiology of childhood ALL, and
in fact in all cancers, which remains inconclusive. The overall data cannot be
said to be pointing towards a definitive etiological link with EMF exposure 10; 166; 170-174. The main problem is that an apparent biological justification is
missing even though there are reported associations.
Medications
Among
the medications reported to have been associated with an elevated risk for
childhood ALL are post-natal use of chloramphenicol 175 and nitrous oxide during delivery 103.
Infections
There
is no proven association of leukemia with childhood infections. Conversely,
there has been some speculation that the occurrence of infections in childhood
is in some way protective for later development of ALL 147. Because of the association of several animal leukemias with viruses,
a viral connection in human leukemia has been frequently considered 176-178. Identification of Epstein-Barr virus (EBV) as the major cause of
specific subtypes of Burkitt's lymphoma and Hodgkin's disease, particularly
paediatric Hodgkin's disease 178-180, and the recent involvement of the human T-cell leukemia virus type I
(HTLV-1) in adult T-cell leukemia (ATL) have given further momentum to the
presumptions that childhood ALL may be a virus-related disease 10. Various reports investigated several infectious agents as possible
etiological agents for childhood leukemia. Among these various animal
retroviruses 181; 182, pre-natal influenza 183-186, chickenpox 187 / varicella 188, enteroviruses 189; post-natal infection with Mycoplasma pneumoniae 190, adenovirus 138; 191; 192and EBV 193-195can be mentioned. An increased
frequency of an influenza-like illness prior to the diagnosis of childhood ALL
has also been reported 196. Most of these suggestions were based on single case reports or
questionnaire-based case-control studies that may have suffered from recall
bias. Biological plausibility of a suggested association has also been an
important issue. In summary, there is no firm evidence available at this time
that consistently associates childhood ALL with either prenatal or postnatal
infection. Two viruses, however, have been thought to be relevant as a result
of sero-epidemiological studies. These are adenovirus and EBV and deserve
further comment.
Lower
titres of antibody to adenovirus indicate either absence of infection or
persistent infection 197. This has been shown in two independent studies for adenovirus in
children with leukemia 191; 192. If this is taken as an indication of persistent infection with
adenovirus in leukemic children, then, one has to justify a biological role for
adenovirus in the development of leukemia. An interaction between a specific
HLA type and specific adenovirus types has been postulated as a promoter in the
clonal evolution of childhood B-lineage ALL 138 (Dorak,
1996). Promotion of pre-existing mutant clones that have arisen
spontaneously to overt malignancy may have a precedent in the form of low-grade
gastric B-cell lymphoma associated with Helicobacter
pylori 198. This tumour occurs in the presence of the bacteria and regresses with
the elimination of the bacteria. The adenovirus model makes use of the B-cell
tropism and the well-known immunoevasive features of adenovirus 197; 199-201, as well as the extensive molecular mimicry between adenoviruses and
HLA-DR53 137. It remains to be a speculation in the absence of experimental data.
PCR studies have shown that adenovirus may cause
fetal infection that was otherwise unrecognized 202. Thus, unless ruled out, it
remains a possibility that adenovirus may take part in the development of
childhood ALL. (Note added in
2008: No
direct data have been generated to support the adenovirus hypothesis proposed
by Dorak with the exception of limited data on the increased frequency of adenoviral
sequences in leukemia cells (Fernandez-Soria,
2002) but that study suffered from a contamination problem. Most recently,
adenovirus DNA was detected in Guthrie cards of childhood ALL cases more
frequently than healthy children (Gustafsson,
2007) although the authors do not seem to be aware of the previously
published hypothesis on this connection (Dorak,
1996)).
In
another study, which did not investigate adenovirus-specific antibodies,
antibodies to EBV were found more frequently in leukemic children under the age
of 6 years than in age-matched control subjects 195. Although this study conflicts with an earlier one 192, since B lymphocytes are a major target also for EBV 197; 201; 203, and EBV mimics the same epitope of HLA-DR53 as adenoviruses do 137, a similar scenario can be valid for EBV.
Infection related hypotheses
In
the late 1980s, Greaves suggested that the most common form of childhood ALL,
common ALL, which is responsible for the age peak, may be due to two separate
genetic events 62; 144. The first event is thought to be a spontaneous mutation in a B cell
precursor and occurs in utero. This
transformed B cell precursor clone will proliferate when exposed to a later
antigenic challenge. The second stage is influenced by external agents which results in an expansion of the transformed B cell
clone into clinically overt ALL. Older children who have delayed exposures to
specific agents may experience more vigorous B-cell proliferation, resulting in
an increased probability of the second genetic event leading to leukemia. In
essence, this hypothesis says that the childhood ALL peak may be due to delayed
antigenic challenge from common infections contracted after the usual exposure
period in infancy. Under his hypothesis, either non-specific antigenic
challenge or infection modulate the late-stage
malignant events leading to common ALL in the childhood peak. This hypothesis
proposes that immunological isolation in infancy increases the risk of common
ALL arising in the childhood peak. Greaves suggests that no specific infectious
agent is involved but reduced antigenic challenge in infancy can lead to
increased proliferation of a preleukemic clone when a later infection occurs.
There are biological and epidemiological data providing indirect support for
this broad hypothesis. The epidemiological data,
reviewed by Greaves and Alexander 64, indicate that risk of common
ALL increases by higher socio-economic status, isolation, and other community characteristics
suggestive of abnormal patterns of infection during infancy. Delayed exposure
to a common infection can indeed behave differently from the earlier exposure,
and may lead to a different pathological condition. The precedent of this model
is paralytic poliomyelitis 204; 205. A similar model has also been
proposed for the development of Hodgkins disease 205-207, multiple sclerosis 208, and atopic diseases 209. In the case of atopic diseases,
isolation as an infant as opposed to going to a child care center, small family
size, and higher socio-economic status are predictors of a higher risk of
allergies in childhood 209.
Kinlen
hypothesized in 1988 that common ALL may be a rare response to an unidentified
mild or subclinical infection, the transmission of which is facilitated when
large numbers of people come together, particularly from a variety of origins 63. He considered the clusters of leukemia surrounding nuclear
installations as a result of massive migration into previously remote and
unpopulated areas 210; 211. He suggests that the influx of individuals into an isolated community
produces conditions in which leukemia is more likely to occur. Isolated
communities newly exposed to migrants from elsewhere could experience an
unusual exposure to some hypothetical infectious agent(s) to which no (herd)
immunity exists 212. The novel mix of infectious agents met by families in these new
environments may cause some immune dysregulation in susceptible children. Kinlen
suggests that isolated communities may be too small to maintain common
infections in endemic form and may experience miniepidemics 63; 210; 213. The study of clusters and clusterings of childhood ALL 45 suggests an etiological role for one or more agent(s). The agent must
be common or even ubiquitous because, for example, it is present in each
instance of population mixing which form the basis of this hypothesis 65. There is also evidence that population density is correlated with
childhood ALL risk which may be indicative of a viral involvement 214.
Another
model, called the aberrant response model, relies heavily on earlier hypotheses
of Kinlen and Greaves but is more general than either of them 45. It states that a substantial proportion of childhood ALL cases arise
as a rare host response to certain patterns of exposure to common infectious
agents. The model does not attempt to define biological mechanisms, and is
consistent with Greavess hypothesis for the childhood peak but extends to all
childhood ALL. Under the model, a specific but yet unknown transmissible agent
is causally associated with childhood ALL. For children diagnosed in the childhood
peak, primary infection may occur shortly before diagnosis while for other
ages, attention has focused on gestational / neonatal exposure leading to
persistent infection. In this situation too, exposure close to diagnosis may be
involved. Thus, the unknown agent is expected to be able to establish
persistent infection.
(Note added in 2008: The latest UKCCS paper
unambiguously reports a correlation between increased infections in infancy and
childhood ALL (earlier onset) (Roman,
2007; see also Dorak, 2007).
The authors acknowledge that these findings do not support the original
(Greaves) hypothesis that a deficit of exposure to infectious agents is
associated with an increased risk of ALL development (i.e., delayed infection
hypothesis) but interpret the data as supporting the hypothesis that a
dysregulated immune response to infection in the first few months of life
promotes transition to overt ALL later in childhood (Roman,
2007). The original hypothesis was that delayed common infections would
cause an abnormal or dysregulated immune response and that would trigger ALL
development (Greaves
1988; 1993;
2006)).
In
summary, the infection-related hypotheses propose delayed exposure to a
childhood infection(s). The agent must be common in childhood, should also
infect adults and should be able to establish persistent infection. The two
infections mentioned above, adenovirus and EBV, meet
these criteria. A recent study found a converse association between EBV
seropositivity and childhood leukemia 215. The adenovirus link has
been neither tested nor challenged.
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Children
with Leukemia Leukemia
Research Fund (LRF) - UK Leukemia
Research Foundation - US Leukemia & Lymphoma Society-US Cancer Research-UK
For
a more up-to-date review of all childhood cancers, please see:
M.Tevfik Dorak,
MD, PhD
Original
Publication in 2000; last edited on 26 February 2008
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