All in ALL

 

Greaves, Kinlen, and Smith have each described different hypotheses describing mechanisms by which infections may cause childhood acute leukemia (See newest study below regarding day care). These theories maintain that childhood acute lymphoblastic leukemia (ALL) results from the lack of immune stimulation from infection in infancy, rare response to a common but unidentified infection in childhood, and infection of the mother while pregnant, respectively. While we have often reviewed studies on infection and leukemia [see C3 Vol. 15(4), 15(1), 13(6), 13(5) among many others], evidence addressing a theory is best assessed as a whole. These data includes ecologic, cohort, and case-control studies of history of infection, infection proxies, breast feeding, vaccination, serology, and spatiotemporal clustering. McNally R and Eden T recently reviewed this literature and interpreted it in light of the three hypotheses [Br J Haematology 2004; 127: 243-263. The authors used PubMed to search the medical literature for articles on infections and childhood leukemia published from 1970 to the present. They then summarized the assembled research with a special concentration on significant results and those from studies published subsequent to Little's review of the literature through 1998 [ Epidemiology of Childhood Cancer . IARC Scientific Publications, No. 149]. Incidence of lymphoid leukemias is clearly higher in industrialized countries compared to developing ones, and shows a marked peak in early childhood. Moreover, incidence of leukemia has increased over time, just as exposure to infectious agents has decreased, in countries with improving standards of living. On the other hand, many factors vary between rich and poor nations. Other ecologic studies have examined whether leukemia clusters in space, time, or both. Significant spatiotemporal clustering has been found for place and time of birth as well as time of diagnosis, which is consistent with a role for infections in leukemia etiology both pre- and postnatally. Several studies have found significant seasonal clustering in leukemia diagnoses but peak seasons have differed. Quite a few studies have also found that leukemia incidence increases following population influxes into previously isolated areas, which may be interpreted as having changed the dynamics of infection to a leukemogenic agent. Twelve studies reported on maternal infection during pregnancy; in four risk of leukemia in offspring was significantly increased, in two risk was non-significantly increased, and in six the results were null. Evidence for associations of childhood infections and vaccinations were similarly equivocal. McNally and Eden concluded that “Overall there was a tendency for longer duration of breast feeding to decrease the risk of childhood leukaemia developing,” but noted that, in case-control studies, these results may be an artifact of the typically higher socioeconomic status of control series. Day care attendance also on balance seemed protective for ALL but may have been susceptible to the same sort of bias. Higher birth order has been found both to raise and to lower risk of leukemia significantly. Finally, a number of studies have looked for the DNA sequences of or antibodies to candidate leukemia viruses in either leukemia cells or in neonatal blood spots. These studies have occasionally found positive results, though for different viruses, and most suffer from an inability to distinguish whether infection or leukemia came first.

 

COMMENT: McNally and Eden have performed a valuable service in assembling and summarizing over 130 references that focused on the infectious hypotheses of leukemia etiology. Although the authors did not weight the evidence based on the quality of studies or perform a formal meta-analysis, it is clear that none of these hypotheses have been proven. The necessity of using the case-control study design, the lumping together of diverse types of leukemia in case series, and the diffuse nature of infectious exposure have hampered research. The need to consider causes for an in utero and a postnatal genetic event, both of which are likely necessary for overt leukemia, also clouds interpretation. Enough evidence supports the infectious hypotheses of leukemia etiology to maintain their intrigue, but innovative approaches are required to move the field further. These could include the development of animal models, biomarker studies that look at the response to delayed infection in populations of children, and the exploitation of the presence of pre-leukemic clones at birth.

Logan G. Spector

 

 

Day care: The early bird catches the germ(s)

 

In a new paper, Gilham C et al [British Medical Journal, published online April 22, 2005] evaluated Greaves hypothesis in a large population-based case-control study of childhood cancer. Greaves hypothesis proposes that a lack of exposure to infections early in life leads to a dysfunctional proliferative response to a common infection later in life, which may help explain the 2-5 year age peak in common childhood ALL (cALL). Parents of 3140 children diagnosed with cancer after the age of 2 years and 6305 children without cancer aged 2-14 years were interviewed regarding the types of social activity with other children experienced during the first year of life (including informal and formal day care). Of these case children, 1286 were diagnosed with ALL (798 cALL, 139 TEL-AML1, and 420 hyperdiploid ALL), 192 with other leukemia, 578 with a CNS tumor, 227 with NHL, 117 with HD, and 740 other tumor types. More control (85.7%) mothers reported social activity of their children in the first year of life compared to case mothers (80.2% for ALL, 82.0% for non-ALL malignancies). For ALL diagnosed between 2 and 5 years, there was a reduction in risk associated with increasing social activity (Odds Ratio (OR)=1.00 for no social activity, OR=0.70 (95% Confidence Interval (CI)=0.54-0.89) for social activity, but no day care; OR=0.59, 95% CI=0.45-0.77 for informal day care only; and OR=0.49, 95% CI=0.35-0.68 for formal day care (p for trend < 0.001). Importantly, a similar, but slightly less striking inverse trend was observed for non-ALL malignancies, suggesting an across-the-board protective effect of increased social contacts. Further, the protective effect for ALL was less pronounced among cases diagnosed 2-5 years of age, and more apparent in older children.

 

COMMENT: This study was well-conducted and suggests that early day care may be related to a decreased risk of childhood cancer, including ALL. The non-specificity of the observed association (i.e., not confined to the 2-5 year ALL age peak), however, is somewhat unexpected. The authors note that the inverse association with day care was seen across all age groups and major groupings of cancer sites. There is some concern that residual confounding such as socioeconomic status (SES) (which is difficult to adjust for) may explain some of these effects. For example, if high SES, which tends to also be associated with ability to afford day care, is associated with less likelihood for children to be exposed to potential leukemogenic agents (such as pesticides, etc), the conclusion may be biased. Another limitation to this study is that a surrogate measure of infections was used. Nevertheless, this is one of the most comprehensive and well-done studies on the topic. The performance of almost 10,000 interviews is a remarkable feat in itself. The underlying biological explanation also makes sense, as a well-primed immune system may decrease the risk of malignancy and other diseases.

Julie A. Ross

 

COAST with the most

 

Not surprisingly, investigations of both allergy and childhood leukemia have inquired about children's exposure to day care and older siblings, which increase the likelihood of infection and are easily measured. A new study [Hoffjan S et al. Am J Hum Genet 2005; 76: 696-704] suggests that immune genotype interacts with day care attendance to modulate immune response. The Childhood Onset of Asthma (COAST) study enrolled 208 white children at birth who, because of a family history of allergy, were considered at high risk of developing asthma. Blood samples were obtained from children at birth and one year of age. These were assayed for serum levels of interferon gamma, interleukin 5, interleukin 10, and interleukin 13 cytokines. Genotypes were also determined for 72 polymorphisms in 45 immune regulating genes. Sibship, day care attendance (defined as >10 hours per week of care outside the home or in the home with the mother caring for other, unrelated children), viral infections, and atopic phenotypes in the first year of life were determined. Using logistic regression, infection proxies and genotype were related to atopic phenotypes and change in cytokine levels. There were 99 children who attended day care and 109 who did not. Of these, 46 and 69 children, respectively, had older siblings in the household. Children who attended day care had more viral infections in the first year of life (mean = 1.73 + 0.16) than did other children (mean = 1.19 + 0.12). There were 22 significant (p < 0.01) interactions between day care attendance and candidate polymorphisms, six of which were estimated to be true associations after adjusting for multiple comparisons. Interestingly, only one polymorphism in IL13 was associated with atopic phenotype in the absence of day care attendance.

 

COMMENT: While the results of the COAST study are not directly applicable to the study of ALL, they do highlight the complexity between environment and immune genotype. They also provide a useful paradigm for the type of study that might inform leukemia research.

Logan G. Spector

 

Hyperactive cytogenetic effects

 

Controversy exists regarding the potential harmful affects of methylphenidate hydrochloride (MH) or Ritalin for the treatment of attention deficit/hyperactivity disorder (AHDH) in children. MH has been in use for over 50 years. One animal model of potential carcinogenicity of MH in mice found an increased risk of liver tumors, while the same study in rats found no elevated risk [Dunnick JK et al, Toxicology 1995; 103:77-84] . In the current report, potential mutagenicity was evaluated in blood samples collected from 12 children who were prescribed MH for ADHD [El-Zein RA, et al. Cancer Letters Feb 16, 2005; online] . A 10ml blood sample was collected prior to MH treatment and after 3 months of treatment. Assays used included a) a conventional cytogenetic assay that evaluates chromosomal aberration frequency, b) a sister-chromatid-exchange (SCE) assay, which examines cross-over events between chromosomes, and c) the micronuclease (MN) assay, which detects damage to chromosomes. For all children, and across all three assays, a significantly higher frequency of cytogenetic aberrations was present in the blood samples following MH therapy compared to no therapy. For example, the mean number of SCEs after treatment was 26.27, compared to 6.09 prior to therapy. The authors conclude that further investigation of MH is warranted.

 

COMMENT: Based on their findings, the authors conclusions are correct. However, there needs to be an appropriate study design. Besides small numbers, the difficulty with interpreting these results includes a) lack of randomization, b) possibility of a lab artifact, and c) possibility of a seasonal effect. To address these concerns, it will be important to design a randomized cross-over study, and include healthy children with no drug treatment over the same time period. It is unknown whether the effects observed here might be due to mitigating factors. While the observation that samples demonstrated high levels of aberrations following drug treatment may suggest that MH is mutagenic, it might also suggest that the processing of blood samples at two separate times (with no randomization) differed and thus influenced the results.

Julie A. Ross

 

C3 Quarterly Newsletter
Children's Cancer Research Fund
Epidemiology Research Unit
Division of Pediatric Epidemiology
Clinical Research
University of Minnesota
420 Delaware St. SE, Box 422
Minneapolis, MN 55455
pedsepi@umn.edu

Editors: 
Stella M. Davies, MD, PhD, and Julie A. Ross, PhD