Etiology Of Childhood Leukemia Research Articles

Leukaemia in children in Papua New Guinea: an unusual pattern.

We report data on 110 children aged <15 years diagnosed with leukaemia during two periods covering 13.25 years. The data sets were consistent. The reported incidence of leukaemia was low. Only 34 (31%) of the children were diagnosed with acute lymphoblastic leukaemia (ALL) compared with 54 (49%) children with acute myeloid leukaemia (AML). The overall mean (SD) age was 6.6 (3.5) years, 6.1 (3.5) for ALL and 6.9 (3.5) for AML. There was no evidence of an early childhood peak of ALL. The male : female ratio was 1.2 : 1 for all leukaemias, 1.3 for ALL and 1.25 for AML. Only eight (22%) of those diagnosed with ALL were classified as type L1. Our figures reflect a relative absence of the common (cALL) cell type in early childhood leukaemia and support the role of infection and its effect on the immune system in the aetiology of childhood leukaemia. Our data also revealed an unusually high proportion of chronic myeloid leukaemia (CML).

Maternal herpesvirus infections and risk of acute lymphoblastic leukemia in the offspring.

A critical role for infection in the etiology of childhood leukemia has repeatedly been suggested. The authors undertook a case-control study nested within national maternity cohorts with altogether 7 million years of follow-up to assess the relative role of three maternal herpesvirus infections in childhood acute lymphoblastic leukemia (ALL). Offspring of 550,000 mothers in Finland and Iceland formed the joint study cohort that was followed up for cancer in the offspring before age 15 years during 1975-1997 through national cancer registries. For each index mother-case pair, three or four matched control mother-control pairs were identified from national population registers. First-trimester sera were retrieved from mothers of 342 ALL and 61 other leukemia cases and from 1,216 control mothers and were tested for antibodies to cytomegalovirus, Epstein-Barr virus (EBV), and human herpesvirus 6. Serum EBV DNA was also analyzed. Conditional logistic regression-based estimates of relative risk (odds ratio) adjusted for birth order and sibship size, and population attributable fractions, were calculated. Only EBV immunoglobulin M positivity in EBV-immunoglobulin-G-positive mothers was associated with a highly significant increased risk of ALL in the offspring (adjusted odds ratio = 2.9, 95% confidence interval: 1.5, 5.8). Results indicate that reactivation of maternal EBV infection is probably associated with childhood ALL.

Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia.

The role of methylenetetrahydrofolate reductase (MTHFR C677T), glutathione S-transferases (GSTM1 and GSTT1 null, GSTP1 Ile105Val), and cytochromes p450 (CYP1A1*2A) genotypes in the etiology of childhood leukemia was simultaneously investigated. 144 Turkish children with acute lymphoblastic leukemia (ALL) and 33 with acute nonlymphoblastic leukemia (ANLL) were studied and compared with 185 healthy pediatric controls. The frequency of MTHFR genotype was insignificantly higher in ALL (7.7%) and ANLL (6.3%) than in controls (4.4%). Equal distribution of the GSTM1 null genotype was detected between ALL patients and controls (55%), while its incidence was slightly higher in ANLL patients (61.3%). Although GSTT1 null genotype was insignificantly lower in ALL patients (20.9%) than controls (22.7%), it was significantly underrepresented in ANLL patients (6.5%) (P = 0.05, OR 0.24, 95% CI 0.05-1.03). The homozygous frequency of GSTP1 genotype did not differ significantly between groups of ALL (3.7%), ANLL patients (9.1%) and controls (4.9%). Homozygous CYP1A1*2A genotype was underrepresented in ALL patients (1%) as compared to control (4.8%) but the differences did not reach to statistical significance (OR 0.21; 95% CI 0.03-1.72). Homozygosity for this genotype was not detected in ANLL patients. No particular association was noted between different combinations of combined genotypes and risk of development of childhood ALL and ANLL. These results suggested that there are no significant associations between the studied genotypes and the risk of developing either form of acute leukemia except GSTT1 null and homozygosity for CYP1A1 genotypes that may play protective roles in the development of ANLL in Turkish children.

Chromosome translocations and covert leukemic clones are generated during normal fetal development.

Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins ( approximately 5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10(-4) to 10(-3)) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia.

Screening for herpesvirus genomes in common acute lymphoblastic leukemia.

There is epidemiological evidence that infection may play a role in the etiology of childhood leukemia in particular common B cell precursor acute lymphoblastic leukemia. A panel of 20 leukemic samples (panel 1) was examined for the presence of four lymphotropic herpesviruses using conventional molecular techniques. A second independent panel of 27 leukemic samples (panel 2), along with 28 control peripheral blood samples from children with other forms of cancer, was tested for the presence of the same four viruses using sensitive real-time quantitative PCR. While herpesvirus genomes were detected, they were present at very low levels; detection rates and levels were similar in the leukemic and control panels. In addition we surveyed 18 leukemic samples (five from panel 1, six from panel 2 and a further seven samples not previously analyzed) using a degenerate PCR assay capable of detecting the genomes of known herpesviruses plus putative new members of the family. No novel herpesvirus genomes were detected suggesting that a herpesvirus is unlikely to be etiologically involved as a transforming agent in common acute lymphoblastic leukemia.

Season of birth and diagnosis of children with leukaemia: an analysis of over 15 000 UK cases occurring from 1953-95.

If infections are involved in the aetiology of childhood leukaemia then seasonal variation in the birth or onset dates of the malignancy may be apparent. Previous studies that have examined seasonality of these dates have produced conflicting results. Using population-based data from the National Registry of Childhood Tumours we conducted a larger study than any to date of 15 835 cases of childhood leukaemia born and diagnosed in the UK between 1953–95. We found no evidence of seasonality in either month of birth or month of diagnosis overall or in any subgroups by age, sex, histology or immunophenotype. We did however find a significant (P= 0.01) February peak in month of birth for cases born before 1960 and a significant (P= 0.02) August peak in month of diagnosis for those diagnosed before 1962. Whilst these findings may be due to chance they are also consistent with changes over time in the seasonality of exposure, or immunological response, to a relevant infection. Changes in the seasonal variation in the fatality rate of a pre-leukaemic illness, such as pneumonia, could be another explanation. © 2001 Cancer Research Campaign http://www.bjcancer.com

Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia.

Infections are suspected to play a role in the aetiology of childhood leukaemia. In 1989–95, we evaluated the relation between childhood acute lymphoblastic leukaemia and pre- and postnatal markers of exposure to infection, as well as breast-feeding. A population-based case-control study was carried out in certain regions of Québec, Canada, in 1989–95 including 491 incident cases diagnosed between 1980 and 1993 and aged between 0 and 9 years. An identical number of healthy controls matched for age, sex and region of residence at the date of diagnosis was included. Having older siblings, mother's use of antibiotics during pregnancy, and being born second or later were all associated with increased risk of leukaemia while early day-care attendance (odds ratio (OR) = 0.49; 95% CI 0.31–0.77), and breast-feeding (OR = 0.68; 95% CI 0.49–0.95) were significantly protective. A marker of population mixing was not a risk factor. When including all variables defining family structure in a model, having older siblings at time of diagnosis was a risk factor among children diagnosed before 4 years of age (OR = 4.54; 95% CI 2.27–9.07) whereas having older siblings in the first year of life was protective among children diagnosed at 4 years of age or later (OR = 0.46; 95% CI 0.22–0.97). © 2000 Cancer Research Campaign http://www.bjcancer.com

Infections, vaccinations, and the risk of childhood leukaemia.

A nationwide case-control study was conducted in New Zealand, to test hypotheses about the role of infections in the aetiology of childhood leukaemia. Children aged 0–14 years with leukaemia were matched on age and sex to controls selected from birth records. Case ascertainment was virtually complete and 121 (92%) of 131 eligible case families took part. The participation rate among the 303 first-choice eligible controls was 69%. Home interviews and serological tests were conducted. Adjusted relative risks were estimated by logistic regression. There was an increased risk of leukaemia in relation to reported influenza infection of the child during the first year of life (adjusted odds ratio 6.8, 95% confidence interval 1.8–25.7). This could be a chance finding due to multiple comparisons, and it should be tested elsewhere. Some key variables relevant to Greaves' hypothesis were not associated with B-cell precursor acute lymphoblastic leukaemia (numbers of infections and vaccinations, firstborn status, attendance at preschool groups), although a small effect could not be ruled out with a study of this size. Leukaemia risk was higher among children in poorer social circumstances, and this was true for all eligible children as well as for the participants. © 1999 Cancer Research Campaign

Insulin-like growth factor-I and binding protein-3 in relation to childhood leukaemia.

The aetiology of most cases of childhood leukaemia remains unknown, but several studies have indicated that increased birthweight and height are risk factors for the disease. Since insulin-like growth factor-I (IGF-I) mediates the effect of growth hormone and has been positively associated with prostate cancer, we have evaluated the role of this hormone and its principal binding protein, IGFBP-3, in the aetiology of childhood leukaemia. Incident cases of childhood leukaemia from those recorded by a national network of childhood oncologists were enrolled in our study. Controls were children hospitalised for acute conditions of no more than moderate severity with matching for gender, age and maternal place of residence. Blood measurements of IGF-I and IGFBP-3 were undertaken using commercially available radioimmunoassays. Serum IGF-I values decreased by about 1.7% per month, and the rate of decline was higher, though not significantly so, among cases (2.1% per month) than among controls (1.4%). There was no significant association between IGF-I and the likelihood of childhood leukaemia, but an increment of 1 microg/ml of IGFBP-3 was associated with a substantial and statistically significant reduction of childhood leukaemia by 28% (95% confidence interval 7% to 45%). Because IGFBP-3 is essentially a binding protein, we interpret our findings as indicating that bioavailable IGF-I may play an important role in the aetiology of childhood leukaemia. The much smaller quantities and the inherent instability of IGF-I in the blood in comparison to those of IGFBP-3 are likely to hinder documentation of an underlying positive association of IGF-I with the disease.

Childhood leukemia and personal monitoring of residential exposures to electric and magnetic fields in Ontario, Canada.

To evaluate the risk of childhood leukemia in relation to residential electric and magnetic field (EMF) exposures. A case control study based on 88 cases and 133 controls used different assessment methods to determine EMF exposure in the child's current residence. Cases comprised incident leukemias diagnosed at 0-14 years of age between 1985-1993 from a larger study in southern Ontario; population controls were individually matched to the cases by age and sex. Exposure was measured by a personal monitoring device worn by the child during usual activities at home, by point-in-time measurements in three rooms and according to wire code assigned to the child's residence. An association between magnetic field exposures as measured with the personal monitor and increased risk of leukemia was observed. The risk was more pronounced for those children diagnosed at less than 6 years of age and those with acute lymphoblastic leukemia. Risk estimates associated with magnetic fields tended to increase after adjusting for power consumption and potential confounders with significant odds ratios (OR) (OR: 4.5, 95% confidence interval (CI): 1.3-15.9) observed for exposures > or = 0.14 microTesla (microT). For the most part point-in-time measurements of magnetic fields were associated with non-significant elevations in risk which were generally compatible with previous research. Residential proximity to power lines having a high current configuration was not associated with increased risk of leukemia. Exposures to electric fields as measured by personal monitoring were associated with a decreased leukemia risk. The findings relating to magnetic field exposures directly measured by personal monitoring support an association with the risk of childhood leukemia. As exposure assessment is refined, the possible role of magnetic fields in the etiology of childhood leukemia becomes more evident.

A multi-level log-linear model of childhood leukaemia mortality

The potential role for multi-level modelling in analysing the distribution of a rare disease is described using data on childhood leukaemia mortality in under 2s in local authority districts of England and Wales for the period 1950–53. There is growing evidence that an infection may be involved in the aetiology of childhood leukaemia, mediated by population mixing processes. In this example, the presence of armed forces personnel is analysed with respect to individual deaths from childhood leukaemia. The discussion focuses on how extra information may be gained from use of a multi-level model, and on methodological issues associated with analysing sparse data sets.

Immunogenetics and the aetiology of childhood leukaemia.

Immunogenetics and the aetiology of childhood leukaemia.

Suggestion of concomitant changes of electric power consumption and childhood leukemia in Greece.

Over a 14-year period (1976-89) 679 deaths from childhood leukemia were registered in Greece and the corresponding mortality over this period declined by almost 70%, with no evidence of differential reduction by gender or population type. For each of the nine geographical regions of the country, slopes of decreasing mortality from childhood leukemia over the study period were calculated and correlated with the corresponding slopes of increasing electric power consumption over the 16-year period 1970-85 (allowing for a postulated latency of about 5 years). A positive association was noted, which however was not statistically significant (p approximately 0.26). Studies of similar nature conducted in larger countries over more extended periods could contribute to the resolution of the controversy surrounding the role of electric power-generated extremely low frequency electric and magnetic fields in the etiology of childhood leukemia.

Infectious aetiology of childhood leukaemia

Infectious aetiology of childhood leukaemia

Etiology of childhood leukemia: A possible alternative to the Greaves hypothesis

Whenever a country has experienced a significant decrease in infant mortality there has always been a concomitant increase in childhood cases of acute lymphoblastic leukemia (ALL). According to Greaves, this increase is the result of a new type of leukemia, which was first seen in Britain between 1920 and 1940. An alternative hypothesis is proposed which assumes that, for childhood cases of ALL, infections are competing causes of death and for juvenile myeloid leukemia (JML) the principal competitor is the sudden infant death syndrome (SIDS). The SIDS association is the result of JML originating in undifferentiated (erythro-myeloid) stem cells and having faulty erythropoiesis as a side effect. With this congenital anomaly as part of the disease process, the low oxygen pressures of deep sleep may be sufficient to cause sudden death from tissue anoxia.