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Our aim was to investigate the ecological association between death from infectious disease of the respiratory system and the risk of acute lymphoid leukaemia (ALL) in children aged less than 7 years. Poisson regression analyses were carried out using overall data and gender-specific models. The study included 176 cases (92(52.3 %) boys and 84 (47.7 %) girls) of ALL in those aged 0-6 years in South Hungary. Eight cases were diagnosed before the age of 1 year. A significant risk of ALL disease was observed with higher levels of mortality from the chronic respiratory diseases (p = 0.035) and pneumonia (p = 0.010) among children aged 2-5 years (Odds Ratio for trend was 1.001 and 95%CI [1.000-1.002] and Odds ratio for trend was 1.013 and 95%CI [1.003-1.023], respectively). Significantly increased risk of childhood ALL was detected among children under 1 year of age residing in areas around birth with higher levels of mortality from influenza (Odds Ratio (OR) for trend was 1.05; 95%CI [1.01-1.09]; p = 0.012). This risk was also detected in girls (p < 0.001), but not in boys (p = 0.43). Our findings provide new evidence that will help to understand the different pattern of female and male childhood ALL occurrence , but further studies are needed using detailed individual medical history to clarify the role of influenza and other infectious diseases in the etiology of childhood ALL and to explain gender-specific effects.

Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21). We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.

Background: Higher birth weight and maternal history of miscarriage has been associated with an increased risk of childhood leukemia. The possibility that this association may be sex-specific has not been explored in detail in previous studies., Methods: In a retrospective case-control study, 732 childhood (< or =14 years) cancer cases from a population-based Registry in Northern England whose hospital birth records could be accessed and 3,723 controls matched for date and hospital of birth to the cases were compared. We examined birth weight for sex-specific associations with childhood cancer. Conditional logistic regression analysis was used for statistical evaluation of associations., Results: In acute lymphoblastic leukemia (ALL) (225 cases and 1,163 matched controls), birth weight and sex showed a strong interaction (P = 0.003). In boys with ALL, but not in girls, there was a nonlinear association with birth weight (P for trend = 0.008; OR = 3.05 for the highest quintile compared to the second lowest quintile, 95% CI = 1.40-6.64; P = 0.005). When birth weights were adjusted using UK standards for gestational age and sex, the risk associations were similar in statistical significance and magnitude. Maternal history of miscarriage showed an association with all cancers and individually with ALL. The miscarriage association with ALL was statistically significant in boys only (OR = 1.91, 95% CI = 1.07-3.42; P = 0.03). A multivariable model for ALL containing other examined maternal and reproductive variables confirmed the independence of the birth weight and miscarriage associations. There was no birth weight or miscarriage associations in other cancers., Conclusions: This study confirmed the risk associations with birth weight and miscarriages in childhood ALL. Statistically significant association of size at birth suggested marked differences in etiology between girls and boys.

There are three current hypotheses concerning infectious mechanisms in the aetiology of childhood leukaemia: exposure in utero or around the time of birth, delayed exposure beyond the first year of life to common infections and unusual population mixing. No specific virus has been definitively linked with childhood leukaemia and there is no evidence to date of viral genomic inclusions within leukaemic cells. The case-control and cohort studies have revealed equivocal results. Maternal infection during pregnancy has been linked with increased risk whilst breast feeding and day care attendance in the first year of life appear to be protective. There is inconclusive evidence from studies on early childhood infectious exposures, vaccination and social mixing. Some supportive evidence for an infectious aetiology is provided by the findings of space-time clustering and seasonal variation. Spatial clustering suggests that higher incidence is confined to specific areas with increased levels of population mixing, particularly in previously isolated populations. Ecological studies have also shown excess incidence with higher population mixing. The marked childhood peak in resource-rich countries and an increased incidence of the childhood peak in acute lymphoblastic leukaemia (ALL) (occurring at ages 2-6 years predominantly with precursor B-cell ALL) is supportive of the concept that reduced early infection may play a role. Genetically determined individual response to infection may be critical in the proliferation of preleukaemic clones as evidenced by the human leucocyte antigen class II polymorphic variant association with precursor B-cell and T-cell ALL.

Childhood leukaemias and lymphomas have been associated with exposure to environmental factors, including infections, which show geographical variation. This study examined the geographical distribution of the incidence of acute leukaemia and lymphoma using Manchester Children's Tumour Registry (MCTR) data 1976-2000. A total of 910 children were included, all of whom had histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses, all the children were aged 0-14 years and were resident in the counties of Greater Manchester or Lancashire. Standardized morbidity ratios were calculated. Poisson regression was used to examine the relationship between incidence rates and small-area (census ward) population density, ethnic composition and deprivation index. There was a monotonic relationship between acute lymphoblastic leukaemia (ALL) incidence and population density (P = 0.05). Higher rates were seen in more densely populated areas. There was evidence for a monotonic relationship between the incidence of the mixed cellularity subtype of Hodgkin's disease (HD) and the Townsend deprivation score (P = 0.001). Markedly higher incidence was associated with greater levels of unemployment and household overcrowding. The results for ALL and mixed cellularity HD support the involvement of environmental factors, such as infections, in disease aetiology.