JC and BK virus sequences are not detectable in leukaemic samples from children with common acute lymphoblastic leukaemia

Epidemiological evidence suggests that childhood leukaemia, and possibly common acute lymphoblastic leukaemia in particular, may have an infectious aetiology. Smith (1997 J Immunother20: 89–100) recently suggested that the critical infectious event occurs during pregnancy, and identified the polyoma virus JC as a candidate agent. In the present study we investigated whether genomes from the JC virus, and closely related BK virus, could be detected in leukaemic cells. No positive results were obtained suggesting that JC virus is unlikely to play a direct role in leukaemogenesis. © 1999 Cancer Research Campaig

Association of childhood acute lymphoblastic leukaemia with cancers in family members

Children whose twins have had leukaemia have a higher risk of contracting acute lymphoblastic leukaemia (ALL), confirming a prenatal origin of the disease. This association was not true when considering other types of affected first-degree relatives. Children whose fathers were diagnosed with testicular cancer have a higher risk of ALL

Population mixing and leukaemia in young people around the La Hague nuclear waste reprocessing plant

In order to investigate for an association between population mixing and the occurrence of leukaemia in young people (less than 25 years), a geographical study was conducted, for the years 1979 to 1998, in Nord Cotentin (France). This area experienced between the years 1978 and 1992 a major influx of workers for the construction of a nuclear power station and a new nuclear waste reprocessing unit. A population mixing index was defined on the basis of the number of workers born outside the French department of ‘La Manche’ and living in each ‘commune’, the basic geographical unit under study. The analyses were done with indirect standardisation and Poisson regression model allowing or not for extra-Poisson variation. Urban ‘communes’ were considered as the reference population. The Incidence Rate Ratio was 2.7 in rural ‘communes’ belonging to the highest tertile of population mixing (95% Bayesian credible interval, 95%BCI=1.2–5.9). A positive trend was observed among rural strata with increasing population mixing index (IRR for trend=1.4, 95%BCI=1.1–1.8). The risk became stronger for Acute Lymphoblastic Leukaemia in children 1–6 years old in the highest tertile of population mixing (IRR=5.5, 95%BCI=1.4–23.3). These findings provide further support for a possible infective basis of childhood leukaemia

Single cell analysis identifies <em>CRLF2</em> rearrangements as both early and late events in Down syndrome and non-Down syndrome acute lymphoblastic leukaemia

Deregulated expression of the type I cytokine receptor, CRLF2, is observed in 5-15% of precursor B-cell acute lymphoblastic leukaemia (B-ALL). We have previously reported the genomic landscape of patients with CRLF2 rearrangements (CRLF2-r) using both whole genome and exome sequencing, which identified a number of potential clonal and sub-clonal genomic alterations. In this study, we aimed to assess when the CRLF2-r; IGH-CRLF2 or P2RY8-CRLF2, arose during the evolution of both Down syndrome-ALL (DS-ALL) and non-DS-ALL. Using fluorescence in situ hybridisation, we were able to track up to four structural variants in single cells from 47 CRLF2-r B-ALL patients, which in association with our multiplex single cell analysis of a further four patients, permitted simultaneous tracking of copy number alterations, structural and single nucleotide variants within individual cells. We observed CRLF2-r arising as both early and late events in DS and non-DS-ALL patients. Parallel evolution of discrete clones was observed in the development of CRLF2-r B-ALL, either involving the CRLF2-r or one of the other tracked abnormalities. In depth single cell analysis identified both linear and branching evolution with early clones harbouring a multitude of abnormalities, including the CRLF2-r in DS-ALL patients

Parental social contact in the work place and the risk of childhood acute lymphoblastic leukaemia

To study the possible relation between parental social contact through occupation, a marker for a child's risk of infection, and childhood acute lymphoblastic leukaemia (ALL), the parents of 294 children with ALL aged 0–14.9 years and 376 matched controls were interviewed about their jobs after their child's birth up to the age of 3 years. Job titles were assigned to a level of social contact, and an index of occupational social contact months was created using the level and the job duration. Positive interactions between this index and rural residence associated with an increased risk of childhood ALL and common ALL (c-ALL) were observed (interaction P-value=0.02 for both, using tertiles of contact months; interaction P-value=0.05 and 0.02 for ALL and c-ALL, respectively, using continuous contact months); such findings were not observed when job durations were ignored. Our data suggest that duration of parental occupation may be important when examining the association between parental social contact in the workplace and childhood leukaemia

Space-time clustering analyses of childhood acute lymphoblastic leukaemia by immunophenotype

Space-time clustering analyses of acute lymphoblastic leukaemia in children, by immunophenotype, were carried out using a population-based registry. Significant evidence was found of space-time clustering for cases of the precursor B-cell sub-type, in the childhood peak, based on time and location at birth

Higher risk for acute childhood lymphoblastic leukaemia in Swedish population centres 1973-94

A population-based sample of acute childhood leukaemia cases in Sweden 1973–94 was analysed by a geographical information system (GIS) for spatial leukaemia distribution in relation to population density. The annual incidence rate for acute lymphoblastic leukaemia (ALL) was 3.6, and for acute non-lymphoblastic leukaemia (ANLL) 0.7, cases per 100 000 children. Incidence rates in population centres, constituting 1.3% of Sweden's land area and approximately 80% of the population, compared with the rest of Sweden showed a statistically significant excess of ALL [odds ratio (OR) 1.68; 95% confidence interval (CI) 1.44–1.95], but not ANLL (OR 1.13; 95% CI 0.98–1.32). An increasing trend, however not statistically significant, was found for ALL incidence with both increasing population density in parishes and increasing degree of urbanity in municipalities. These findings support the theories that some environmental factors associated with high population density, such as infectious agents, may be of aetiological importance for childhood acute lymphoblastic leukaemia. © 1999 Cancer Research Campaig

Spectrum of HLA associations: the case of medically refractory pediatric acute lymphoblastic leukemia

Although studies of HLA and disease now date back some 50 years, a principled understanding of that relationship has been slow to emerge. Here, we examine the associations of three HLA loci with medically refractory pediatric acute lymphoblastic leukemia (pALL) patients in a case–control study involving 2,438 cases and 41,750 controls. An analysis of alleles from the class I loci, HLA-A and HLA-B, and the class II locus DRB1 illuminates a spectrum of extremely significant allelic associations conferring both predisposition and protection. Genotypes constructed from predisposing, protective, and neutral allelic categories point to an additive mode of disease causation. For all three loci, genotypes homozygous for predisposing alleles are at highest disease risk while the favorable effect of homozygous protective genotypes is less striking. Analysis of A–B and B–DRB1 haplotypes reveals locus-specific differences in disease effects, while that all three loci influence pALL; the influence of HLA-B is greater than that of HLA-A, and the predisposing effect of DRB1 exceeds that of HLA-B. We propose that the continuum in disease susceptibility suggests a system in which many alleles take part in disease predisposition based on differences in binding affinity to one or a few peptides of exogenous origin. This work provides evidence that an immune response mediated by alleles from several HLA loci plays a critical role in the pathogenesis of pALL, adding to the numerous studies pointing to a role for an infectious origin in pALL