Geographical and ecological analyses of childhood Wilms' tumours and soft-tissue sarcomas in North West England.

The aim of this paper was to study the geographical distribution of Wilms' tumours (WT) and soft-tissue sarcomas (STS) for 0-14 year olds included in a population-based registry from North West England during 1976-2000. Standardised morbidity ratios (SMRs) were calculated. Relationships between incidence rates and small area (ward) population density, ethnic composition, deprivation index and urban-rural status were examined using Poisson regression. There was a non-linear relationship between WT incidence and population density (P=0.008), with a higher incidence associated with wards with low deprivation scores (P=0.02); and which included a greater proportion of whites (P=0.01). For STS, a higher incidence was associated with wards with low deprivation scores (P=0.04); and which were 'more rural/less urban' (P=0.03). These results are consistent with a role for localised environmental exposures, in combination with lifestyle factors, in the aetiology of WT. For STS, there is some evidence for the involvement of environmental and/or lifestyle factors.

Rhabdomyosarcoma in Nijmegen breakage syndrome: strong association with perianal primary site.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder resulting from mutations in the NBS1 gene, which encodes for the DNA double strand break repair protein nibrin. NBS is clinically characterized by microcephaly, dysmorphic features, immunodeficiency, and increased susceptibility to malignancy, mainly of lymphoid origin. Here, we describe a 7-year-old girl with NBS who is homozygous for the NBS1 698del4 mutation. She had been diagnosed with perianal rhabdomyosarcoma (RMS) and experienced severe toxicity from chemotherapy. RMS arising perianally is extremely uncommon but has been previously described in two cases with NBS. The strong association of perianal RMS with NBS should, therefore, be considered when confronted with a perianal RMS, as this carries important clinical implications in terms of potential need for therapy modification and follow up investigations. In addition, it suggests a role for the NBS1 gene and the nibrin dependent pathway in the pathogenesis of RMS, especially those arising perianally.

A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations.

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital and developmental abnormalities, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and strong predisposition to acute myeloid leukemia (AML). In this article, we describe clinical and molecular findings in a boy with a severe FA phenotype who developed AML by the age of 2. Although he lacked a strong family history of cancer, he was subsequently shown to carry biallelic mutations in the FANCD1/BRCA2 gene. These included an IVS7 splice-site mutation, which is strongly associated with early AML in homozygous or compound heterozygous carrier status in FA-D1 patients. Myeloid leukemia cells from this patient have been maintained in culture for more than 1 year and have been designated as the SB1690CB cell line. Growth of SB1690CB is dependent on granulocyte macrophage colony stimulating factor or interleukin-3. This cell line has retained its MMC sensitivity and has undergone further spontaneous changes in the spectrum of cytogenetic aberrations compared with the primary leukemia. This is the second AML cell line derived from an FA-D1 patient and the first proof that malignant clones arising in FA patients can retain inherited MMC sensitivity. As FA-derived malignancies are normally not very responsive to treatment, this implies there are important mechanisms of acquiring correction of the cellular FA phenotype that would explain the poor chemoresponsiveness observed in FA-associated malignancies and might also play a role in the initiation and progression of cancer in the general population.

Geographical and ecological analyses of childhood acute leukaemias and lymphomas in north-west England.

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.

Constitutional sequence variation in the Fanconi anaemia group C (FANCC) gene in childhood acute myeloid leukaemia.

The extent to which genetic susceptibility contributes to the causation of childhood acute myeloid leukaemia (AML) is not known. The inherited bone marrow failure disorder Fanconi anaemia (FA) carries a substantially increased risk of AML, raising the possibility that constitutional variation in the FA (FANC) genes is involved in the aetiology of childhood AML. We have screened genomic DNA extracted from remission blood samples of 97 children with sporadic AML and 91 children with sporadic acute lymphoblastic leukaemia (ALL), together with 104 cord blood DNA samples from newborn children, for variations in the Fanconi anaemia group C (FANCC) gene. We found no evidence of known FANCC pathogenic mutations in children with AML, ALL or in the cord blood samples. However, we detected 12 different FANCC sequence variants, of which five were novel to this study. Among six FANCC variants leading to amino-acid substitutions, one (S26F) was present at a fourfold greater frequency in children with AML than in the cord blood samples (odds ratio: 4.09, P = 0.047; 95% confidence interval 1.08-15.54). Our results thus do not exclude the possibility that this polymorphic variant contributes to the risk of a small proportion of childhood AML.

Successful treatment without cranial radiotherapy of children receiving intensified chemotherapy for acute lymphoblastic leukaemia: results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI (ISRC TN 16757172).

Concern about late adverse effects of cranial radiotherapy (XRT) has led to alternative approaches to eliminate leukaemia from the central nervous system (CNS) in childhood acute lymphoblastic leukaemia (ALL). The Medical Research Council UKALL XI trial recruited 2090 children with ALL between 1990 and 1997. Median follow-up is 7 years 9 months; event-free survival (EFS) and overall survival were 63.1% and 84.6%, respectively, at 5 years and 59.8% and 79.4% at 10 years. The isolated CNS relapse rate was 7.0% at 10 years. Patients were randomized for CNS-directed therapy within white blood cell (WBC) groups. For WBC <50 x 10(9)/l, high-dose intravenous methotrexate (HDMTX) (6-8 g/m2) with intrathecal methotrexate (ITMTX) was compared with ITMTX alone, and was significantly better at preventing isolated and combined CNS relapse, but non-CNS relapses were similar. There was no significant difference in EFS at 10 years, 64.1% [95% confidence interval (CI) 60.4-67.8] with HDMTX plus ITMTX, and 63.0% (95% CI 59.5-66.5) with ITMTX alone. For WBC >/=50 x 10(9)/l, HDMTX with ITMTX was compared with XRT and a short course of ITMTX. CNS relapses were significantly fewer with XRT, but there was a non-significant increase in non-CNS relapses. EFS was not significantly different, being 55.2% (95% CI 47.8-62.6) at 10 years with XRT and 52.1% (95% CI 44.8-59.4) with HDMTX plus ITMTX.

Space-time clustering patterns in childhood solid tumours other than central nervous system tumours.

The aetiology of most childhood solid tumours (other than central nervous system [CNS] tumours) is unclear. To investigate whether certain environmental exposures may be involved, we have analysed for space-time clustering using population-based data from North West England for the period 1954-98. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space, <5 km, and close in time, <1 year apart. Addresses at birth and at diagnosis were used. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. There was significant evidence of space-time clustering for Wilms' tumours (p = 0.03 and 0.04, using the geographical distance and nearest neighbour versions of the Knox test; and p = 0.07 and 0.03, using the geographical distance and nearest neighbour versions of the K-function method), and soft tissue sarcomas (p = 0.01, using both the geographical distance and nearest neighbour versions of the Knox test; and p = 0.001 and 0.002, using the geographical distance and nearest neighbour versions of the K-function method) based on time and location at birth, but not time and location at diagnosis. There was little or no evidence of space-time clustering amongst other diagnostic groups. These are the first results to demonstrate space-time clustering for childhood Wilms' tumours and soft tissue sarcomas. The results are consistent with environmental exposure hypotheses, relating to locations pre-natally or peri-natally.

Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201.

In a previous study, we obtained preliminary evidence in a small series of patients (n = 63) suggesting that susceptibility to childhood common acute lymphoblastic leukaemia (c-ALL) was associated with an allele at the HLA-DPB1 locus, DPB1*0201. We have now tested this hypothesis by comparing the frequency of children with leukaemia (n = 982) who typed for specific DPB1 alleles and two groups of non-leukaemic children, one consisting of children with solid tumours, excluding lymphomas (n = 409), the other consisting of normal infants (n = 864). We found that significantly more children with c-ALL and T-ALL, but not pro-B ALL or acute non-ALL typed for DPB1*0201 as compared with children with solid tumours [odds ratio (OR), 95% confidence interval (CI) for c-ALL: 1.76, 1.20-2.56; T-ALL: 1.93, 1.01-3.80] and normal infants (OR, 95% CI for c-ALL: 1.83, 1.34-2.48; T-ALL: 2.00, 1.10-3.82). In childhood c-ALL, significantly more children than those with solid tumours or normal infants typed for DPB1 alleles coding specific polymorphic amino acids lining the antigen-binding site of the DPbeta1*0201 allotypic protein, suggesting that susceptibility to childhood c-ALL may be influenced by DPbeta ABS amino acid polymorphisms shared by DPbeta1*0201 and other DPbeta1 allotypes. These results point to a mechanism of c-ALL susceptibility that involves the presentation of specific antigenic peptides, possibly derived from infectious agents, by DPbeta1*0201-related allotypic proteins, leading to the activation of helper T cells mediating proliferative stress on preleukaemic cells.