[Show abstract][Hide abstract] ABSTRACT: Geographical variation operates at a variety of scales. Methods of mapping variation in disease incidence between different countries or even counties are relatively well developed. When, however, the question relates to much smaller aggregations (that is, “clustering”), attention has mainly been restricted to areas near putative point hazards; the majority of cases are excluded from such an investigation. In this study we show how clustering may be investigated and displayed in such a way that it becomes a powerful tool in epidemiological research. As examples we use incidence data from the Yorkshire health region for selected childhood cancers and adult haematopoietic malignancies. The methods would readily extend to any small clusters of rare events.
[Show abstract][Hide abstract] ABSTRACT: A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.
Proceedings of the National Academy of Sciences 03/2010; 107(14):6400-5. DOI:10.1073/pnas.0915054107 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The descriptive epidemiology of non-Hodgkin's lymphoma (NHL) (1984–1988) in parts of England and Wales is described by low grade (LG) and high grade (HG) subtypes. Major differences in age specific incidence are evident particularly in those under 35 years where LG-NHL is virtually absent in childhood and rare in young adulthood. Over the 5 year period of registration of cases significant increases in incidence were noted for males with both HG and LG disease.
The geographical analyses demonstrate clear epidemiological differences between LG-NHL and HG-NHL. The SMRs for 22 English and Welsh counties are not correlated for LG and HG-NHL disease, whose distributions are significantly different. Regression analyses at the electoral ward level show a strong association between LG-NHL and high-socio economic status and there is a weaker link between HG-NHL and residence in an urban area. Formal comparison of LG and HG-NHL shows significant differences for the effect of socio-economic grouping but not for urban-rural status.
There is strong evidence to show that major differences exist in patterns of LG and HG-NHL for age specific incidence, geographical distribution and area risk factors. Interpretation of these epidemiological features are highly suggestive of differing aetiologies.
Leukemia and Lymphoma 07/2009; 4(2). DOI:10.3109/10428199109068055 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Between 1980 and 1986 a case control study of leukaemias aid lymphomas in Yorkshire conducted face to face interviews on 1362 cases and 2442 age and sex matched hospital controls. Case diagnoses were histopathologically confirmed and grouped into non-Hodgkin's lymphomma (NHL), Hodgkin's Disease (HD), malignant lymphocytic lymphoma (MLL.), chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL). Multivariate analyses were completed on each separate disease to evaluate risk factors relating to past medical history, occupation, environmental exposures and social contact variables. The results show a significant association (with OR adjusted for other risk factors) between a family history of leukaemia/lymphoma and HD (OR = 4.29), NHL (OR = 1.98) and AML (OR = 6.36). For HD other cancers in the family also conveyed a significant risk (OR = 1.61). Use of heart drugs l(and heart disease) was linked to the chronic leukaemias (CML, CLL). A previous cancer and NHL, CLL and AML were associated even after adjustment for radiotherapy. A complex set of risk factors including prior skin lesions and steroid use showed significant links with HD, NHL and CLL., Increasing risk of NHL was linked to small family size. A significant excess of NHL cases reported exposure to glues and similarly ALL cases with agricultural chemical exposure. There present data provide both confirmatory and novel results. Overall they concur with the hypothesis of a multifactoral aetiology encompassing both genetic and immunological components.
Leukemia and Lymphoma 06/2009; 2(1-2):67-80. DOI:10.3109/10428199009042516 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aetiology of childhood cancer is poorly understood. Both genetic and environmental factors are likely to be involved. The presence of spatial clustering is indicative of a very localized environmental component to aetiology. Spatial clustering is present when there are a small number of areas with greatly increased incidence or a large number of areas with moderately increased incidence. To determine whether localized environmental factors may play a part in childhood cancer aetiology, we analyzed for spatial clustering using a large set of national population-based data from Great Britain diagnosed 1969-1993. The Potthoff-Whittinghill method was used to test for extra-Poisson variation (EPV). Thirty-two thousand three hundred and twenty-three cases were allocated to 10,444 wards using diagnosis addresses. Analyses showed statistically significant evidence of clustering for acute lymphoblastic leukaemia (ALL) over the whole age range (estimate of EPV = 0.05, p = 0.002) and for ages 1-4 years (estimate of EPV = 0.03, p = 0.015). Soft-tissue sarcoma (estimate of EPV = 0.03, p = 0.04) and Wilms tumours (estimate of EPV = 0.04, p = 0.007) also showed significant clustering. Clustering tended to persist across different time periods for cases of ALL (estimate of between-time period EPV = 0.04, p =0.003). In conclusion, we observed low level spatial clustering that is attributable to a limited number of cases. This suggests that environmental factors, which in some locations display localized clustering, may be important aetiological agents in these diseases. For ALL and soft tissue sarcoma, but not Wilms tumour, common infectious agents may be likely candidates.
International Journal of Cancer 02/2009; 124(4):932-6. DOI:10.1002/ijc.23965 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A population-based case-control study of diet, inherited susceptibility and prostate cancer was undertaken in the lowlands and central belt of Scotland to investigate the effect of phyto-oestrogen intake and serum concentrations on prostate cancer risk. A total of 433 cases and 483 controls aged 50-74 years were asked to complete a validated FFQ and provide a non-fasting blood sample. Multivariate logistic regression analysis found significant inverse associations with increased serum concentrations of enterolactone (adjusted OR 0.40, 95 % CI 0.22, 0.71] and with the consumption of soy foods (adjusted OR 0.52, 95 % CI 0.30, 0.91). However, no significant associations were observed for isoflavone intake or serum genistein, daidzein and equol. This study supports the hypotheses that soy foods and enterolactone metabolised from dietary lignans protect against prostate cancer in older Scottish men.
British Journal Of Nutrition 08/2007; 98(2):388-96. DOI:10.1017/S0007114507700703 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A proportion of Hodgkin lymphoma (HL) cases are causally associated with the Epstein-Barr virus (EBV) but the aetiology of the remaining cases remains obscure. Over the last 3 decades several studies have found an association between HL and measles virus (MV) including a recent cohort study describing the detection of MV antigens in Hodgkin and Reed-Sternberg cells, the tumour cells in HL. In the present study we looked at the relationship between history of MV infection and risk of developing HL in a population-based, case/control study of HL. In addition we used immunohistochemistry and RT-PCR to look for direct evidence of MV in HL biopsies. There was no significant difference in the proportion of cases reporting previous measles compared to controls in the entire data set or when young adults were considered separately. Using a robust immunohistochemical assay for MV infection, we failed to find evidence of MV in biopsies from 97 cases of HL and RT-PCR studies similarly gave negative results. This study therefore provides no evidence that MV is directly involved in the development of HL. However, when age at first reported MV infection was investigated, significant differences emerged with children infected before school-age having higher risk, especially of EBV-ve HL, when compared with children infected at older ages; the interpretation of these latter results is unclear.
International Journal of Cancer 07/2007; 121(2):442-7. DOI:10.1002/ijc.22629 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Risk of Hodgkin's disease (HD) in young adults has frequently been associated with limited access to social contact in childhood and related correlates of childhood social class. In addition, case clustering has sometimes been associated with influxes of population into relatively isolated communities. To investigate this further, disease incidence rates for HD at ages 0 to 24 from a specialist tumour registry have been regressed against relevant electoral ward characteristics derived from routine census and Ordnance Survey data for England and Wales. Proximity to built-up areas and higher socio-economic status (SES) emerge as significant risk factors. The relative risks are 1.21 (95% Cl: 1.01-1.46) for high SES wards and 1.29 (1.05-1.58) for "inner zone" wards. No association of disease risk with distance travelled to work was apparent. Regions farther from built-up areas have a lower overall incidence and a shift, particularly for males, of the age distribution towards older ages. The distribution resembles the intermediate pattern for HD reported from European rural areas of low SES but never previously for high SES. Isolated areas also show an increased intensity of spatial clustering (29% of cases being classified as clustered). These findings have implications for the 'late host response' model which suggest a viral aetiology for Hodgkin's disease in young people and provide a basis for future analytical studies.
International Journal of Cancer 04/2007; 48(1):10-4. DOI:10.1002/ijc.2910480103 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Maternal smoking during pregnancy inhibits fetal growth, and is a major cause of childhood and adult morbidity, including increased risks of cardiovascular disease and diabetes. However, the use of birthweight as a proxy for future smoking-related morbidity is hindered by its wide variability, suggesting a role for other birthweight-modifying factors. We report here, for the first time, that interactions between specific fetal HLA-DQA1 and DQB1 alleles and maternal smoking can influence birthweight. We compared mean birthweights of a series of term, HLA-DQ typed white UK newborns (n = 552) whose mothers had either smoked (n = 211) or not smoked (n = 341) during pregnancy. Maternal smoking during pregnancy resulted in an average birthweight reduction of 244 g, but the combined effects of maternal smoking and fetal DQA1*0101 or DQB1*0501 alleles resulted in a 230 and 240 g further reduction in mean birthweight, respectively, resulting from interactions between smoking and these DQ types. Other fetal DQ allele-specific interactions with maternal smoking are suggested by a "protective" effect on smoking-associated birthweight reduction in newborns typing for DQA1*0201 and DQB1*0201. Our results suggest biological interactions between maternal cigarette smoking during pregnancy and specific fetal DQ alleles that affect fetal growth. The precise nature of these interactions merits further investigation, as knowledge of fetal HLA-DQ type may be useful in refining risk estimates of severe fetal growth restriction because of maternal smoking during pregnancy.
[Show abstract][Hide abstract] ABSTRACT: Previous studies have provided evidence that infections may play a part in the aetiology of certain childhood cancers. The finding of space-time clustering indicates the presence of an environmental component to aetiology and is especially supportive of a role for infections. Space-time clustering occurs when excess numbers of cases of a disease are observed within small geographical locations at limited periods of time and this cannot be explained in terms of general excesses in those locations or at those times. To investigate whether infections may be involved in the aetiology of childhood cancer, we have analysed for space-time clustering using a large set of national population-based data from Great Britain for the period 1969-1993. Data were examined by a second-order procedure based on K-functions, with fixed thresholds of closeness in space (0.5-7.5 km) and closeness in time (0.1-1.5 years). Locations were addresses at diagnosis. Tests were repeated, replacing geographical distances with distances to the 19th-33rd nearest neighbours and this provided the primary result for each analysis. There were a total of 32,295 cases of childhood cancer. The analyses showed statistically significant evidence of space-time clustering for acute lymphoblastic leukaemia over the whole age range (p = 0.04), but especially for ages 1-4 years (p = 0.03). There was less statistically significant evidence for total leukaemia (p = 0.048). Significant space-time clustering was also evident for soft tissue sarcomas (p = 0.03) and osteosarcomas (p = 0.02). Results support other evidence suggesting a role for infections in the aetiology of these particular diagnostic groups.
International Journal of Cancer 06/2006; 118(11):2840-6. DOI:10.1002/ijc.21726 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study dietary intake and serum concentrations of isoflavones in order to provide relative validation of isoflavone intake estimates from the Scottish Collaborative Group - Food-Frequency Questionnaire (SCG-FFQ).
Dietary intake of isoflavones was estimated using the semiquantitative SCG-FFQ and rank correlation and Kappa statistics were used for the relative validation of intakes against serum isoflavone concentrations in 203 male participants who were population controls in a case-control study of diet and prostate cancer.
The median intake of isoflavones (daidzein and genistein) was 1.0mg/day (l-QR 0.6-1.8). The median serum concentration of genistein was 33.79 nmol/l (I-QR 14.12-64.93), nearly twice that of daidzein (18.00 nmol/l, I-QR 8.26-29.45). Equol was detected in 49% of subjects; in these subjects the median was 0.67 nmol/l (I-QR 0.34-1.51). Isoflavone intake was significantly correlated with serum concentrations of daidzein (p = 0.24, P = 0.001), genistein (p = 0.26, P < 0.001) and total isoflavonoids (sum of daidzein, genistein and equol) ( p = 0.27, P < 0.001). Whereas values for weighted Kappa ranged from 0.16 (P = 0.002) for daidzein and equol combined to 0.22 (P < 0.001) for genistein.
These results demonstrate the suitability of the SCG-FFQ to rank usual isoflavone intakes in older Scottish men, a population observed to have low consumption of soy foods.
European Journal of Clinical Nutrition 01/2006; 60(1):129-35. DOI:10.1038/sj.ejcn.1602277 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously demonstrated significant space-time clustering amongst cases of childhood leukaemia (in particular acute lymphoblastic leukaemia (ALL)), central nervous system (CNS) tumour (especially astrocytoma), soft tissue sarcoma and Wilms' tumour. We hypothesised that there may be common aetiological mechanisms between some of these diagnostic groups. To test this hypothesis we analysed for cross-space-time clustering between these diagnostic groups, using population-based data from north-west England. Data were examined by a second-order procedure based on K-functions. Reference points in time and space were dates and addresses at birth and diagnosis. The results showed statistically significant (P < 0.05) cross-clustering between cases of leukaemia and CNS tumour and between cases of ALL and astrocytoma. There was no statistically significant cross-clustering of Wilms' tumours and soft tissue sarcomas with any other malignancy. In conclusion, these findings are consistent with common, possibly infectious, aetiological mechanisms for childhood leukaemia (particularly ALL) and CNS tumours (particularly astrocytoma).
European Journal of Cancer 12/2005; 41(18):2911-6. DOI:10.1016/j.ejca.2005.04.051 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The association between tumor Epstein-Barr virus (EBV) status and clinical outcome in Hodgkin lymphoma (HL) is controversial. This population-based study assessed the impact of EBV status on survival in age-stratified cohorts of adults with classic HL (cHL). Data from 437 cases were analyzed with a median follow-up of 93 months. Overall survival (OS) was significantly better for EBV-negative compared with EBV-positive patients (P < .001), with 5-year survival rates of 81% and 66%, respectively; disease-specific survival (DSS) was also greater for EBV-negative patients (P = .03). The impact of EBV status varied with age at diagnosis. In patients aged 16 to 34 years, EBV-associated cases had a survival advantage compared with EBV-negative cases, but differences were not statistically significant (P = .21). Among patients 50 years or older, EBV positivity was associated with a significantly poorer outcome (P = .003). Excess deaths occurred in EBV-positive patients with both early- and advanced-stage disease. In multivariate analysis of OS in the older patients, EBV status retained statistical significance after adjusting for the effects of sex, stage, and B symptoms (P = .01). Impaired immune status may contribute to the development of EBV-positive cHL in older patients, and strategies aimed at boosting the immune response should be investigated in the treatment of these patients.
[Show abstract][Hide abstract] ABSTRACT: Somatic inactivation of NFKBIA, the gene encoding IkappaBalpha, is a frequent occurrence in the malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL). Impairment of IkappaBalpha function results in deregulated NF-kappaB activity, a characteristic of HRS cells. The molecular basis for familial HL, which accounts for approximately 4% of all HL cases, is unclear. To date, familial HL cases have not been evaluated for germline NFKBIA mutations. We screened the entire NFKBIA gene in 8 individuals with familial HL but found no mutations in the coding region or promoter sequences. We identified the first germline NFKBIA missense mutation in a patient with presumed sporadic HL. The frequency of 4 polymorphisms within the NFKBIA gene and promoter region was investigated in a series of HL and control samples; no significant differences emerged but a novel polymorphism was identified in the promoter region. Overall, our results suggest that germline mutations of NFKBIA are not a significant cause of familial aggregation of HL but may contribute to inherited susceptibility to HL.
International Journal of Cancer 09/2005; 116(4):646-51. DOI:10.1002/ijc.21036 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An accumulating body of data suggests that the Epstein-Barr virus (EBV), a lymphotropic herpesvirus, is involved in the pathogenesis of a proportion of cases of Hodgkin lymphoma (HL). In this study, we showed that the frequency of circulating EBV-infected cells was significantly higher (P < 0.001) in pretreatment blood samples from EBV-associated cases when compared with non-EBV-associated cases. We further showed that in patients with EBV-associated disease, the virus persisted in the peripheral blood in memory B cells. This phenotype is consistent with that seen in healthy seropositive controls, post-transplant patients and patients with acute infectious mononucleosis. The data suggest that an increased frequency of EBV carrying B cells in peripheral blood is associated with EBV-associated HL.
British Journal of Haematology 06/2005; 129(4):511-9. DOI:10.1111/j.1365-2141.2005.05483.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report.
One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products.
We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (< 65 years; 42%; P = 0.012). Additionally, when PSA genotype was cross classified with CAG repeat, significantly more cases than both BPH and population controls were observed to have a short (< 22) CAG/GG genotype (P = 0.006).
Our results indicate that the PSA/ARE GG genotype confers an increased risk of PC especially among younger men. Moreover, we confirm previous results that a short glutamine repeat in conjunction with GG genotype significantly increases the risk of malignant disease.
The Prostate 06/2005; 63(4):309-15. DOI:10.1002/pros.20178 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To test the hypothesis that reduced exposure to common infections in the first year of life increases the risk of developing acute lymphoblastic leukaemia. Design and setting The United Kingdom childhood cancer study (UKCCS) is a large population based case-control study of childhood cancer across 10 regions of the UK.
6305 children (aged 2-14 years) without cancer; 3140 children with cancer (diagnosed 1991-6), of whom 1286 had acute lymphoblastic leukaemia (ALL).
Day care and social activity during the first year of life were used as proxies for potential exposure to infection in infancy.
Increasing levels of social activity were associated with consistent reductions in risk of ALL; a dose-response trend was seen. When children whose mothers reported no regular activity outside the family were used as the reference group, odds ratios for increasing levels of activity were 0.73 (95% confidence interval 0.62 to 0.87) for any social activity, 0.62 (0.51 to 0.75) for regular day care outside the home, and 0.48 (0.37 to 0.62) for formal day care (attendance at facility with at least four children at least twice a week) (P value for trend < 0.001). Although not as striking, results for non-ALL malignancies showed a similar pattern (P value for trend < 0.001). When children with non-ALL malignancies were taken as the reference group, a significant protective effect for ALL was seen only for formal day care (odds ratio = 0.69, 0.51 to 0.93; P = 0.02). Similar results were obtained for B cell precursor common ALL and other subgroups, as well as for cases diagnosed above and below age 5 years.
These results support the hypothesis that reduced exposure to infection in the first few months of life increases the risk of developing acute lymphoblastic leukaemia.
[Show abstract][Hide abstract] ABSTRACT: A single nucleotide polymorphism (SNP) is present at position -174 of the human interleukin-6 gene. The risk of developing Hodgkin's lymphoma (HL) in young adults decreases with an increasing number of C alleles at this position. We analysed the effect of this SNP on incidence and outcome in HL. DNA samples from 408 cases and 349 controls were screened and analysed following stratification by age, histological subtype and Epstein-Barr virus status. Although the risk of classical HL in young adults decreased with increasing C alleles, case-control differences were not significant. An excess of G alleles was observed for nodular lymphocyte predominant HL in young adults (n = 21), which was significant.
British Journal of Haematology 03/2005; 128(4):493-5. DOI:10.1111/j.1365-2141.2004.05353.x · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have examined space-time clustering amongst cases of lymphoma in children, aged 0-14 years, using population-based data from the North West of England for the period 1954-2001. There was little or no evidence for space-time clustering amongst all the lymphomas or amongst those sub-groups identified in advance.
European Journal of Cancer 04/2004; 40(4):585-9. DOI:10.1016/j.ejca.2003.10.004 · 5.42 Impact Factor