Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic ...counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.
In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium ICGC PedBrain, Medulloblastoma Advanced Genomics International Consortium MAGIC, and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.
We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence 14% in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five 71% of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight 57% of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40–69) and 5-year overall survival was 65% (95% CI 52–81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.
Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.
German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.
The development and performance in practice of a commercial automatically controlled wood stove is described. The digital control system controls the three combustion air inlets individually, based ...on the combustion phase, measured flue gas temperature, measured O2 outlet concentration and desired room temperature. The control system ensured a well-controlled combustion cycle with respect to temperature and oxygen concentration, yielding improved thermal efficiency and minimized carbon monoxide emissions. A minimum in CO emissions was identified for the oxygen operation range 10–13% O2. The improved performance has been verified by field tests in 5 private homes, demonstrating more stable and optimal O2 concentrations and temperatures compared to manual operation. This resulted in significant lower CO concentrations (up to 27%) alongside higher thermal efficiency (up to 20%) when comparing manually and automatically controlled wood stoves. This new technology has a great potential for improving the stove efficiency/biomass utilisation and reducing the emissions of pollutants at low altitude close to private homes.
•A new automatically controlled wood stove has been developed.•3 process parameters (Tflue, Troom and O2 concentration) used to control air inlets.•A minimum in CO emissions was identified at 10–13% O2.•Practical tests demonstrated a well-controlled combustion cycle.•The system ensures optimized combustion conditions and reduces the net CO emissions.
The Cohort Study of Mobile Phone Use and Health (COSMOS) has repeatedly collected self-reported and operator-recorded data on mobile phone use. Assessing health effects using self-reported ...information is prone to measurement error, but operator data were available prospectively for only part of the study population and did not cover past mobile phone use. To optimize the available data and reduce bias, we evaluated different statistical approaches for constructing mobile phone exposure histories within COSMOS. We evaluated and compared the performance of four regression calibration (RC) methods (simple, direct, inverse, and generalized additive model for location, shape, and scale), complete-case (CC) analysis and multiple imputation (MI) in a simulation study with a binary health outcome. We used self-reported and operator-recorded mobile phone call data collected at baseline (2007-2012) from participants in Denmark, Finland, the Netherlands, Sweden, and the UK. Parameter estimates obtained using simple, direct, and inverse RC methods were associated with less bias and lower mean squared error than those obtained with CC analysis or MI. We showed that RC methods resulted in more accurate estimation of the relation between mobile phone use and health outcomes, by combining self-reported data with objective operator-recorded data available for a subset of participants.
We previously reported that children exposed to elevated extremely low-frequency magnetic fields (ELF-MF) had a five to six times higher risk of leukaemia, central nervous system (CNS) tumour and ...malignant lymphoma. Here we extend the study from 1968 to 1986 through 2003.
We included 3277 children with leukaemia, CNS tumour or malignant lymphoma during 1968-2003 recorded in the Danish Cancer Registry and 9129 controls randomly selected from the Danish childhood population. ELF-MF from 50 to 400 kV facilities were calculated at the residences.
For recently diagnosed cases (1987-2003), the relative risk (RR) was 0.88 (95% confidence interval (CI): 0.32-2.42), while for the total period (1968-2003) it was 1.63 (95% CI: 0.77-3.46) for leukaemia, CNS tumour and malignant lymphoma combined for exposures ⩾0.4 μT compared with <0.1 μT. These results were based on five cases (recent period) and 11 cases (total period) in the highest exposure group.
We did not confirm the previous finding of a five- to six-fold higher risk for leukaemia, CNS tumour and malignant lymphoma when including data from the more recent time period. For the total time period, the results for childhood leukaemia were in line with large pooled analyses showing RRs between 1.5 and 2.
Background: The widespread use of cellular telephones has heightened concerns about possible adverse health effects. The objective of this study was to investigate cancer risk among Danish cellular ...telephone users who were followed for up to 21 years. Methods: This study is an extended follow-up of a large nationwide cohort of 420 095 persons whose first cellular telephone subscription was between 1982 and 1995 and who were followed through 2002 for cancer incidence. Standardized incidence ratios (SIRs) were calculated by dividing the number of observed cancer cases in the cohort by the number expected in the Danish population. Results: A total of 14 249 cancers were observed (SIR = 0.95; 95% confidence interval CI = 0.93 to 0.97) for men and women combined. Cellular telephone use was not associated with increased risk for brain tumors (SIR = 0.97), acoustic neuromas (SIR = 0.73), salivary gland tumors (SIR = 0.77), eye tumors (SIR = 0.96), or leukemias (SIR = 1.00). Among long-term subscribers of 10 years or more, cellular telephone use was not associated with increased risk for brain tumors (SIR = 0.66, 95% CI = 0.44 to 0.95), and there was no trend with time since first subscription. The risk for smoking-related cancers was decreased among men (SIR = 0.88, 95% CI = 0.86 to 0.91) but increased among women (SIR = 1.11, 95% CI = 1.02 to 1.21). Additional data on income and smoking prevalence, primarily among men, indicated that cellular telephone users who started subscriptions in the mid-1980s appeared to have a higher income and to smoke less than the general population. Conclusions: We found no evidence for an association between tumor risk and cellular telephone use among either short-term or long-term users. Moreover, the narrow confidence intervals provide evidence that any large association of risk of cancer and cellular telephone use can be excluded.
Purpose: Epidemiological studies have found an association between exposure to extremely low-frequency magnetic fields (ELF-MF) and childhood leukemia. In 2005, a large British study showed an ...association between proximity of residence to high-voltage power lines and the risk of childhood leukemia. The association extended beyond distances at which the 'power line' induced magnetic fields exceed background levels, suggesting that the association was not explained by the magnetic field, but might be due to chance, bias, or other risk factors associated with proximity to power lines. Our aim was to conduct a comparable study in an independent setting (Denmark). Methods: We included 1,698 cases aged <15, diagnosed with leukemia during 1968–2006, from the Danish Cancer Registry and 3,396 controls randomly selected from the Danish childhood population and individually matched by gender and year of birth. We used geographical information systems to determine the distance between residence at birth and the nearest 132-400 kV overhead power line. Results: Odds ratios (ORs) were 0.76 95 % confidence interval (CI) 0.40–1.45 for children who lived 0-199 m from the nearest power line and 0.92 (95 % CI 0.62–1.25) for those who lived 200–599 m away when compared with children who lived ≥600 m away. When restricting the analysis to 220 and 400 kV overhead power lines, the OR for children who lived 200–599 m from a power line was 1.76 (95 % CI 0.82–3.77) compared to children who lived ≥600 m away. However, chance is a likely explanation for this finding as the result was not significant, numbers were small, and there were no indications of an higher risk closer to the lines since no cases were observed within 200 m of these. Conclusions: We found no higher risk of leukemia for children living 0–199 m or for children living 200–599 m of a 132–400 kV overhead power line. A slightly elevated OR for children living between 200 and 599 m of a 220–400 kV overhead power line is likely to be a chance finding.
Filaggrin is hydrolyzed in a humidity-sensitive fashion to its constituent amino acids and their deiminated carboxylic acid derivates, including UCA.3 This process typically accelerates during the ...winter in temperate climates because of forced indoor heating. ...skin inflammation, as observed in subjects with AD, reduces filaggrin levels and is often most severe in the winter.7 Hence reduced solar radiation in the winter in combination with humidity and inflammatory driven hydrolization in mutation and nonmutation carriers might explain the reduced effect of FLG mutations over the winter. ...in the adult studies AD would only have a small effect on vitamin D status.
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