Serially measured pre-diagnostic levels of serum cytokines and risk of brain cancer in active component military personnel.

BACKGROUND: There is growing evidence that history of allergic or autoimmune disease is associated with reduced risk of glioma, but few prospective studies have explored the biological basis. To assess associations with immune conditions and levels of 14 cytokines in serial prediagnostic serum samples, we conducted a study of glioma/brain cancer nested in a cohort of active component military personnel. METHODS: A total of 457 case-control sets were ascertained from the Department of Defense (DoD) Automated Central Tumour Registry, Defense Medical Surveillance System (DMSS) database, and DoD Serum Repository. These were individually matched on sex, race/ethnicity, birth year, number of serum samples (1, 2 or 3), and date(s) of sample collection. We obtained diagnoses of pre-existing immune-related conditions from the DMSS database and measured cytokines using Meso Scale Discovery assays. Statistical analyses included conditional logistic regression. RESULTS: Overall association between glioma and prior immune-related conditions was null. Higher levels of IL-15 and IL-16 were independently associated with lower glioma risks (Ptrend = 0.002 and Ptrend = 0.001); both associations were more pronounced in individuals with prior immune conditions (Pheterogeneity = 0.0009 and Pheterogeneity = 0.031). CONCLUSIONS: Associations with pre-diagnostic levels of IL-15 and IL-16 and their modification by diagnosis of immune-related conditions support the importance of immune alterations in glioma aetiology years before diagnosis.

Solid cancer incidence among Chinese medical diagnostic x-ray workers, 1950-1995: Estimation of radiation-related risks.

The objective of this study was to estimate solid cancer risk attributable to long-term, fractionated occupational exposure to low doses of ionizing radiation. Based on cancer incidence for the period 1950-1995 in a cohort of 27,011 Chinese medical diagnostic X-ray workers and a comparison cohort of 25,782 Chinese physicians who did not use X-ray equipment in their work, we used Poisson regression to fit excess relative risk (ERR) and excess absolute risk (EAR) dose-response models for incidence of all solid cancers combined. Radiation dose reconstruction was based on a previously published method that relied on simulating measurements for multiple X-ray machines, workplaces and working conditions, information about protective measures, including use of lead aprons, and work histories. The resulting model was used to estimate calendar year-specific badge dose calibrated as personal dose equivalent (Sv). To obtain calendar year-specific colon doses (Gy), we applied a standard organ conversion factor. A total of 1,643 cases of solid cancer were identified in 1.45 million person-years of follow-up. In both ERR and EAR models, a statistically significant radiation dose-response relationship was observed for solid cancers as a group. Averaged over both sexes, and using colon dose as the dose metric, the estimated ERR/Gy was 0.87 (95% CI: 0.48, 1.45), and the EAR was 22 per 10(4)PY-Gy (95% CI: 14, 32) at age 50. We obtained estimates of the ERR and EAR of solid cancers per unit dose that are compatible with those derived from other populations chronically exposed to low dose-rate occupational or environmental radiation.

Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data.

We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 × 10(-11) ), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with ∼3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma.

Chernobyl cleanup workers from Estonia: cohort description and related epidemiological research.

The Estonian study of Chernobyl cleanup workers was one of the first investigations to evaluate the possible health consequences of working in the Chernobyl area (the 30 km exclusion zone and/or adjacent territories) after the 1986 reactor accident. The cohort consists of 4831 men who were dispatched in 1986-1991 for tasks involving decontamination, construction of buildings, transport, radiation measurement, guard duty or other activities. By 31 December 2012, the follow-up of the cohort yielded 102 158 person-years of observation. Exposure and health data were collected by postal questionnaires, biodosimetry evaluations, thyroid screenings, and record-linkages with cancer, causes of death and health insurance reimbursement registers and databases. These data cover socio-demographic factors, employment history, aspects of health behaviour, medical history, work and living conditions in the Chernobyl area, biomarkers of exposure, cancer and non-cancer disease occurrence and causes of death. Cancer incidence data were obtained for 1986-2008, mortality data for 1986-2011 and non-cancer morbidity data for 2004-2012. Although the cohort is relatively small, it has been extensively examined and benefited from comprehensive nationwide population and health registers. The major finding was an increased risk of suicide. Thyroid examinations did not reveal an association with thyroid nodular disease and radiation dose, but did indicate the importance of accounting for screening when making comparisons with unscreened populations. No risk of leukaemia was observed and risks higher than 2.5-fold could be excluded with 95% confidence. Biodosimetry included GPA analyses and chromosomal translocation analyses and indicated that the Estonian cleanup workers experienced a relatively low mean exposure of the order of 0.1 Gy. One value of the Estonian study is in the methodologic processes brought to bear in addressing possible health effects from the Chernobyl accident. Twenty-five years of research are summarised and opportunities for the future listed.

Known glioma risk loci are associated with glioma with a family history of brain tumours -- a case-control gene association study.

Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.

Joint effects between five identified risk variants, allergy, and autoimmune conditions on glioma risk.

Common variants in two of the five genetic regions recently identified from genome-wide association studies (GWAS) of risk of glioma were reported to interact with a history of allergic symptoms. In a pooled analysis of five epidemiologic studies, we evaluated the association between the five GWAS implicated gene variants and allergies and autoimmune conditions (AIC) on glioma risk (851 adult glioma cases and 3,977 controls). We further evaluated the joint effects between allergies and AIC and these gene variants on glioma risk. Risk estimates were calculated as odds ratios (OR) and 95 % confidence intervals (95 % CI), adjusted for age, gender, and study. Joint effects were evaluated by conducting stratified analyses whereby the risk associations (OR and 95 % CI) with the allergy or autoimmune conditions for glioma were evaluated by the presence or absence of the 'at-risk' variant, and estimated p interaction by fitting models with the main effects of allergy or autoimmune conditions and genotype and an interaction (product) term between them. Four of the five SNPs previously reported by others were statistically significantly associated with increased risk of glioma in our study (rs2736100, rs4295627, rs4977756, and rs6010620); rs498872 was not associated with glioma in our study. Reporting any allergies or AIC was associated with reduced risks of glioma (allergy: adjusted OR = 0.71, 95 % CI 0.55-0.91; AIC: adjusted OR = 0.65, 95 % CI 0.47-0.90). We did not observe differential association between allergic or autoimmune conditions and glioma by genotype, and there were no statistically significant p interactions. Stratified analysis by glioma grade (low and high grade) did not suggest risk differences by disease grade. Our results do not provide evidence that allergies or AIC modulate the association between the four GWAS-identified SNPs examined and risk of glioma.

Chernobyl cleanup workers from Estonia: follow-up for cancer incidence and mortality.

This study examined cancer incidence (1986-2008) and mortality (1986-2011) among the Estonian Chernobyl cleanup workers in comparison with the Estonian male population. The cohort of 4810 men was followed through nationwide population, mortality and cancer registries. Cancer and death risks were measured by standardised incidence ratio (SIR) and standardised mortality ratio (SMR), respectively. Poisson regression was used to analyse the effects of year of arrival, duration of stay and time since return on cancer and death risks. The SIR for all cancers was 1.06 with 95% confidence interval 0.93-1.20 (232 cases). Elevated risks were found for cancers of the pharynx, the oesophagus and the joint category of alcohol-related sites. No clear evidence of an increased risk of thyroid cancer, leukaemia or radiation-related cancer sites combined was apparent. The SMR for all causes of death was 1.02 with 95% confidence interval 0.96-1.08 (1018 deaths). Excess mortality was observed for mouth and pharynx cancer, alcohol-related cancer sites together and suicide. Duration of stay rather than year of arrival was associated with increased mortality. Twenty-six years of follow-up of this cohort indicates no definite health effects attributable to radiation, but the elevated suicide risk has persisted.

Retinopathy, Optic Neuropathy, and Cataract in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: Few reports describe the risks of late ocular toxicities after radiation therapy (RT) for childhood cancers despite their effect on quality of life. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) ocular task force aims to quantify the radiation dose dependence of select late ocular adverse effects. Here, we report results concerning retinopathy, optic neuropathy, and cataract in childhood cancer survivors who received cranial RT. METHODS AND MATERIALS: A systematic literature search was performed using the PubMed, MEDLINE, and Cochrane Library databases for peer-reviewed studies published from 1980 to 2021 related to childhood cancer, RT, and ocular endpoints including dry eye, keratitis/corneal injury, conjunctival injury, cataract, retinopathy, and optic neuropathy. This initial search yielded abstracts for 2947 references, 269 of which were selected as potentially having useful outcomes and RT data. Data permitting, treatment and outcome data were used to generate normal tissue complication probability models. RESULTS: We identified sufficient RT data to generate normal tissue complication probability models for 3 endpoints: retinopathy, optic neuropathy, and cataract formation. Based on limited data, the model for development of retinopathy suggests 5% and 50% risk of toxicity at 42 and 62 Gy, respectively. The model for development of optic neuropathy suggests 5% and 50% risk of toxicity at 57 and 64 Gy, respectively. More extensive data were available to evaluate the risk of cataract, separated into self-reported versus ophthalmologist-diagnosed cataract. The models suggest 5% and 50% risk of self-reported cataract at 12 and >40 Gy, respectively, and 50% risk of ophthalmologist-diagnosed cataract at 9 Gy (>5% long-term risk at 0 Gy in patients treated with chemotherapy only). CONCLUSIONS: Radiation dose effects in the eye are inadequately studied in the pediatric population. Based on limited published data, this PENTEC comprehensive review establishes relationships between RT dose and subsequent risks of retinopathy, optic neuropathy, and cataract formation.

Genome-wide association study of glioma and meta-analysis.

Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.

Occupational exposure to chlorinated solvents and risks of glioma and meningioma in adults.

OBJECTIVES: Chlorinated solvents are classified as probable or possible carcinogens. It is unknown whether exposure to these agents increases the risk of malignant or benign brain tumours. Our objective was to evaluate associations of brain tumour risk with occupational exposure to six chlorinated solvents (i.e., dichloromethane, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, trichloroethylene and perchloroethylene). METHODS: 489 glioma cases, 197 meningioma cases and 799 controls were enrolled in a hospital-based case-control study conducted at three U.S.A. hospitals in Arizona, Massachusetts and Pennsylvania. Information about occupational history was obtained through a detailed inperson interview that included job-specific modules of questions such that the interview was tailored to each individual's particular work history. An industrial hygienist assessed potential solvent exposure based on this information and an exhaustive review of the relevant industrial hygiene literature. Unconditional logistic regression models were used to calculate OR and 95% CI for each solvent for ever/never, duration, cumulative, average weekly and highest exposure. RESULTS: Overall, we found no consistent evidence of an increased risk of glioma or meningioma related to occupational exposure to the six chlorinated solvents evaluated. There was some suggestion of an association between carbon tetrachloride and glioma in analyses restricted to exposed subjects, with average weekly exposure above the median associated with increased risk compared with below the median exposure (OR = 7.1, 95% CI 1.1 to 45.2). CONCLUSIONS: We found no consistent evidence for increased brain tumour risk related to chlorinated solvents.

Pooled Analysis of Meningioma Risk Following Treatment for Childhood Cancer.

Importance: Meningioma is the most common subsequent neoplasm following cranial irradiation among survivors of childhood cancer, but there are still uncertainties regarding the magnitude of the radiation dose-response association, potential modifiers of radiation risks, and the role of chemotherapy. Objective: To evaluate meningioma risk in survivors of childhood cancer following radiotherapy and chemotherapy and identify possible modifying factors of radiation-associated risk. Design, Setting, and Participants: This international case-control study pooled data from 4 nested case-control studies of survivors of childhood cancer diagnosed between 1942 and 2000, followed through 2016. Cases were defined as participants diagnosed with a subsequent meningioma. Controls were matched to cases based on sex, age at first cancer diagnosis, and duration of follow-up. Data were analyzed from July 2019 to June 2022. Exposures: Radiation dose (Gy) to the meningioma site and cumulative chemotherapy doses, including intrathecal and systemic methotrexate doses. Main Outcomes and Measures: The main outcome was subsequent meningioma, assessed using odds ratios (ORs) and excess odds ratios per gray (EOR/Gy). Results: The analysis included 273 survivors of childhood cancer who developed meningioma (cases) and 738 survivors who did not (controls), with a total of 1011 individuals (median [IQR] age at first cancer diagnosis 5.0 [3.0-9.2] years; 599 [59.2%] female). Median (IQR) time since first cancer was 21.5 (15.0-27.0) years. Increasing radiation dose was associated with increased risk of meningioma (EOR/Gy, 1.44; 95% CI, 0.62-3.61), and there was no evidence of departure from linearity (P = .90). Compared with survivors who were not exposed to radiation therapy, those who received doses of 24 Gy or more had more than 30-fold higher odds of meningioma (OR, 33.66; 95% CI, 14.10-80.31). The radiation dose-response association was significantly lower among patients treated at age 10 years or older compared with those treated before age 10 years (EOR/Gy, 0.57; 95% CI, 0.18-1.91 vs 2.20; 95% CI, 0.87-6.31; P for heterogeneity = .03). Risk associated with radiation remained significantly elevated 30 years after exposure (EOR/Gy, 3.76; 95% CI, 0.77-29.15). We found an increased risk of meningioma among children who had received methotrexate (OR, 3.43; 95% CI, 1.56-7.57), but no evidence of a dose-response association or interaction with radiation dose. Conclusions and Relevance: These findings suggest that the meninges are highly radiosensitive, especially for children treated before age 10 years. These results support the reduction in whole-brain irradiation over recent decades and the prioritization of approaches that limit radiation exposure in healthy tissue for children. The persistence of elevated risks of meningiomas for 30 years after cranial radiotherapy could help inform surveillance guidelines.

Sex disparities in colorectal cancer incidence by anatomic subsite, race and age.

Although incidence of colorectal cancer (CRC) in the United States has declined in recent years, rates remain higher in men than in women and the male-to-female incidence rate ratio (MF IRR) increases progressively across the colon from the cecum to the rectum. Rates among races/ethnicities other than Whites or Blacks have not been frequently reported. To examine CRC rates by sex across anatomic subsite, age and racial/ethnic groups, we used the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program for cases diagnosed among residents of 13 registries during 1992-2006. Incidence rates were expressed per 100,000 person-years and age-adjusted to the 2000 US Standard Population; MF IRR and 95% confidence intervals were also calculated. Among each racial/ethnic group, the MF IRR increased fairly monotonically from close to unity for cecal cancers to 1.81 (Hispanics) for rectal cancers. MF IRRs increased with age most rapidly for distal colon cancers from <1.0 at ages <50 years to 1.4-1.9 at older ages. The MF IRR for rectal cancers also rose with age from about 1.0 to 2.0. For proximal cancer, the MF IRR was consistently <1.5; among American Indian/Alaska Natives, it was <1.0 across all ages. The MF IRRs for CRC vary markedly according to subsite and age but less by racial/ethnic group. These findings may partially reflect differences in screening experiences and access to medical care but also suggest that etiologic factors may be playing a role.

Joint associations between genetic variants and reproductive factors in glioma risk among women.

In a pooled analysis of 4 US epidemiologic studies (1993-2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12-13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.

Comparison of occupational exposure assessment methods in a case-control study of lead, genetic susceptibility and risk of adult brain tumours.

OBJECTIVES: There is great interest in evaluating gene-environment interactions with chemical exposures, but exposure assessment poses a unique challenge in case-control studies. Expert assessment of detailed work history data is usually considered the best approach, but it is a laborious and time-consuming process. We set out to determine if a less intensive method of exposure assessment (a job exposure matrix (JEM)) would produce similar results to a previous analysis that found evidence of effect modification of the association between expert-assessed lead exposure and risk of brain tumours by a single nucleotide polymorphism in the ALAD gene (rs1800435). METHODS: We used data from a study of 355 patients with glioma, 151 patients with meningioma and 505 controls. Logistic regression models were used to examine associations between brain tumour risk and lead exposure and effect modification by genotype. We evaluated Cohen's κ, sensitivity and specificity for the JEM compared to the expert-assessed exposure metrics. RESULTS: Although effect estimates were imprecise and driven by a small number of cases, we found evidence of effect modification between lead exposure and ALAD genotype when using expert- but not JEM-derived lead exposure estimates. κ Values indicated only modest agreement (<0.5) for the exposure metrics, with the JEM indicating high specificity (∼0.9) but poor sensitivity (∼0.5). Disagreement between the two methods was generally due to having additional information in the detailed work history. CONCLUSION: These results provide preliminary evidence suggesting that high quality exposure data are likely to improve the ability to detect genetic effect modification.

Comparison of Radiation Dose Reconstruction Methods to Investigate Late Adverse Effects of Radiotherapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

Quantification of radiation dose to normal tissue during radiotherapy is critical for assessing risk for radiotherapy-related late effects, including subsequent neoplasms (SNs). Case-control studies of SNs typically reconstruct absorbed radiation dose to the specific SN location using individual treatment parameters. A simplified method estimates the maximum prescribed target dose to the body region in which the SN arises. We compared doses and risk estimates from these methods using data from case-control studies of subsequent brain tumors (64 cases, 244 controls) and breast cancer (94 cases, 358 controls) nested within the Childhood Cancer Survivor Study (≥5-year survivors of childhood cancer diagnosed 1970-1986). The weighted kappa statistic [95% confidence interval (CI)] evaluating agreement between categorical (>0-9.9/10-19.9/20-29.9/≥30 Gy) body-region and tumor location-specific doses was 0.95 (0.91-0.98) for brain and 0.76 (0.69-0.82) for breast. The body-region and location-specific doses were assigned to the same dose category for a smaller proportion of patients treated with fields delivering a heterogeneous dose across the tissue of interest (e.g., partial brain field = 57.1%; mantle field = 61.3%) than patients treated with fields delivering a more homogeneous dose (e.g., whole brain field = 100%). Excess odds ratios per Gy (95% CI) from conditional logistic regression were 1.25 (0.33-6.33) and 1.20 (0.31-6.14) for brain tumors and 0.21 (0.05-0.77) and 0.10 (0.02-0.44) for breast cancer, using location-specific and body-region doses, respectively. We observed that body-region doses can approximate location-specific doses when the tissue of interest is clearly in the radiation field or outside the treated body region. Agreement is lower when there is greater ambiguity of SN location relative to the treatment field.

Associations between polymorphisms in DNA repair genes and glioblastoma.

A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme, the most common and deadliest form of adult brain tumors. Genetic data for approximately 1,000 glioblastoma multiforme cases and 2,000 controls were combined from four centers in the United States that have conducted case-control studies on adult glioblastoma multiforme, including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University of Texas M. D. Anderson Cancer Center, and the University of California at San Francisco. Twelve DNA repair single-nucleotide polymorphisms were selected for investigation in the pilot collaborative project. The C allele of the PARP1 rs1136410 variant was associated with a 20% reduction in risk for glioblastoma multiforme (odds ratio(CT or CC), 0.80; 95% confidence interval, 0.67-0.95). A 44% increase in risk for glioblastoma multiforme was found for individuals homozygous for the G allele of the PRKDC rs7003908 variant (odds ratio(GG), 1.44; 95% confidence interval, 1.13-1.84); there was a statistically significant trend (P = 0.009) with increasing number of G alleles. A significant, protective effect was found when three single-nucleotide polymorphisms (ERCC2 rs13181, ERCC1 rs3212986, and GLTSCR1 rs1035938) located near each other on chromosome 19 were modeled as a haplotype. The most common haplotype (AGC) was associated with a 23% reduction in risk (P = 0.03) compared with all other haplotypes combined. Few studies have reported on the associations between variants in DNA repair genes and brain tumors, and few specifically have examined their impact on glioblastoma multiforme. Our results suggest that common variation in DNA repair genes may be associated with risk for glioblastoma multiforme.

Sex disparities in cancer incidence by period and age.

BACKGROUND: Cancer epidemiology articles often point out that cancer rates tend to be higher among males than females yet rarely is this theme the subject of investigation. METHODS: We used the Surveillance, Epidemiology and End Results program data to compute age-adjusted (2000 U.S. standard population) sex-specific incidence rates and male-to-female incidence rate ratios (IRR) for specific cancer sites and histologies for the period 1975 to 2004. RESULTS: The 10 cancers with the largest male-to-female IRR were Kaposi sarcoma (28.73), lip (7.16), larynx (5.17), mesothelioma (4.88), hypopharynx (4.13), urinary bladder (3.92), esophagus (3.49), tonsil (3.07), oropharynx (3.06), and other urinary organs (2.92). Only 5 cancers had a higher incidence in females compared with males: breast (0.01), peritoneum, omentum, and mesentery (0.18), thyroid (0.39), gallbladder (0.57), and anus, anal canal, and anorectum (0.81). Between 1975 and 2004, the largest consistent increases in male-to-female IRR were for cancers of the tonsil, oropharynx, skin excluding basal and squamous, and esophagus, whereas the largest consistent decreases in IRR were for cancers of the lip and lung and bronchus. Male-to-female IRRs varied considerably by age, the largest increases of which were for ages 40 to 59 years for tonsil cancer and hepatocellular carcinoma. The largest decreases in male-to-female IRR by age, meanwhile, were for ages 30 to 49 years for thyroid cancer, ages >70 years for esophageal squamous cell carcinoma, and ages >30 years for lung and bronchus cancer. CONCLUSION: These observations emphasize the importance of sex in cancer etiopathogenesis and may suggest novel avenues of investigation.

Common variation in genes related to innate immunity and risk of adult glioma.

Current evidence suggests that immune system alterations contribute to the etiology of adult glioma, the most common adult brain tumor. Although previous studies have focused on variation in candidate genes in the adaptive immune system, the innate immune system has emerged as a critical avenue for research given its known link with carcinogenesis. To identify genetic markers in pathways critical to innate immunity, we conducted an association study of 551 glioma cases and 865 matched controls of European ancestry to investigate "tag" single nucleotide polymorphisms (SNP) in 148 genetic regions. Two independent U.S. case-control studies included were as follows: a hospital-based study conducted by the National Cancer Institute (263 cases, 330 controls) and a community-based study conducted by the National Institute for Occupational Safety and Health (288 cases, 535 controls). Tag SNPs (1,397) chosen on the basis of an r(2) of >0.8 and minor allele frequency of >5% in Caucasians in HapMap1 were genotyped. Glioma risk was estimated by odds ratios. Nine SNPs distributed across eight genetic regions (ALOX5, IRAK3, ITGB2, NCF2, NFKB1, SELP, SOD1, and STAT1) were associated with risk of glioma with P value of <0.01. Although these associations were no longer statistically significant after controlling for multiple comparisons, the associations were notably consistent in both studies. Region-based tests were statistically significant (P < 0.05) for SELP, SOD, and ALOX5. Analyses restricted to glioblastoma (n = 254) yielded significant associations for the SELP, DEFB126/127, SERPINI1, and LY96 genetic regions. We have identified a promising set of innate immunity-related genetic regions for further investigation.

Occupational exposure to magnetic fields and the risk of brain tumors.

We investigated the association between occupational exposure to extremely low-frequency magnetic fields (MFs) and the risk of glioma and meningioma. Occupational exposure to MF was assessed for 489 glioma cases, 197 meningioma cases, and 799 controls enrolled in a hospital-based case-control study. Lifetime occupational history questionnaires were administered to all subjects; for 24% of jobs, these were supplemented with job-specific questionnaires, or "job modules," to obtain information on the use of electrically powered tools or equipment at work. Job-specific quantitative estimates for exposure to MF in milligauss were assigned using a previously published job exposure matrix (JEM) with modification based on the job modules. Jobs were categorized as < or =1.5 mG, >1.5 to <3.0 mG, and > or =3.0 mG. Four exposure metrics were evaluated: (1) maximum exposed job; (2) total years of exposure >1.5 mG; (3) cumulative lifetime exposure; and (4) average lifetime exposure. Odds ratios (ORs) were calculated using unconditional logistic regression with adjustment for the age, gender, and hospital site. The job modules increased the number of jobs with exposure > or =3.0 mG from 4% to 7% relative to the JEM. No statistically significant elevation in ORs or trends in ORs across exposure categories was observed using four different exposure metrics for the three tumor types analyzed. Occupational exposure to MFs assessed using job modules was not associated with an increase in the risk for glioma, glioblastoma, or meningioma among the subjects evaluated in this study.

Estimation of Radiation Doses to U.S. Military Test Participants from Nuclear Testing: A Comparison of Historical Film-Badge Measurements, Dose Reconstruction and Retrospective Biodosimetry.

Retrospective radiation dose estimations, whether based on physical or biological measurements, or on theoretical dose reconstruction, are limited in their precision and reliability, particularly for exposures that occurred many decades ago. Here, we studied living U.S. military test participants, believed to have received high-dose radiation exposures during nuclear testing-related activities approximately six decades ago, with two primary goals in mind. The first was to compare three different approaches of assessing past radiation exposures: 1. Historical personnel monitoring data alone; 2. Dose reconstruction based on varying levels of completeness of individual information, which can include film badge data; and 3. Retrospective biodosimetry using chromosome aberrations in peripheral blood lymphocytes. The second goal was to use the collected data to make the best possible estimates of bone marrow dose received by a group with the highest military recorded radiation doses of any currently living military test participants. Six nuclear test participants studied had been on Rongerik Atoll during the 1954 CASTLE Bravo nuclear test. Another six were present at the Nevada Test Site (NTS) and/or Pacific Proving Ground (PPG) and were believed to have received relatively high-dose exposures at those locations. All were interviewed, and all provided a blood sample for cytogenetic analysis. Military dose records for each test participant, as recorded in the Defense Threat Reduction Agency's Nuclear Test Review and Information System, were used as the basis for historical film badge records and provided exposure scenario information to estimate dose via dose reconstruction. Dose to bone marrow was also estimated utilizing directional genomic hybridization (dGH) for high-resolution detection of radiation-induced chromosomal translocations and inversions, the latter being demonstrated for the first time for the purpose of retrospective biodosimetry. As the true dose for each test participant is not known these many decades after exposure, this study gauged the congruence of different methods by assessing the degree of correlation and degree of systematic differences. Overall, the best agreement between methods, defined by statistically significant correlations and small systematic differences, was between doses estimated by a dose reconstruction methodology that exploited all the available individual detail and the biodosimetry methodology derived from a weighted average dose determined from chromosomal translocation and inversion rates. Employing such a strategy, we found that the Rongerik veterans who participated in this study appear to have received, on average, bone marrow equivalent doses on the order of 300-400 mSv, while the NTS/ PPG participants appear to have received approximately 250-300 mSv. The results show that even for nuclear events that occurred six decades in the past, biological signatures of exposure are still present, and when taken together, chromosomal translocations and inversions can serve as reliable retrospective biodosimeters, particularly on a group-average basis, when doses received are greater than statistically-determined detection limits for the biological assays used.