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1.  Calibrating a population-based job-exposure matrix using inspection measurements to estimate historical occupational exposure to lead for a population-based cohort in Shanghai, China 
The epidemiologic evidence for the carcinogenicity of lead is inconsistent and requires improved exposure assessment to estimate risk. We evaluated historical occupational lead exposure for a population-based cohort of women (n=74,942) by calibrating a job-exposure matrix (JEM) with lead fume (n=20,084) and lead dust (n=5,383) measurements collected over four decades in Shanghai, China. Using mixed-effect models, we calibrated intensity JEM ratings to the measurements using fixed-effects terms for year and JEM rating. We developed job/industry-specific estimates from the random-effects terms for job and industry. The model estimates were applied to subjects’ jobs when the JEM probability rating was high for either job or industry; remaining jobs were considered unexposed. The models predicted that exposure increased monotonically with JEM intensity rating and decreased 20–50-fold over time. The cumulative calibrated JEM estimates and job/industry-specific estimates were highly correlated (Pearson correlation=0.79–0.84). Overall, 5% of the person-years and 8% of the women were exposed to lead fume; 2% of the person-years and 4% of the women were exposed to lead dust. The most common lead-exposed jobs were manufacturing electronic equipment. These historical lead estimates should enhance our ability to detect associations between lead exposure and cancer risk in future epidemiologic analyses.
PMCID: PMC3508334  PMID: 22910004
lead; cancer; exposure assessment; occupational exposure; job exposure matrix; mixed-effects model
2.  Persistence of urothelial carcinoma of the bladder risk among former smokers: Results from a contemporary, prospective cohort study 
Urologic oncology  2013;32(1):10.1016/j.urolonc.2012.09.001.
Cigarette smoking is a known risk factor for urothelial carcinoma (UC) of the bladder. However, the persistence of an increased risk for UC following smoking cessation is not well established. We assessed the risk of UC among former smokers using a recent, prospective cohort with a high proportion of former smokers.
Materials and methods
Study participants were members of the VITamins And Lifestyle cohort (VITAL), a group of 77,719 men and women between the ages of 50 and 76 years from western Washington State. Smoking history and other risk factors were obtained at the time of recruitment. The primary outcome was a new diagnosis of UC (n = 385), as determined through linkage to a population-based cancer registry.
Results and limitations
The cohort included 8% current and 44% former smokers, and among the UC cases, 15% were current and 60% former smokers. Both the current and former smoker had an increased risk of UC compared with never smokers (hazard ratio [HRs]: 3.81; 95% confidence intervals [CI] 2.71–5.35 and 2.0; 95% CI 1.55–2.58, respectively). Among former smokers, the risk of UC increased with the pack-years smoked and decreased with the years since quitting. When both the measures of smoking were considered together, the risk of UC was similar for long-term quitters and recent quitters for a given level of pack-years. For example, for those with pack-years of 22.5–37.5, the HR of UC was 1.91 (95% CI 1.17–3.11) for the distant quitters (≥23.5 y before baseline) and HR = 1.92 (95% CI 1.26–2.94) among the recent quitters. Limitations include the small number of cases at the extremes of smoking history and errors in self-reported smoking history.
The risk of bladder cancer in former smokers remains elevated >32 years after quitting, even among those with moderate smoking histories. This argues that a history of smoking confers a lifelong increased risk of UC.
PMCID: PMC3737375  PMID: 23506963
Smoking; Urothelial carcinoma; Bladder; Smoking cessation
3.  The Childhood Leukemia International Consortium 
Cancer epidemiology  2013;37(3):336-347.
Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions.
The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies.
By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31 000 cases and 50 000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens.
CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic groups.
PMCID: PMC3652629  PMID: 23403126
Leukemia; Children; Consortium; Epidemiology; Genetics
4.  Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists 
Exposure to ionizing radiation has been consistently associated with increased risk of female breast cancer. Although the majority of DNA damage caused by ionizing radiation is corrected by the base-excision repair pathway, certain types of multiple-base damage can only be repaired through the nucleotide excision repair pathway. In a nested case–control study of breast cancer in US radiologic technologists exposed to low levels of ionizing radiation (858 cases, 1,083 controls), we examined whether risk of breast cancer conferred by radiation was modified by nucleotide excision gene polymorphisms ERCC2 (XPD) rs13181, ERCC4 (XPF) rs1800067 and rs1800124, ERCC5 (XPG) rs1047769 and rs17655; and ERCC6 rs2228526. Of the 6 ERCC variants examined, only ERCC5 rs17655 showed a borderline main effect association with breast cancer risk (ORGC = 1.1, ORCC = 1.3; p-trend = 0.08), with some indication that individuals carrying the C allele variant were more susceptible to the effects of occupational radiation (EOR/GyGG = 1.0, 95% CI = <0, 6.0; EOR/GyGC/CC = 5.9, 95% CI = 0.9, 14.4; phet = 0.10). ERCC2 rs13181, although not associated with breast cancer risk overall, statistically significantly modified the effect of occupational radiation dose on risk of breast cancer (EOR/GyAA = 9.1, 95% CI = 2.1–21.3; EOR/GyAC/CC = 0.6, 95% CI = <0, 4.6; phet = 0.01). These results suggest that common variants in nucleotide excision repair genes may modify the association between occupational radiation exposure and breast cancer risk.
PMCID: PMC3984912  PMID: 18767034
5.  Nightshift work and risk of ovarian cancer 
Animal evidence suggests that circadian disruption may be associated with ovarian cancer, though very little epidemiologic work has been done to assess this potential association. We evaluated the association between self-reported nightshift work, a known circadian disruptor, and ovarian cancer in a population-based case-control study.
The study included 1,101 women with invasive epithelial ovarian cancer, 389 women with borderline epithelial ovarian tumors and 1,832 controls and was conducted in Western Washington State. Shift work data was collected as part of in-person interviews.
Working the nightshift was associated with an increased risk of invasive (OR=1.24, 95% CI: 1.04–1.49) and borderline (OR=1.48, 95% CI: 1.15–1.90) tumors; however, we observed little evidence that risks increased with increasing cumulative duration of nightshift work, and risks were not elevated in the highest duration category (>7 nightshift work-years). Increased risks were restricted to women who were 50 years of age and older and to serous and mucinous histologies of invasive and borderline tumors. There was suggestive evidence of a decreased risk of ovarian cancer among women reporting a preference for activity during evenings rather than mornings.
We found evidence suggesting an association between shift work and ovarian cancer. This observation should be followed up in future studies incorporating detailed assessments of diurnal preference (i.e. chronotype) in addition to detailed data on shift schedules.
PMCID: PMC3777774  PMID: 23343856
shift work; ovarian cancer; circadian; chronotype
6.  No Evidence for Differences in DNA Damage Assessed before and after a Cancer Diagnosis 
The overwhelming majority of studies that have found increased cancer risk associated with functional deficits in DNA repair used a case-control design, in which measurements were made after cancer diagnosis. However, there are concerns about whether the cancer itself or cancer treatment affected the conclusions (reverse causation bias). We assessed the effect of cancer diagnosis among 26 breast cancer controls who had blood collected during 2001 to 2003 and again in 2005 to 2006 after being diagnosed with cancer. Using the alkaline comet assay, we quantified DNA damage in untreated lymphoblastoid cell lines. Comet distributed moment, olive tail moment, percentage of DNA in tail, and comet tail length were summarized as the geometric mean of 100 cells. For comet distributed moment, olive tail moment, tail DNA, and tail length, the proportions of women with before diagnosis values higher than after diagnosis were 65%, 50%, 50%, and 46%, respectively. We found no significant differences in the before or after diagnosis mean comet values. Median cut-points were determined from the before diagnosis distribution, and we used conditional logistic regression to calculate odds ratios (OR) and upper 95% bounds of the confidence intervals. ORs ranged from 0.6 to 0.9 with upper confidence interval bounds of 1.9 and 2.6, meaning biased ORs above 2.6 are unlikely. We found no evidence that reverse causation bias is an important concern in case-control studies using the comet assay applied to cell lines collected after cancer diagnosis. More work is needed to characterize the effect of cancer diagnosis on other phenotypic assays.
PMCID: PMC3950930  PMID: 18398043
7.  Racial Differences in the Association Between Night Shift Work and Melatonin Levels Among Women 
American Journal of Epidemiology  2013;177(5):388-393.
Reduced suppression of melatonin in response to working the night shift among people of Asian ancestry has been suggested as a possible explanation for the null results observed in a recent analysis of shift work and breast cancer risk in a Chinese cohort. The authors analyzed the impact of Asian versus white race on previously reported differences in urinary 6-sulfatoxymelatonin levels in a 2003–2008 study in Seattle, Washington, of female health-care workers that exclusively worked night or day shifts. A total of 225 white and 51 Asian participants were included in the analysis. Although 6-sulfatoxymelatonin levels were affected by night shift work in both racial groups, Asian night shift workers consistently showed 6-sulfatoxymelatonin levels that were closer to levels in day shift workers than did white night shift workers. Furthermore, differences in 6-sulfatoxymelatonin levels between white and Asian night shift workers relative to day shift workers were statistically significant in every instance (P < 0.05). These results suggest that Asians may be better able to maintain a “normal” circadian pattern of melatonin production compared with whites and suggest a biological mechanism by which Asian night shift workers may be at a reduced risk of cancer.
PMCID: PMC3626046  PMID: 23380044
cancer; melatonin; race; shift work
8.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
PMCID: PMC3530689  PMID: 23169509
9.  Sunlight, Polymorphisms of Vitamin D-related Genes and Risk of Breast Cancer 
Anticancer research  2013;33(2):543-551.
Geographic gradients in breast cancer incidence and mortality suggest that vitamin D may reduce risk. The enzyme 25-hydroxyvitamin D 24-hydroxylase (CYP24A1), which degrades the active form of vitamin D, and the vitamin D receptor (VDR) are both found in breast tissue. We investigated six polymorphisms in CYP24A1 and two in the VDR gene in association with breast cancer risk.
Materials and Methods
We conducted a case--control study within the nationwide U.S. Radiologic Technologists cohort, including 845 controls and 484 incident breast cancer cases. Associations of polymorphic variants and ecologic and personal measures of sun exposure with breast cancer risk were assessed using unconditional logistic regression.
Two polymorphisms in CYP24A1 were associated with increased breast cancer risk (rs34043203, Ptrend = 0.03; rs2762934, Ptrend = 0.005) and one with reduced breast cancer risk (rs1570669, Ptrend=0.048). Risk was inversely associated with minor alleles for the VDR Bsm1 polymorphism (rs1544410, Ptrend = 0.05) but not Fok1 (rs2228570). Sunlight measures were not associated with breast cancer risk, however significant interactions between time outdoors in the teen years and three unlinked genotypes were found for VDR (rs1544410, rs2228570) and CYP24A1 (rs1570669).
In this nation-wide breast cancer case--control study, we found the vitamin D pathway was involved in disease etiology and further suggest that reduced cancer risk in association with sunlight may depend on timing of exposure and genetic background. These findings merit further investigation.
PMCID: PMC3866631  PMID: 23393347
Vitamin D; sunlight; polymorphisms; breast cancer; gene; case—control
10.  Comparison of occupational exposure assessment methods in a case-control study of lead, genetic susceptibility and risk of adult brain tumors 
Occupational and environmental medicine  2010;68(1):10.1136/oem.2009.048132.
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 between expert assessed-lead exposure and risk of brain tumors by a single nucleotide polymorphism in the ALAD gene (rs1800435).
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 tumor risk and lead exposure and effect modification by genotype. We evaluated Cohen’s kappa, sensitivity and specificity for the JEM compared to the expert-assessed exposure metrics.
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. Kappa 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.
These results provide preliminary evidence suggesting that high quality exposure data are likely to improve the ability to detect genetic effect modification.
PMCID: PMC3828743  PMID: 20798009
11.  A Pooled Analysis of Thyroid Cancer Incidence Following Radiotherapy for Childhood Cancer 
Radiation research  2012;178(4):365-376.
Childhood cancer five-year survival now exceeds 70–80%. Childhood exposure to radiation is a known thyroid carcinogen; however, data are limited for the evaluation of radiation dose-response at high doses, modifiers of the dose-response relationship and joint effects of radiotherapy and chemotherapy. To address these issues, we pooled two cohort and two nested case-control studies of childhood cancer survivors including 16,757 patients, with 187 developing primary thyroid cancer. Relative risks (RR) with 95% confidence intervals (CI) for thyroid cancer by treatment with alkylating agents, anthracyclines or bleomycin were 3.25 (0.9–14.9), 4.5 (1.4–17.8) and 3.2 (0.8–10.4), respectively, in patients without radiotherapy, and declined with greater radiation dose (RR trends, P = 0.02, 0.12 and 0.01, respectively). Radiation dose-related RRs increased approximately linearly for <10 Gy, leveled off at 10–15-fold for 10–30 Gy and then declined, but remained elevated for doses >50 Gy. The fitted RR at 10 Gy was 13.7 (95% CI: 8.0–24.0). Dose-related excess RRs increased with decreasing age at exposure (P < 0.01), but did not vary with attained age or time-since-exposure, remaining elevated 25+ years after exposure. Gender and number of treatments did not modify radiation effects. Thyroid cancer risks remained elevated many decades following radiotherapy, highlighting the need for continued follow up of childhood cancer survivors.
PMCID: PMC3488851  PMID: 22857014
12.  Chemotherapy and thyroid cancer risk: A report from the Childhood Cancer Survivor Study 
While ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the chemotherapy-related risk of thyroid cancer in childhood cancer survivors, and the possible joint effects of chemotherapy and radiotherapy.
The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated using life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.
Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0–1.6) for females and 0.6% (0.4–0.8) for males. Among patients with thyroid radiation doses ≤ 20 Gy, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3–4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (P-trend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses >20 Gy.
Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range under 20 Gy, where cell sparing likely predominates over cell killing.
Our study adds to the evidence for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy.
PMCID: PMC3253948  PMID: 22028399
Thyroid cancer; second cancer; chemotherapy; radiation risk; cohort study
13.  Wood Dust Exposure and Risk of Lung Cancer 
Despite the compelling association between wood dust and sinonasal cancer, there has been little systematic and rigorous study of the relationship between wood dust and lung cancer. We investigated whether a history of exposure to wood dust through occupational and hobby-related activities was associated with increased lung cancer risk.
We conducted a population-based case-control study, with 440 cases, identified from 1993 to 1996 through the Fred Hutchinson Cancer Research Center Cancer Surveillance System for western Washington State, and 845 age-matched controls, identified by random-digit dialing. Using detailed work and personal histories, quantitative estimates of cumulative exposure to wood dust (thought to be primarily from softwood) were calculated for each participant. Using unconditional logistic regression adjusted for age and smoking status, risk of lung cancer was examined in relation to employment in wood-related occupations, working with wood as a hobby, as well as cumulative wood dust exposure that took into account both occupational and hobby-related sources.
While we observed an increased risk of lung cancer associated with working in a sawmill (OR=1.5; 95% CI: 1.1, 2.1), we found no evidence of increased risks with other occupations, working with wood as a hobby or with estimated cumulative exposure to wood dust (OR = 0.9; 95% CI: 0.6, 1.3, for highest compared to lowest quartile of exposure). Contrary to our hypothesis, we observed modest non-significant decreased risks with exposure to wood dust, although no dose-response relationship was apparent.
This study provided somewhat reassuring evidence that softwood dust does not increase the risk of lung cancer, but future studies should closely evaluate exposure to hardwood dusts. Suggestive evidence for an inverse association may be attributable to the presence of endotoxin in the wood dust, but the lack of a dose-response relationship suggests a non-causal relationship.
PMCID: PMC3184400  PMID: 21071755
14.  Long-Term Use of Supplemental Vitamins and Minerals Does Not Reduce the Risk of Urothelial Cell Carcinoma of the Bladder in the VITamins And Lifestyle Study 
The Journal of urology  2011;185(4):1210-1215.
Urothelial Carcinoma (UC) has the highest lifetime treatment cost of any cancer making it an ideal target for preventative therapies. Previous work has suggested that certain vitamin and mineral supplements may reduce the risk of UC. We sought to use the prospective VITamins And Lifestyle (VITAL) cohort to examine the association of all commonly taken vitamin and mineral supplements as well as 6 common anti-inflammatory supplements with incident UC in a United States population.
77,050 eligible VITAL participants completed a detailed questionnaire at baseline on supplement use and cancer risk factors. . After 6 years of follow-up, 330 incident UC cases occurring in the cohort were identified via linkage to the Seattle-Puget Sound Surveillance, Epidemiology and End Results (SEER) cancer registry. We analyzed use of supplemental vitamins (multivitamins, beta-carotene, retinol, folic acid, vitamins B1, B3, B6, B12, C, D and E), minerals (calcium, iron, magnesium, zinc, and selenium), and anti-inflammatory supplements (glucosamine, chondroitin, saw-palmetto, ginko-biloba, fish oil and garlic). For each supplement, the hazard ratios (risk ratios) for UC comparing each category of users to nonusers, and 95% confidence intervals, were determined using Cox proportional hazards regression., adjusted for potential confounders.
None of the vitamin, mineral or anti-inflammatory supplements was significantly associated with UC risk in either age-adjusted or multivariate models.
The results of this study do not support the use of commonly taken vitamin or mineral supplements or 6 common anti-inflammatory supplements for chemoprevention of UC.
PMCID: PMC3215292  PMID: 21334017
Urothelial Carcinoma; Supplement; Diet; Nutrition; Cancer Prevention
15.  Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study 
Radiation research  2010;174(6):741-752.
Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose–response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8–31.5). At thyroid radiation doses >20 Gy, a downturn in the dose–response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.
PMCID: PMC3080023  PMID: 21128798
16.  Diagnostic X-ray examinations and increased chromosome translocations: evidence from three studies 
Controversy regarding potential health risks from increased use of medical diagnostic radiologic examinations has come to public attention. We evaluated whether chromosome damage, specifically translocations, which are a potentially intermediate biomarker for cancer risk, was increased after exposure to diagnostic X-rays, with particular interest in the ionizing radiation dose–response below the level of approximately 50 mGy. Chromosome translocation frequency data from three separately conducted occupational studies of ionizing radiation were pooled together. Studies 1 and 2 included 79 and 150 medical radiologic technologists, respectively, and study 3 included 83 airline pilots and 50 university faculty members (total = 155 women and 207 men; mean age = 62 years, range 34–90). Information on personal history of radiographic examinations was collected from a detailed questionnaire. We computed a cumulative red bone marrow (RBM) dose score based on the numbers and types of X-ray examinations reported with 1 unit approximating 1 mGy. Poisson regression analyses were adjusted for age and laboratory method. Mean RBM dose scores were 49, 42, and 11 for Studies 1–3, respectively (overall mean = 33.5, range 0–303). Translocation frequencies significantly increased with increasing dose score (P < 0.001). Restricting the analysis to the lowest dose scores of under 50 did not materially change these results. We conclude that chromosome damage is associated with low levels of radiation exposure from diagnostic X-ray examinations, including dose scores of approximately 50 and lower, suggesting the possibility of long-term adverse health effects.
PMCID: PMC3075914  PMID: 20602108
17.  Polymorphisms in oxidative stress and inflammation pathway genes, low-dose ionizing radiation, and the risk of breast cancer among US radiologic technologists 
Cancer causes & control : CCC  2010;21(11):1857-1866.
Ionizing radiation, an established breast cancer risk factor, has been shown to induce oxidative damage and chronic inflammation. Polymorphic variation in oxidative stress and inflammatory-mediated pathway genes may modify radiation-related breast cancer risk.
We estimated breast cancer risk for 28 common variants in 16 candidate genes involved in these pathways among 859 breast cancer cases and 1,083 controls nested within the US Radiologic Technologists cohort. We estimated associations between occupational and personal diagnostic radiation exposures with breast cancer by modeling the odds ratio (OR) as a linear function in logistic regression models and assessed heterogeneity of the dose–response across genotypes.
There was suggestive evidence of an interaction between the rs5277 variant in PTGS2 and radiation-related breast cancer risk. The excess OR (EOR)/Gy from occupational radiation exposure = 5.5 (95%CI 1.2–12.5) for the GG genotype versus EOR/Gy < 0 (95%CI < 0–3.8) and EOR/Gy < 0 (95%CI < 0–14.8) for the GC and CC genotypes, respectively, (pinteraction = 0.04). The association between radiation and breast cancer was not modified by other SNPs examined.
This study suggests that variation in PTGS2 may modify the breast cancer risk from occupational radiation exposure, but replication in other populations is needed to confirm this result.
PMCID: PMC3076104  PMID: 20711808
PTGS2; COX-2; Inflammation; Breast cancer; Radiation
18.  Novel breast cancer risk alleles and interaction with ionizing radiation among U.S. Radiologic Technologists 
Radiation research  2010;173(2):214-224.
As genome-wide association studies of breast cancer are replicating findings and refinement studies are narrowing the signal location, additional efforts are necessary to elucidate the underlying functional relationships. One approach is to evaluate variation in risk by genotype based on known breast carcinogens, such as ionizing radiation. Given the public health concerns associated with recent increases in medical radiation exposure, this approach may also identify potentially susceptible sub-populations. We examined interaction between 27 newly identified breast cancer risk alleles (identified within the NCI Cancer Genetic Markers of Susceptibility and the Breast Cancer Association Consortium genome-wide association studies) and occupational and medical diagnostic radiation exposure among 859 cases and 1083 controls nested within the United States Radiologic Technologists cohort. We did not find significant variation in the radiation-related breast cancer risk for the variant in RAD51L1 (rs10483813) on 14q24.1 as we had hypothesized. In exploratory analyses, we found that the radiation-associated breast cancer risk varied significantly by linked markers in 5p12 (rs930395, rs10941679, rs2067980, and rs4415084) in the mitochondrial ribosomal protein S30 (MRPS30) gene (pinteraction=0.04). Chance, however, may explain these findings, and as such, these results need to be confirmed in other populations with low to moderate levels of radiation exposure. Even though a complete understanding by which these variants may increase breast cancer risk remains elusive, this approach may yield clues for further investigation.
PMCID: PMC2922870  PMID: 20095854
Ionizing radiation-associated breast cancer risk appears to be modified by timing of reproductive events such as age at radiation exposure, parity, age at first live birth, and age at menopause. However, potential breast cancer risk modification of low- to moderate radiation dose by polymorphic estrogen metabolism-related gene variants has not been routinely investigated. We assessed breast cancer risk of 12 candidate variants in 12 genes involved in steroid metabolism, catabolism, binding, or receptor functions in a study of 859 cases and 1083 controls within the US Radiologic Technologists (USRT) cohort. Using cumulative breast dose estimates from a detailed assessment of occupational and personal diagnostic ionizing radiation exposure, we investigated the joint effects of genotype on the risk of breast cancer. In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the CYP3A4 M445T minor allele (rs4986910, OR=0.3; 95% CI 0.1–0.9). We found a borderline increased breast cancer risk with having both minor alleles of CYP1B1 V432L (rs1056836, CC vs. GG, OR=1.2; 95% CI 0.9–1.6). Assuming a recessive model, the minor allele of CYP1B1 V432L significantly increased the dose-response relationship between personal diagnostic x-ray exposure and breast cancer risk, adjusted for cumulative occupational radiation dose (pinteraction=0.03) and had a similar joint effect for cumulative occupational radiation dose adjusted for personal diagnostic x-ray exposure (pinteraction=0.06). We found suggestive evidence that common variants in selected estrogen metabolizing genes may modify the association between ionizing radiation exposure and breast cancer risk.
PMCID: PMC2860373  PMID: 19214745
20.  A multi-stage genome-wide association in breast cancer identifies two novel risk alleles at 1p11.2 and 14q24.1 (RAD51L1) 
Nature genetics  2009;41(5):579-584.
The Cancer Genetic Markers of Susceptibility (CGEMS) initiative has conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls. In Stage 1, we genotyped 528,173 single nucleotide polymorphisms (SNPs) in 1,145 cases of invasive breast cancer among postmenopausal white women, and 1,142 controls; in Stage 2, 24,909 SNPs with low p values observed in Stage 1 were analyzed in 4,547 cases and 4,434 controls. In Stage 3 we investigated 21 loci in 4,078 cases and 5,223 controls with low p values from Stage 1 and 2 combined. Two novel loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2, rs11249433, (p=6.74 × 10-10 adjusted genotype test with 2 degrees of freedom) resides in a large block of linkage disequilibrium neighboring NOTCH2 and FCGR1B and is predominantly associated with estrogen receptor-positive breast cancer. A second SNP, rs999737 on chromosome 14q24.1 (p=1.74 × 10−7), localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway, a prior candidate pathway for breast cancer susceptibility. We confirmed previously reported markers on chromosome 2q35, 5q11.2, 5p12, 8q24, 10q26, and 16q12.1. Our results underscore the importance of large-scale replication in the identification of low penetrance breast cancer alleles.
PMCID: PMC2928646  PMID: 19330030
21.  Lead exposure, polymorphisms in genes related to oxidative stress and risk of adult brain tumors 
There is some evidence that oxidative stress plays a role in lead-induced toxicity. Mechanisms for dealing with oxidative stress may be of particular relevance in the brain, given the high rate of oxygen metabolism. Using a hospital-based case-control study, we investigated the role of oxidative stress in the potential carcinogenicity of lead through examination of effect modification of the association between occupational lead exposure and brain tumors by single nucleotide polymorphisms (SNPs) in genes with functions related to oxidative stress. The study included 362 patients with glioma [176 of which had glioblastoma (GBM)], 134 patients with meningioma and 494 controls. Lead exposure was estimated by expert review of detailed job history data for each participant. We evaluated effect modification with 142 SNPs using likelihood ratio tests that compared nested unconditional logistic regression models that did and did not include a cross-product term for cumulative lead exposure and genotype. When the analyses were restricted to cases with GBM, RAC2 rs2239774 and two highly correlated GPX1 polymorphisms (rs1050450 and rs18006688) were found to significantly modify the association with lead exposure (p ≤ 0.05) after adjustment for multiple comparisons. Furthermore, the same GPX1 polymorphisms and XDH rs7574920 were found to significantly modify the association between cumulative lead exposure and meningioma. While the results of this study provide some evidence that lead may cause GBM and meningioma through mechanisms related to oxidative damage, the results must be confirmed in other populations.
PMCID: PMC2750838  PMID: 19505917
glioma; meningioma; lead exposure; oxidative stress; polymorphism
22.  Thyroid nodules, polymorphic variants in DNA repair and RET-related genes, and interaction with ionizing radiation exposure from nuclear tests in Kazakhstan 
Radiation research  2009;171(1):77-88.
Risk factors for thyroid cancer remain largely unknown except for ionizing radiation exposure during childhood and a history of benign thyroid nodules. Because thyroid nodules are more common than thyroid cancers and are associated with thyroid cancer risk, we evaluated several polymorphisms potentially relevant to thyroid tumors and assessed interaction with ionizing radiation exposure to the thyroid gland. Thyroid nodules were detected in 1998 by ultrasound screening of 2997 persons who lived near the Semipalatinsk nuclear test site in Kazakhstan when they were children (1949-62). Cases with thyroid nodules (n=907) were frequency matched (1:1) to those without nodules by ethnicity (Kazakh or Russian), gender, and age at screening. Thyroid gland radiation doses were estimated from fallout deposition patterns, residence history, and diet. We analyzed 23 polymorphisms in 13 genes and assessed interaction with ionizing radiation exposure using likelihood ratio tests (LRT). Elevated thyroid nodule risks were associated with the minor alleles of RET S836S (rs1800862, p = 0.03) and GFRA1 -193C>G (rs not assigned, p = 0.05) and decreased risk with XRCC1 R194W (rs1799782, p-trend = 0.03) and TGFB1 T263I (rs1800472, p = 0.009). Similar patterns of association were observed for a small number of papillary thyroid cancers (n=25). Ionizing radiation exposure to the thyroid gland was associated with significantly increased risk of thyroid nodules (age and gender adjusted excess odds ratio/Gy = 0.30, 95% confidence interval 0.05-0.56), with evidence for interaction by genotype found for XRCC1 R194W (LRT p value = 0.02). Polymorphisms in RET signaling, DNA repair, and proliferation genes may be related to risk of thyroid nodules, consistent with some previous reports on thyroid cancer. Borderline support for gene-radiation interaction was found for a variant in XRCC1, a key base excision repair protein. Other pathways, such as genes in double strand break repair, apoptosis, and genes related to proliferation should also be pursued.
PMCID: PMC2875679  PMID: 19138047
Thyroid nodules; single nucleotide polymorphisms; epidemiology; thyroid cancer; ionizing radiation; interaction
23.  Predictors of 2,4-dichlorophenoxyacetic acid exposure among herbicide applicators 
To determine the major factors affecting the urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) among county noxious weed applicators in Kansas, we used a regression technique that accounted for multiple days of exposure. We collected 136 12-h urine samples from 31 applicators during the course of two spraying seasons (April to August of 1994 and 1995). Using mixed-effects models, we constructed exposure models that related urinary 2,4-D measurements to weighted self-reported work activities from daily diaries collected over 5 to 7 days before the collection of the urine sample. Our primary weights were based on an earlier pharmacokinetic analysis of turf applicators; however, we examined a series of alternative weighting schemes to assess the impact of the specific weights and the number of days before urine sample collection that were considered. The derived models accounting for multiple days of exposure related to a single urine measurement seemed robust with regard to the exact weights, but less to the number of days considered; albeit the determinants from the primary model could be fitted with marginal losses of fit to the data from the other weighting schemes that considered a different numbers of days. In the primary model, the total time of all activities (spraying, mixing, other activities), spraying method, month of observation, application concentration, and wet gloves were significant determinants of urinary 2,4-D concentration and explained 16% of the between-worker variance and 23% of the within-worker variance of urinary 2,4-D levels. As a large proportion of the variance remained unexplained, further studies should be conducted to try to systematically assess other exposure determinants.
PMCID: PMC2823960  PMID: 19319162
2,4-D; biomonitoring; herbicide; exposure determinants
24.  Blood spots as an alternative to whole blood collection and the effect of a small monetary incentive to increase participation in genetic association studies 
Collection of buccal cells from saliva for DNA extraction offers a less invasive and convenient alternative to venipuncture blood collection that may increase participation in genetic epidemiologic studies. However, dried blood spot collection, which is also a convenient method, offers a means of collecting peripheral blood samples from which analytes in addition to DNA can be obtained.
To determine if offering blood spot collection would increase participation in genetic epidemiologic studies, we conducted a study of collecting dried blood spot cards by mail from a sample of female cancer cases (n = 134) and controls (n = 256) who were previously selected for a breast cancer genetics study and declined to provide a venipuncture blood sample. Participants were also randomized to receive either a $2.00 bill or no incentive with the blood spot collection kits.
The average time between the venipuncture sample refusal and recruitment for the blood spot collection was 4.4 years. Thirty-seven percent of cases and 28% of controls provided a dried blood spot card. While the incentive was not associated with participation among controls (29% for $2.00 incentive vs. 26% for no incentive, p = 0.6), it was significantly associated with participation among the breast cancer cases (48% vs. 27%, respectively, p = 0.01). There did not appear to be any bias in response since no differences between cases and controls and incentive groups were observed when examining several demographic, work history and radiation exposure variables.
This study demonstrates that collection of dried blood spot cards in addition to venipuncture blood samples may be a feasible method to increase participation in genetic case-control studies.
PMCID: PMC2781815  PMID: 19912630
Cancer research  2008;68(21):8825-8831.
The U.S. population has nearly one radiographic examination per person per year and concern about cancer risks associated with medical radiation has increased. Radiologic technologists were surveyed to determine whether their personal cumulative exposure to diagnostic x-rays was associated with increased frequencies of chromosome translocations, an established radiation biomarker and possible intermediary suggesting increased cancer risk. Within a large cohort of U. S. radiologic technologists, 150 provided a blood sample for whole chromosome painting and were interviewed about past x-ray examinations. The number and types of examinations reported were converted to a red bone marrow (RBM) dose score with units that approximated 1 mGy. The relationship between dose score and chromosome translocation frequency was assessed using Poisson regression. The estimated mean cumulative RBM radiation dose score was 49 (range 0 – 303). After adjustment for age, translocation frequencies significantly increased with increasing RBM dose score with an estimate of 0.004 translocations per 100 cell equivalents per score unit (95% confidence interval 0.002 to 0.007; P < 0.001). Removing extreme values or adjustment for gender, cigarette smoking, occupational radiation dose, allowing practice x-rays while training, work with radioisotopes, and radiotherapy for benign conditions did not affect the estimate. Cumulative radiation exposure from routine x-ray examinations was associated independently with increased chromosome damage, suggesting the possibility of elevated long-term health risks, including cancer. The slope estimate was consistent with expectation based on cytogenetic experience and atomic bomb survivor data.
PMCID: PMC2586176  PMID: 18974125
Radiation exposure; diagnostic x-rays; chromosome translocations; FISH; risk factors

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