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1.  Cancer mortality among women frequently exposed to radiographic exams for spinal disorders 
Radiation research  2010;174(1):83-90.
We studied cancer mortality in a cohort of 5,573 women with scoliosis and other spine disorders diagnosed between 1912 and 1965, and who were exposed to frequent diagnostic X-ray procedures. Patients were identified from medical records in 14 orthopedic medical centers in the United States and followed for vital status and address through Dec 31, 2004, using publicly available regional, state, and nation-wide databases. Causes of death were obtained from death certificates or through linkage with the National Death Index (NDI). Statistical analyses included standardized mortality ratios (SMR=observed/expected) based on death rates for U.S. females, and internal comparisons using Cox regression models with attained age as the time scale. Diagnostic radiation exposure was estimated from radiology files for over 137,000 procedures; estimated average cumulative radiation doses to the breast, lung, thyroid and bone marrow were 10.9, 4.1, 7.4, and 1.0 cGy, respectively. After a median follow-up period of 47 years, 1527 women died including 355 from cancer. Cancer mortality was 8% higher than expected (95% CI=0.97–1.20). Mortality from breast cancer was significantly elevated (SMR=1.68; 95% CI: 1.38–2.02), whereas death rates from several other cancers were below expectation, in particular lung (SMR=0.77), cervical (SMR=0.31), and liver (SMR=0.17). The excess relative risk (ERR) for breast cancer mortality increased significantly with 10-yr lagged radiation dose to the breast (ERR/Gy=3.9; 95% CI: 1.0–9.3).
doi:10.1667/RR2022.1
PMCID: PMC3982592  PMID: 20681802
breast neoplasms; radiation-induced; mortality; radiation; radiography; scoliosis; cohort study; epidemiology
2.  Sunlight and Other Determinants of Circulating 25-Hydroxyvitamin D Levels in Black and White Participants in a Nationwide US Study 
American Journal of Epidemiology  2013;177(2):180-192.
Circulating 25-hydroxyvitamin D (25(OH)D), a marker for vitamin D status, is associated with bone health and possibly cancers and other diseases; yet, the determinants of 25(OH)D status, particularly ultraviolet radiation (UVR) exposure, are poorly understood. Determinants of 25(OH)D were analyzed in a subcohort of 1,500 participants of the US Radiologic Technologists (USRT) Study that included whites (n = 842), blacks (n = 646), and people of other races/ethnicities (n = 12). Participants were recruited monthly (2008–2009) across age, sex, race, and ambient UVR level groups. Questionnaires addressing UVR and other exposures were generally completed within 9 days of blood collection. The relation between potential determinants and 25(OH)D levels was examined through regression analysis in a random two-thirds sample and validated in the remaining one third. In the regression model for the full study population, age, race, body mass index, some seasons, hours outdoors being physically active, and vitamin D supplement use were associated with 25(OH)D levels. In whites, generally, the same factors were explanatory. In blacks, only age and vitamin D supplement use predicted 25(OH)D concentrations. In the full population, determinants accounted for 25% of circulating 25(OH)D variability, with similar correlations for subgroups. Despite detailed data on UVR and other factors near the time of blood collection, the ability to explain 25(OH)D was modest.
doi:10.1093/aje/kws223
PMCID: PMC3590034  PMID: 23292956
dietary supplements; 25-hydroxyvitamin D; race; seasons; sex; sunlight; ultraviolet rays; vitamin D
3.  Basal cell carcinoma and anthropometric factors in the U.S. Radiologic Technologists Cohort Study 
Basal cell carcinoma (BCC) is the most common cancer in Caucasian populations. Although several risk factors are well-established, including ultraviolet radiation (UVR) sensitivity and exposure, few studies have examined anthropometric measures and BCC. Using Cox proportional hazards regression analysis, we prospectively investigated the relationship between height, weight, and body mass index (BMI) and BCC in 58,213 Caucasian participants (11,631 men and 46,582 women) from the United States Radiological Technologists cohort. This analysis was limited to participants who were cancer-free at baseline. The baseline questionnaire provided self-reported anthropometric factors and the subsequent questionnaire collected skin cancer susceptibility factors, lifetime UVR exposure derived from residential and personal UVR exposure (time outdoors), and health outcomes. During 509,465 person-years of follow-up, we identified 2,291 BCC cases (486 men; 1,805 women). BCC risk increased with increasing height, and decreased with increasing weight and BMI in both sexes, even after adjusting for UVR susceptibility factors and exposures. For BMI categories: <25 (reference); 25–<30; 30–<35; and ≥ 35 kg/m2, multivariate hazard ratios (HR) in women were: 1.00; 0.74 (95% CI=0.66–0.83); 0.67 (0.56–0.81); and 0.57 (0.44–0.74) respectively, p-trend ≤0.0001. Risks were similar in men. The inverse association between BMI and BCC was unaffected by controlling for sun-related exposures. Nevertheless, it may at least partly reflect residual UVR confounding. Further research with more detailed sun exposure data, including clothing patterns, would help clarify the relationship between BMI and BCC.
doi:10.1002/ijc.26480
PMCID: PMC3873091  PMID: 21989791
Basal cell carcinoma; weight; height; body mass index
4.  Sunlight, Polymorphisms of Vitamin D-related Genes and Risk of Breast Cancer 
Anticancer research  2013;33(2):543-551.
Background/Aim
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.
Results
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).
Conclusion
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
5.  Common genetic variants in metabolism and detoxification pathways and the risk of papillary thyroid cancer 
Endocrine-Related Cancer  2012;19(3):333-344.
Relationships are unclear between polymorphisms in genes involved in metabolism and detoxification of various chemicals and papillary thyroid cancer (PTC) risk as well as their potential modification by alcohol or tobacco intake. We evaluated associations between 1647 tagging single nucleotide polymorphisms (SNPs) in 132 candidate genes/regions involved in metabolism of exogenous and endogenous compounds (Phase I/II, oxidative stress, and metal binding pathways) and PTC risk in 344 PTC cases and 452 controls. For 15 selected regions and their respective SNPs, we also assessed interaction with alcohol and tobacco use. Logistic regression models were used to evaluate the main effect of SNPs (Ptrend) and interaction with alcohol/tobacco intake. Gene- and pathway-level associations and interactions (Pgene interaction) were evaluated by combining Ptrend values using the adaptive rank-truncated product method. While we found associations between PTC risk and nine SNPs (Ptrend≤0.01) and seven genes/regions (Pregion<0.05), none remained significant after correction for the false discovery rate. We found a significant interaction between UGT2B7 and NAT1 genes and alcohol intake (Pgene interaction=0.01 and 0.02 respectively) and between the CYP26B1 gene and tobacco intake (Pgene interaction=0.02). Our results are suggestive of interaction between the genetic polymorphisms in several detoxification genes and alcohol or tobacco intake on risk of PTC. Larger studies with improved exposure assessment should address potential modification of PTC risk by alcohol and tobacco intake to confirm or refute our findings.
doi:10.1530/ERC-11-0372
PMCID: PMC3394851  PMID: 22389382
6.  Hormone-related Risk Factors and Postmenopausal Breast Cancer Among Nulliparous Versus Parous Women: An Aggregated Study 
American Journal of Epidemiology  2011;173(5):509-517.
Nulliparity is an established breast cancer risk factor, particularly when compared with parity at young ages. The authors aggregated data from 4 US prospective studies (1979–2006) including 32,641 nulliparous (1,612 breast cancers) and 204,270 parous (8,180 breast cancers) women to examine the hypothesis that nulliparity may increase susceptibility to established postmenopausal breast cancer risk factors. The aggregated hazard ratio for nulliparous versus all parous women = 1.27 (95% confidence interval: 1.21, 1.34), and that for nulliparous versus women <25 years of age at first birth = 1.38 (95% confidence interval: 1.30, 1.46). Among nulliparous women, the hazard ratios for current menopausal hormone therapy use (vs. never use), body mass index ≥30 kg/m2 (vs. <25 kg/m2), and weekly consumption of ≥7 alcoholic drinks (vs. none) ranged from 1.3 to 1.6. The hazard ratios did not differ by parity. In a model including all women, the joint association for each of these factors and nulliparity combined compared with first birth before age 25 years was an approximately 2-fold increased breast cancer risk. Although the baseline risk is higher for nulliparous women compared with parous women, these results suggest that the associations between hormone-related factors and breast cancer do not differ by parity.
doi:10.1093/aje/kwq404
PMCID: PMC3105439  PMID: 21266505
alcohol drinking; body mass index; breast neoplasms; hormone replacement therapy; parity; prospective studies; risk factors
7.  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.
doi:10.1007/s00411-010-0307-z
PMCID: PMC3075914  PMID: 20602108
8.  A role for XRCC2 gene polymorphisms in breast cancer risk and survival 
Journal of medical genetics  2011;48(7):477-484.
Background
The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. We hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer.
Methods
We genotyped 12 XRCC2 tagging SNPs in 1,131 breast cancer cases and 1,148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating odds ratios (ORs) and hazard ratios (HRs), and their corresponding 95% confidence intervals (CIs). Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8,074 cases) from the Breast Cancer Association Consortium (BCAC).
Results
The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10−4, MAF=0.23). This SNP yielded an ORrec (95% CI) of 1.64 (1.25–2.16) in a two-site analysis of SBCS and UBCS, and a meta-ORrec (95% CI) of 1.33 (1.12–1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by 2 in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR (95% CI) of 1.58 (1.01–2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8,781 breast cancer patients from the BCAC [HR (95% CI) of 1.19 (1.05–1.36), p=0.01].
Conclusions
Our findings suggest that XRCC2 SNPs may influence breast cancer risk and survival.
doi:10.1136/jmedgenet-2011-100018
PMCID: PMC3932658  PMID: 21632523
Single nucleotide polymorphism; XRCC2; breast cancer risk; breast cancer survival
9.  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.
doi:10.1667/RR1985.1
PMCID: PMC2922870  PMID: 20095854
10.  POLYMORPHISMS IN ESTROGEN BIOSYNTHESIS AND METABOLISM-RELATED GENES, IONIZING RADIATION EXPOSURE, AND RISK OF BREAST CANCER AMONG U.S. RADIOLOGIC TECHNOLOGISTS 
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.
doi:10.1007/s10549-009-0307-3
PMCID: PMC2860373  PMID: 19214745
11.  Blood spots as an alternative to whole blood collection and the effect of a small monetary incentive to increase participation in genetic association studies 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2288-9-76
PMCID: PMC2781815  PMID: 19912630
12.  Increased Frequency of Chromosome Translocations Associated with Diagnostic X-Ray Examinations 
Radiation research  2008;170(2):149-155.
Informative studies of cancer risks associated with medical radiation are difficult to conduct owing to low radiation doses, poor recall of diagnostic X rays, and long intervals before cancers occur. Chromosome aberrations have been associated with increased cancer risk and translocations are a known radiation biomarker. Seventy-nine U.S. radiologic technologists were selected for blood collection, and translocations were enumerated by whole chromosome painting. We developed a dose score to the red bone marrow for medical radiation exposure from X-ray examinations reported by the technologists that they received as patients. Using Poisson regression, we analyzed translocations in relation to the dose scores. Each dose score unit approximated 1 mGy. The estimated mean cumulative red bone marrow radiation dose score was 42 (range 1–265). After adjustment for age, occupational radiation, and radiotherapy for benign conditions, translocation frequencies significantly increased with increasing red bone marrow dose score with an estimate of 0.007 translocations per 100 CEs per score unit (95% CI, 0.002 to 0.013; P = 0.01). Chromosome damage has been linked with elevated cancer risk, and we found that cumulative radiation exposure from medical X-ray examinations was associated with increased numbers of chromosome translocations.
doi:10.1667/RR1422.1
PMCID: PMC2766815  PMID: 18666821
13.  Breast cancer risk polymorphisms and interaction with ionizing radiation among U.S. Radiologic Technologists 
Genome-wide association studies are discovering relationships between single nucleotide polymorphisms (SNPs) and breast cancer, but the functions of these SNPs are unknown and environmental exposures are likely to be important. We assessed whether breast cancer risk SNPs interacted with ionizing radiation, a known breast carcinogen, among 859 cases and 1083 controls nested in the United States Radiologic Technologists cohort. Among eleven Breast Cancer Association Consortium risk SNPs, we found that the genotype-associated breast cancer risk varied significantly by radiation dose for rs2107425 in the H19 gene (pinteraction=0.001). H19 is a maternally expressed imprinted mRNA that is closely involved in regulating the IGF2 gene and could exert its influence by this or by some other radiation-related pathway.
doi:10.1158/1055-9965.EPI-08-0300
PMCID: PMC2583248  PMID: 18708391
14.  The ATM missense mutation Ser49Cys and risk of breast cancer 
Human mutation  2006;27(6):538-544.
Homozygous mutation in the ATM gene causes ataxia telangiectasia and heterozygous mutation carriers may be at increased risk of breast cancer. We studied a total of 22 ATM variants in two large population-based studies of 2856 breast cancer cases and 3344 controls from the U.S. and Poland. The missense mutation Ser49Cys (S49C), carried by approximately 2% of subjects, was more common in cases than controls in both study populations, combined odds ratio (OR) 1.69, 95% CI 1.19 – 2.40, P = 0.004. Another missense mutation at approximately 2% frequency, F858L, was associated with a significant increased risk in the U.S. study but not in Poland, combined OR of 1.44, 95% CI 0.98 – 2.11, P = 0.06. These analyses provide the most convincing evidence thus far that some missense mutations in ATM, particularly S49C, may be breast cancer susceptibility alleles. Because of their low frequency, even larger sample sizes are required to more firmly establish these associations.
doi:10.1002/humu.20323
PMCID: PMC1850333  PMID: 16652348
15.  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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s10552-010-9613-7
PMCID: PMC3076104  PMID: 20711808
PTGS2; COX-2; Inflammation; Breast cancer; Radiation

Results 1-15 (15)