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1.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
Purpose
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.
Results
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).
Conclusion
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.
doi:10.1200/JCO.2012.41.8996
PMCID: PMC3530689  PMID: 23169509
2.  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
3.  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
4.  A Prospective Study of Medical Diagnostic Radiography and Risk of Thyroid Cancer 
American Journal of Epidemiology  2013;177(8):800-809.
Although diagnostic x-ray procedures provide important medical benefits, cancer risks associated with their exposure are also possible, but not well characterized. The US Radiologic Technologists Study (1983–2006) is a nationwide, prospective cohort study with extensive questionnaire data on history of personal diagnostic imaging procedures collected prior to cancer diagnosis. We used Cox proportional hazard regressions to estimate thyroid cancer risks related to the number and type of selected procedures. We assessed potential modifying effects of age and calendar year of the first x-ray procedure in each category of procedures. Incident thyroid cancers (n = 251) were diagnosed among 75,494 technologists (1.3 million person-years; mean follow-up = 17 years). Overall, there was no clear evidence of thyroid cancer risk associated with diagnostic x-rays except for dental x-rays. We observed a 13% increase in thyroid cancer risk for every 10 reported dental radiographs (hazard ratio = 1.13, 95% confidence interval: 1.01, 1.26), which was driven by dental x-rays first received before 1970, but we found no evidence that the relationship between dental x-rays and thyroid cancer was associated with childhood or adolescent exposures as would have been anticipated. The lack of association of thyroid cancer with x-ray procedures that expose the thyroid to higher radiation doses than do dental x-rays underscores the need to conduct a detailed radiation exposure assessment to enable quantitative evaluation of risk.
doi:10.1093/aje/kws315
PMCID: PMC3668423  PMID: 23529772
radiation; radiography; thyroid gland; thyroid neoplasms; x-rays
5.  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.
doi:10.1002/ijc.23779
PMCID: PMC3984912  PMID: 18767034
6.  ROUTINE DIAGNOSTIC X-RAY EXAMINATIONS AND INCREASED FREQUENCY OF CHROMOSOME TRANSLOCATIONS AMONG U. S. RADIOLOGIC TECHNOLOGISTS 
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.
doi:10.1158/0008-5472.CAN-08-1691
PMCID: PMC2586176  PMID: 18974125
Radiation exposure; diagnostic x-rays; chromosome translocations; FISH; risk factors
7.  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.
doi:10.1158/1055-9965.EPI-07-2871
PMCID: PMC3950930  PMID: 18398043
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.  Common obesity-related genetic variants and papillary thyroid cancer risk 
Background
Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single nucleotide polymorphisms (SNPs).
Methods
We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case-control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate P-trends.
Results
Nine out of 10 top-ranking SNPs (Ptrend<0.01) were located in the FTO (fat mass and obesity associated) gene region, while the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing.
Conclusions
Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC.
Impact
Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk.
doi:10.1158/1055-9965.EPI-12-0790
PMCID: PMC3518668  PMID: 23064004
single nucleotide polymorphisms; case-control study; obesity; body mass index; thyroid neoplasms
10.  Radiation-Related Risk of Basal Cell Carcinoma: A Report From the Childhood Cancer Survivor Study 
Background
Basal cell carcinoma (BCC) is the most common malignancy in the United States. Ionizing radiation is an established risk factor in certain populations, including cancer survivors. We quantified the association between ionizing radiation dose and the risk of BCC in childhood cancer survivors.
Methods
Participants in the Childhood Cancer Survivor Study who reported a BCC (case subjects, n = 199) were matched on age and length of follow-up to three study participants who had not developed a BCC (control subjects, n = 597). The radiation-absorbed dose (in Gy) to the BCC location was calculated based on individual radiotherapy records using a custom-designed dosimetry program. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic and treatment factors, therapeutic radiation dose, and surrogate markers of sun sensitivity (skin and hair color) and the risk of BCC. A linear dose–response model was fitted to evaluate the excess odds ratio per Gy of radiation dose.
Results
Among case subjects, 83% developed BCC between the ages of 20 and 39 years. Radiation therapy, either alone or in combination with chemotherapy, was associated with an increased risk of BCC compared with no chemotherapy or radiation. The odds ratio for subjects who received 35 Gy or more to the skin site vs no radiation therapy was 39.8 (95% CI = 8.6 to 185). Results were consistent with a linear dose–response relationship, with an excess odds ratio per Gy of 1.09 (95% CI = 0.49 to 2.64). No other treatment variables were statistically significantly associated with an increased risk of BCC.
Conclusions
Radiation doses to the skin of more than 1 Gy are associated with an increased risk of BCC.
doi:10.1093/jnci/djs298
PMCID: PMC3611815  PMID: 22835387
11.  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
12.  Common genetic variants in the 8q24 region and risk of papillary thyroid cancer 
The Laryngoscope  2012;122(5):1040-1042.
Objectives/Hypothesis
Single nucleotide polymorphisms (SNPs) in the 8q24 chromosomal region identified from genome-wide scans have been associated with risk of several cancers including breast (rs1562430), prostate and colon (rs1447295 and rs6983267). A genome-wide scan in 26 families with papillary thyroid cancer (PTC) also found susceptibility loci in 8q24, supporting a closer evaluation of this chromosomal region in relation to risk of sporadic PTC.
Study Design
We evaluated 157 tag SNPs in the 8q24 chromosomal region between 120.91 Mb and 128.78 Mb (including rs1562430, rs1447295, and rs6983267) in a case-control study of 344 PTC cases and 452 age and gender frequency-matched controls.
Methods
We used logistic regression to estimate odds ratios and compute P-values of linear trend for PTC with genotypes of interest. To account for multiple comparisons, we applied the false discovery rate (FDR) method.
Results
We did not find a significant association between rs1562430, rs1447295, or rs6983267, and PTC risk. We found that one SNP (rs4733616) was associated with PTC risk at P = 0.003, and twelve other SNPs were associated with PTC risk at P < 0.05. However, no SNPs remained significant after FDR correction.
Conclusions
Our findings do not support a strong association between SNPs in the 8q24 chromosomal region and risk of sporadic PTC but several SNPs with small effects might exist.
doi:10.1002/lary.23209
PMCID: PMC3408055  PMID: 22275265
8q24; thyroid cancer
13.  Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors 
Nickels, Stefan | Truong, Thérèse | Hein, Rebecca | Stevens, Kristen | Buck, Katharina | Behrens, Sabine | Eilber, Ursula | Schmidt, Martina | Häberle, Lothar | Vrieling, Alina | Gaudet, Mia | Figueroa, Jonine | Schoof, Nils | Spurdle, Amanda B. | Rudolph, Anja | Fasching, Peter A. | Hopper, John L. | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Beckmann, Matthias W. | Ekici, Arif B. | Fletcher, Olivia | Gibson, Lorna | dos Santos Silva, Isabel | Peto, Julian | Humphreys, Manjeet K. | Wang, Jean | Cordina-Duverger, Emilie | Menegaux, Florence | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Clarke, Christina A. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Harth, Volker | The GENICA Network,  | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | kConFab,  | Group, AOCS Management | Lambrechts, Diether | Smeets, Dominiek | Neven, Patrick | Paridaens, Robert | Flesch-Janys, Dieter | Obi, Nadia | Wang-Gohrke, Shan | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine M. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Offit, Kenneth | John, Esther M. | Miron, Alexander | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Chanock, Stephen J. | Lissowska, Jolanta | Liu, Jianjun | Cox, Angela | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Dunning, Alison M. | Shah, Mitul | Trentham-Dietz, Amy | Newcomb, Polly | Titus, Linda | Egan, Kathleen | Cahoon, Elizabeth K. | Rajaraman, Preetha | Sigurdson, Alice J. | Doody, Michele M. | Guénel, Pascal | Pharoah, Paul D. P. | Schmidt, Marjanka K. | Hall, Per | Easton, Doug F. | Garcia-Closas, Montserrat | Milne, Roger L. | Chang-Claude, Jenny
PLoS Genetics  2013;9(3):e1003284.
Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10−5), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
Author Summary
Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as BRCA1 and BRCA2, account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in LSP1 differs with the number of births and that the risk associated with a CASP8 variant is altered by high alcohol consumption. The effect of an additional genetic variant might also be modified by reproductive factors. This knowledge will stimulate new research towards a better understanding of breast cancer development.
doi:10.1371/journal.pgen.1003284
PMCID: PMC3609648  PMID: 23544014
14.  Baldness, acne and testicular germ cell tumors 
International journal of andrology  2010;34(4 Pt 2):e59-e67.
Androgen levels during critical periods of testicular development may be involved in the etiology of testicular germ cell tumors (TGCT). We evaluated the roles of adolescent and early adult life correlates of androgen exposure and TGCT in a hospital-based case control study. TGCT cases (n=187) and controls (n=148), matched on age, race and state of residence, participated in the study. Unconditional logistic regression was used to estimate associations between TGCT and male pattern baldness, severe acne, markers of puberty onset and body size. Cases were significantly less likely to report hair loss than controls (OR, 0.6; 95% CI, 0.4, 1.0). Amount of hair loss, increasing age at onset and increasing rate of loss were all inversely associated with TGCT (rate of hair loss: p-trend=0.03; age at onset: p-trend=0.03; amount of hair loss: p-trend=0.01). History of severe acne was inversely associated with TGCT (OR, 0.5; 95% CI, 0.3, 0.9) and height was positively associated with TGCT (p-trend=0.02). Increased endogenous androgen levels during puberty and early adulthood may be associated with decreased risk of TGCT. Additional studies of endogenous hormone levels during puberty and early adult life are warranted, especially studies evaluating the role of androgen synthesis, metabolism and uptake.
doi:10.1111/j.1365-2605.2010.01125.x
PMCID: PMC3607953  PMID: 21128977
Testicular germ cell tumors; baldness; acne; hospital-based; case-control
15.  Common Single Nucleotide Polymorphisms in Genes Related to Immune Function and Risk of Papillary Thyroid Cancer 
PLoS ONE  2013;8(3):e57243.
Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kB pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (PSNP-trend) for the association between genotype (common homozygous, heterozygous, variant homozygous) and risk of PTC. To correct for multiple comparisons, we applied the false discovery rate method (FDR). Gene region- and pathway-level associations (PRegion and PPathway) were assessed by combining individual PSNP-trend values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (PSNP-FDR/PSNP-trend = 0.02/6×10−6 and PSNP-FDR/PSNP-trend = 0.04/2×10−5, respectively). These associations were independent of a history of autoimmune thyroiditis (OR = 6.4; 95% confidence interval: 3.0–13.4). At the gene region level, SERPINA5 was suggestively associated with risk of PTC (PRegion-FDR/PRegion = 0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (PPathway = 0.02) associated with PTC risk largely due to the strong effect of SERPINA5. Our results require replication but suggest that the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC.
doi:10.1371/journal.pone.0057243
PMCID: PMC3592848  PMID: 23520464
16.  Common Genetic Variants in Sex Hormone Pathway Genes and Papillary Thyroid Cancer Risk 
Thyroid  2012;22(2):151-156.
Background
Hormonal differences are hypothesized to contribute to the approximately ≥2-fold higher thyroid cancer incidence rates among women compared with men worldwide. Although thyroid cancer cells express estrogen receptors and estrogen has a proliferative effect on papillary thyroid cancer (PTC) cells in vitro, epidemiologic studies have not found clear associations between thyroid cancer and female hormonal factors. We hypothesized that polymorphic variation in hormone pathway genes is associated with the risk of developing papillary thyroid cancer.
Methods
We evaluated the association between PTC and 1151 tag single nucleotide polymorphisms (SNPs) in 58 candidate gene regions involved in sex hormone synthesis and metabolism, gonadotropins, and prolactin in a case-control study of 344 PTC cases and 452 controls, frequency matched on age and sex. Odds ratios and p-values for the linear trend for the association between each SNP genotype and PTC risk were estimated using unconditional logistic regression. SNPs in the same gene region or pathway were aggregated using adaptive rank-truncated product methods to obtain gene region-specific or pathway-specific p-values. To account for multiple comparisons, we applied the false discovery rate method.
Results
Seven SNPs had p-values for linear trend <0.01, including four in the CYP19A1 gene, but none of the SNPs remained significant after correction for multiple comparisons. Results were similar when restricting the dataset to women. p-values for examined gene regions and for all genes combined were ≥0.09.
Conclusions
Based on these results, SNPs in selected hormone pathway genes do not appear to be strongly related to PTC risk. This observation is in accord with the lack of consistent associations between hormonal factors and PTC risk in epidemiologic studies.
doi:10.1089/thy.2011.0309
PMCID: PMC3271376  PMID: 22224819
17.  Chemotherapy and thyroid cancer risk: A report from the Childhood Cancer Survivor Study 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Impact
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.
doi:10.1158/1055-9965.EPI-11-0576
PMCID: PMC3253948  PMID: 22028399
Thyroid cancer; second cancer; chemotherapy; radiation risk; cohort study
18.  Common genetic variants related to genomic integrity and risk of papillary thyroid cancer 
Carcinogenesis  2011;32(8):1231-1237.
DNA damage is an important mechanism in carcinogenesis, so genes related to maintaining genomic integrity may influence papillary thyroid cancer (PTC) risk. Candidate gene studies targeting some of these genes have identified only a few polymorphisms associated with risk of PTC. Here, we expanded the scope of previous candidate studies by increasing the number and coverage of genes related to maintenance of genomic integrity. We evaluated 5077 tag single-nucleotide polymorphisms (SNPs) from 340 candidate gene regions hypothesized to be involved in DNA repair, epigenetics, tumor suppression, apoptosis, telomere function and cell cycle control and signaling pathways in a case–control study of 344 PTC cases and 452 matched controls. We estimated odds ratios for associations of single SNPs with PTC risk and combined P values for SNPs in the same gene region or pathway to obtain gene region-specific or pathway-specific P values using adaptive rank-truncated product methods. Nine SNPs had P values <0.0005, three of which were in HDAC4 and were inversely related to PTC risk. After multiple comparisons adjustment, no SNPs remained associated with PTC risk. Seven gene regions were associated with PTC risk at P < 0.01, including HUS1, ALKBH3, HDAC4, BAK1, FAF1_CDKN2C, DACT3 and FZD6. Our results suggest a possible role of genes involved in maintenance of genomic integrity in relation to risk of PTC.
doi:10.1093/carcin/bgr100
PMCID: PMC3166197  PMID: 21642358
19.  Iodine-131 Dose Dependent Gene Expression in Thyroid Cancers and Corresponding Normal Tissues Following the Chernobyl Accident 
PLoS ONE  2012;7(7):e39103.
The strong and consistent relationship between irradiation at a young age and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis in humans. We thus evaluated differential gene expression in thyroid tissue in relation to iodine-131 (I-131) doses received from the Chernobyl accident. Sixty three of 104 papillary thyroid cancers diagnosed between 1998 and 2008 in the Ukrainian-American cohort with individual I-131 thyroid dose estimates had paired RNA specimens from fresh frozen tumor (T) and normal (N) tissue provided by the Chernobyl Tissue Bank and satisfied quality control criteria. We first hybridized 32 randomly allocated RNA specimen pairs (T/N) on 64 whole genome microarrays (Agilent, 4×44 K). Associations of differential gene expression (log2(T/N)) with dose were assessed using Kruskall-Wallis and trend tests in linear mixed regression models. While none of the genes withstood correction for the false discovery rate, we selected 75 genes with a priori evidence or P kruskall/P trend <0.0005 for validation by qRT-PCR on the remaining 31 RNA specimen pairs (T/N). The qRT-PCR data were analyzed using linear mixed regression models that included radiation dose as a categorical or ordinal variable. Eleven of 75 qRT-PCR assayed genes (ACVR2A, AJAP1, CA12, CDK12, FAM38A, GALNT7, LMO3, MTA1, SLC19A1, SLC43A3, ZNF493) were confirmed to have a statistically significant differential dose-expression relationship. Our study is among the first to provide direct human data on long term differential gene expression in relation to individual I-131 doses and to identify a set of genes potentially important in radiation carcinogenesis.
doi:10.1371/journal.pone.0039103
PMCID: PMC3405097  PMID: 22848350
20.  Variation in Base Excision Repair Capacity 
Mutation research  2010;711(1-2):100-112.
The major DNA repair pathway for coping with spontaneous forms of DNA damage, such as natural hydrolytic products or oxidative lesions, is base excision repair (BER). In particular, BER processes mutagenic and cytotoxic DNA lesions such as non-bulky base modifications, abasic sites, and a range of chemically distinct single-strand breaks. Defects in BER have been linked to cancer predisposition, neurodegenerative disorders, and immunodeficiency. Recent data indicate a large degree of sequence variability in DNA repair genes and several studies have associated BER gene polymorphisms with disease risk, including cancer of several sites. The intent of this review is to describe the range of BER capacity among individuals and the functional consequences of BER genetic variants. We also discuss studies that associate BER deficiency with disease risk and the current state of BER capacity measurement assays.
doi:10.1016/j.mrfmmm.2010.12.004
PMCID: PMC3101302  PMID: 21167187
DNA repair capacity; base excision; pathway assay; polymorphism; disease susceptibility
21.  Nonsteroidal Antiinflammatory Drugs and Bladder Cancer: A Pooled Analysis 
American Journal of Epidemiology  2011;173(7):721-730.
Case-control studies have shown that regular use of nonsteroidal antiinflammatory drugs (NSAIDs) decreases bladder cancer risk, but few cohort studies have evaluated this association. The authors investigated NSAID use and bladder cancer in 3 large prospective studies (NIH-AARP Diet and Health Study; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; and U.S. Radiologic Technologists Study). Frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using self-administered questionnaires. Study-specific hazard ratios and 95% confidence intervals were estimated using Cox regression models and were combined using a fixed-effects meta-analytic model. Data from all studies were aggregated, and aggregated hazard ratios were estimated. The analysis included 508,842 individuals, with 2,489 incident cases of bladder cancer. A reduction in risk was observed for individuals who reported regular use (>2 times/week) of nonaspirin NSAIDs compared with those who reported no use (hazard ratio (HR) = 0.92, 95% confidence interval (CI): 0.81, 1.04). The risk reduction was limited to nonsmokers (HR = 0.58, 95% CI: 0.41, 0.83) (Ptrend = 0.008) (Pinteraction = 0.02). No association was observed between regular aspirin use and bladder cancer risk (HR = 1.04, 95% CI: 0.94, 1.15). Results suggest that nonaspirin NSAIDs, but not aspirin, are associated with a reduction in risk of bladder cancer, particularly for nonsmokers.
doi:10.1093/aje/kwq437
PMCID: PMC3105281  PMID: 21367875
anti-inflammatory agents, non-steroidal; aspirin; meta-analysis; urinary bladder neoplasms
22.  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
23.  Marijuana use and testicular germ cell tumors 
Cancer  2010;117(4):848-853.
Background
Since the early 1970's the incidence of testicular germ cell tumors (TGCT) in the U.S. has been increasing, however, potential environmental exposures accounting for this rise have not been identified. A prior study reported a significant association among frequent and long-term current users of marijuana and TGCT risk. We aimed to evaluate the relationship of marijuana use and TGCT in a hospital-based case-control study conducted at The University of Texas M. D. Anderson Cancer Center.
Methods
TGCT cases diagnosed between January 1990 and October 1996 (n=187) and male friend controls (n=148) were enrolled in the study. All participants were between the ages of 18 and 50 at the time of cases' diagnosis and resided in Texas, Louisiana, Arkansas, or Oklahoma. Associations of marijuana use and TGCT were estimated using unconditional logistic regression, adjusting for age, race, prior cryptorchidism, cigarette smoking and alcohol intake.
Results
Overall, TGCT cases were more likely to be frequent marijuana users (daily or greater) than were controls [OR: 2.2, 95% CI: 1.0, 5.1]. In the histologic-specific analyses nonseminoma cases were significantly more likely than controls to be frequent users [OR: 3.1, 95% CI: 1.2, 8.2] and long-term users (10+ years) [OR: 2.4, 95% CI: 1.0, 6.1].
Discussion
Our finding of an association between frequent marijuana use and TGCT, particularly among men with nonseminoma, is consistent with the findings of a previous report. Additional studies of marijuana use and TGCT are warranted, especially studies evaluating the role of endocannabinoid signaling and cannabinoid receptors in TGCT.
doi:10.1002/cncr.25499
PMCID: PMC3017734  PMID: 20925043
marijuana use; seminomas; nonseminomas; testicular germ cell tumors; hospital-based case-control
24.  Prospective analysis of DNA damage and repair markers of lung cancer risk from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial 
Carcinogenesis  2010;32(1):69-73.
Mutagen challenge and DNA repair assays have been used in case–control studies for nearly three decades to assess human cancer risk. The findings still engender controversy because blood was drawn after cancer diagnosis so the results may be biased, a type called ‘reverse causation’. We therefore used Epstein–Barr virus-transformed lymphoblastoid cell lines established from prospectively collected peripheral blood samples to evaluate lung cancer risk in relation to three DNA repair assays: alkaline Comet assay, host cell reactivation (HCR) assay with the mutagen benzo[a]pyrene diol epoxide and the bleomycin mutagen sensitivity assay. Cases (n = 117) were diagnosed with lung cancer between 0.3 and 6 years after blood collection and controls (n = 117) were frequency matched on calendar year and age at blood collection, gender and smoking history; all races were included. Case and control status was unknown to laboratory investigators. In unconditional logistic regression analyses, statistically significantly increased lung cancer odds ratios (ORadjusted) were observed for bleomycin mutagen sensitivity as quartiles of chromatid breaks/cell [relative to the lowest quartile, OR = 1.2, 95% confidence interval (CI): 0.5–2.5; OR = 1.4, 95% CI: 0.7–3.1; OR = 2.1, 95% CI: 1.0–4.4, respectively, Ptrend = 0.04]. The magnitude of the association between the bleomycin assay and lung cancer risk was modest compared with those reported in previous lung cancer studies but was strengthened when we included only incident cases diagnosed more than a year after blood collection (Ptrend = 0.02), supporting the notion the assay may be a measure of cancer susceptibility. The Comet and HCR assays were unrelated to lung cancer risk.
doi:10.1093/carcin/bgq204
PMCID: PMC3010173  PMID: 20929901
25.  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.
doi:10.1667/RR2240.1
PMCID: PMC3080023  PMID: 21128798

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