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1.  Association between endogenous sex steroid hormones and insulin-like growth factor proteins in US men 
Cancer causes & control : CCC  2014;25(3):353-363.
Purpose
Sex steroid hormone concentrations and insulin-like growth factor (IGF) proteins have been independently associated with risk of cancer, chronic diseases, and mortality. However, studies that evaluated the inter-relation between the sex hormones and IGF pathways have provided mixed results. We examined the association between endogenous sex hormones and sex hormone-binding globulin (SHBG) with IGF-1 and IGF-binding protein 3 (IGFBP-3) in a population-based sample of US men.
Methods
Data from 1,135 men aged 20 years or older participating in the third National Health and Nutrition Examination Survey (NHANES III) were analyzed. Weighted linear regression was used to estimate geometric means and 95 % confidence intervals for IGF-1 and IGFBP-3 concentrations by sex steroid hormones and SHBG after adjusting for age, race/ethnicity, body mass index, waist circumference, alcohol consumption, cigarette smoking, physical activity, diabetes, and mutually adjusting for other sex hormones and SHBG.
Results
No significant association was observed between sex steroid hormones, SHBG, and IGF-1 concentrations. Total estradiol (% difference in Q5 − Q1 geometric means −9.7 %; P-trend 0.05) and SHBG (% difference −7.3 %; P-trend 0.02) were modestly inversely associated with IGFBP-3. Total testosterone was modestly inversely associated with IGFBP-3 (% difference −6.2 %; P-trend 0.01), but this association disappeared after adjustment for total estradiol and SHBG (% difference 2.6 %; P-trend 0.23). Androstanediol glucuronide was not associated with IG-FBP-3.
Conclusions
These findings suggest that there may be inter-relationships between circulating total estradiol, SHBG, and IGFBP-3 concentrations. Future research may consider these inter-relationships when evaluating potential joint effects of the sex hormones and IGF pathways.
doi:10.1007/s10552-013-0336-4
PMCID: PMC4332790  PMID: 24395140
Testosterone; Estradiol; Sex hormone-binding globulin (SHBG); Insulin growth factor-1 (IGF-1); Insulin growth factor-binding protein 3 (IGFBP-3)
2.  Associations between time spent sitting and cancer-related biomarkers in postmenopausal women: an exploration of effect modifiers 
Cancer causes & control : CCC  2014;25(11):1427-1437.
Purpose
Despite evidence that prolonged periods of sitting may influence biological mediators of cancer development, few studies have considered these relationships in a cancer-specific context.
Methods
This cross-sectional study included 755 post-menopausal women enrolled in an ancillary study of the Women’s Health Initiative. Plasma levels of Insulin-like growth factor-I (IGF-I), IGF-binding protein-3, leptin, insulin, C-peptide, C-reactive protein (CRP), and Interleukin (IL)-6 were measured. The time spent sitting per day was categorized as quartiles (Qs). The relationships between sedentary time and biomarkers were modified by race, physical activity, and exogenous estrogen use.
Results
IGF-I levels among African American (AA) women were higher than those of white women across the Qs of sedentary time. Likewise, IL-6 levels in AA women were higher than those in white women at Q3 and Q4 of sedentary time. IGFBP-3 levels were higher and insulin levels were lower across the Qs of sedentary time among women meeting guidelines for physical activity than women who were not. Additionally, CRP levels were higher among estrogen users than nonusers at Q1, Q2, and Q4 of sedentary time.
Conclusions
These results suggest that relationship between time spent sitting and cancer-related biomarkers may not be simply linear, but differ in the context of effect modifiers.
doi:10.1007/s10552-014-0434-y
PMCID: PMC4316818  PMID: 25238978
Sedentary behavior; Cancer-relevant biomarkers; Effect modifier; Postmenopausal women
3.  [No title available] 
PMCID: PMC3903305  PMID: 24249438
4.  [No title available] 
PMCID: PMC3922298  PMID: 24276357
5.  [No title available] 
PMCID: PMC3932534  PMID: 24281852
6.  [No title available] 
PMCID: PMC3946890  PMID: 24194259
7.  Influence of reproductive history and exogenous hormone use on prevalence and frequency of circulating t(14;18)-positive cells in a population-based cross-sectional study 
Cancer Causes & Control  2015;26(3):455-465.
Purpose
The t(14;18) translocation might represent an intermediate step in the pathogenesis of follicular lymphoma (FL), one of the most common subtypes of non-Hodgkin lymphoma. Circulating t(14;18)-positive cells can also be detected in 30–60 % of healthy individuals at low frequencies. Some studies found a negative association between reproductive factors or use of menopausal hormone therapy (MHT) with FL. The objective of this study was to evaluate whether there is an association between number of frequencies, oral contraceptive (OC) use, menopausal status and MHT, and t(14;18) prevalence and frequency in a representative population analysis based on an epidemiologic study in the northeastern part of Germany.
Methods
The analysis is based on results of buffy coat samples from 1,981 women of the Study of Health in Pomerania (SHIP-0) and data obtained in standardized face-to-face interviews. For prevalence, odds ratios (OR) and 95 % confidence intervals (CI) were calculated using unconditional logistic regression. Frequency data were analyzed using negative binomial regression. The multivariable models included age, number of pregnancies, menopausal status (premenopausal, natural, medical/surgical menopause), OC use and MHT as a measure for exogenous hormone exposure use.
Results
We found no association between reproductive history and combined exogenous hormone use on the prevalence of circulating t(14;18)-positive cells. Modeling MHT and OC use separately in a sensitivity analysis, the MHT parameter yielded statistical significance [OR 1.37 (95 % CI 1.04;1.81)]. t(14;18) frequency was associated with use of OC [incidence rate ratio (IRR) for ever use 3.18 (95 % CI 1.54;6.54)], current use [IRR 3.86 (1.56;9.54)], >10 years use [IRR 3.93 (1.67;9.23)] and MHT [restricted to postmenopausal women; IRR 2.63 (95 % CI 1.01;6.85)] in bivariate age-adjusted analyses. In the multivariable model, medical/surgical menopause [IRR 2.46 (1.11;5.44)] and the category ever use of OC and MHT were statistically significant [IRR 2.41 (1.09;5.33)].
Conclusions
Exogenous hormone use might be a risk factor for t(14;18) frequency rather than for t(14;18) prevalence. Further research on healthy individuals carrying a t(14;18) translocation and possible risk factors for malignant lymphoma is necessary to determine the additional molecular or immunological events that have to occur to develop FL.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-015-0525-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10552-015-0525-4
PMCID: PMC4331597  PMID: 25634026
t(14;18) translocation; Healthy individuals; Reproductive history; Exogenous hormone use
8.  Low cancer incidence rates in Ohio Amish 
Cancer causes & control : CCC  2009;21(1):69-75.
Background
The Amish have not been previously studied for cancer incidence, yet they have the potential to help in the understanding of its environmental and genetic contributions. The purpose of this study was to estimate the incidence of cancer among the largest Amish population.
Methods
Adults from randomly selected households were interviewed and a detailed cancer family history was taken. Using both the household interview data and a search of the Ohio cancer registry data, a total of 191 cancer cases were identified between the years 1996 and 2003.
Results
The age-adjusted cancer incidence rate for all cancers among the Amish adults was 60% of the age-adjusted adult rate in Ohio (389.5/105 vs. 646.9/105; p < 0.0001). The incidence rate for tobacco-related cancers in the Amish was 37% of the rate for Ohio adults (p < 0.0001). The incidence rate for non-tobacco-related cancers in the Amish was 72% of the age-adjusted adult rate in Ohio (p = 0.0001).
Conclusion
Cancer incidence is low in the Ohio Amish. These data strongly support reduction of cancer incidence by tobacco abstinence but cannot be explained solely on this basis. Understanding these contributions may help to identify additional important factors to target to reduce cancer among the non-Amish.
doi:10.1007/s10552-009-9435-7
PMCID: PMC4308689  PMID: 19779840
Cancer incidence; Amish; Tobacco; Founder population
9.  Perceived Risk of Breast Cancer among Latinas Attending Community Clinics: Risk Comprehension and Relationship with Mammography Adherence 
Cancer causes & control : CCC  2008;19(10):1373-1382.
Objective
To describe breast cancer risk perceptions, determine risk comprehension, and evaluate mammography adherence among Latinas.
Methods
Latina women age ≥ 35, primarily from Central and South America, were recruited from community-based clinics to complete in-person interviews (n=450). Risk comprehension was calculated as the difference between numeric perceived risk and Gail risk score. Based on recommended guidelines from the year data were collected (2002), mammography adherence was defined as having a mammogram every one to two years for women ≥ 40 years of age.
Results
Breast cancer risk comprehension was low, as 81% of women overestimated their risk and only 6.9% of women were high risk based on Gail risk scores. Greater cancer worry and younger age were significantly associated with greater perceived risk and risk overestimation. Of women age eligible for mammography (n = 328), 29.0% were non-adherent to screening guidelines. Adherence was associated with older age, (OR = 2.99, 95% CI = 1.76 – 5.09), having insurance (OR = 1.81, 95% CI = 1.03 – 3.17), greater acculturation (OR = 1.18, 95% CI = 1.02 – 1.36), and higher breast cancer knowledge (OR = 2.03, 95% CI = 1.21 – 3.40).
Conclusions
While most Latinas over-estimated their breast cancer risk, older age, having insurance, being more acculturated, and having greater knowledge were associated with greater screening adherence in this Latino population. Perceived risk, risk comprehension, and cancer worry were not associated with adherence. In Latinas, screening interventions should emphasize knowledge and target education efforts at younger, uninsured, and less acculturated mammography-eligible women.
doi:10.1007/s10552-008-9209-7
PMCID: PMC4309545  PMID: 18704716
Latina; breast cancer; risk perception; risk comprehension; mammography adherence; acculturation
10.  A Pooled Multisite Analysis of the Effects of Female Reproductive Hormones on Glioma Risk 
Cancer causes & control : CCC  2014;25(8):1007-1013.
Purpose
The association between female reproductive factors and glioma risk is unclear, but most published studies have been limited by small sample size. We conducted a pooled multisite study of pre- and post-menopausal women, investigating the effect of female reproductive factors, including hormonal medications.
Methods
Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals assessing the effects of female reproductive factors and female hormonal medications in glioma cases and unrelated controls.
Results
Menarche over the age of 15 as compared to under 12 was associated with a statistically significant risk for glioma (OR = 2.00, 95% CI, 1.47–2.71). Use of Oral Contraceptive Pills (OCP) was inversely associated with risk of glioma (OR= 0.61, 95% CI, 0.50–0.74) and there was an inverse trend with longer duration of OCP use (p for trend< 0.0001). Use of Hormone Replacement Therapy (HRT) was also inversely associated with risk of glioma (OR=0.55, 95% CI, 0.44–0.68) and there was an inverse trend with longer duration of use (p for trend< 0.0001). Compared to those reporting neither OCP use nor HRT use, those who reported using both were less likely to have a diagnosis of glioma (OR = 0.34, 95% CI, 0.24–0.48).
Conclusions
Female reproductive hormones may decrease the risk for glioma. The association appears to be strongest with greater length of use and use of both HRT and OCP.
doi:10.1007/s10552-014-0400-8
PMCID: PMC4288736  PMID: 24890803
HRT; Hormones; Females; Contraceptives; Glioma
11.  Circadian clock genes and risk of fatal prostate cancer 
Cancer causes & control : CCC  2014;26(1):25-33.
Purpose
Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and morning void urinary 6-sulfatoxymelatonin levels.
Methods
We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across twelve circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n=24 cases), the Health Professionals Follow-Up Study (HPFS) (n=40 cases), and the Physicians’ Health Study (PHS) (n=105 cases). We used linear regression to evaluate the association between SNPs and morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP-sets in the pathway (gene based) were associated with our outcomes.
Results
None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p-values = 0.01, 0.01, 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPS in TIMELESS (4 SNPs), NPAS2 (6 SNPs), PER3 (2 SNPs) and CSNK1E (1 SNP) were nominally associated with 6-sulfatoxymelatonin levels.
Conclusion
We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.
doi:10.1007/s10552-014-0478-z
PMCID: PMC4282953  PMID: 25388799
Circadian genes; prostate cancer; genetic polymorphisms
12.  Screening for colorectal cancer: using data to set prevention priorities 
Cancer causes & control : CCC  2013;25(1):93-98.
Introduction
Adherence to colorectal cancer screening recommendations is known to vary by state, but less information is available about within-state variability. In the current study, we assess county-level screening rates for Missouri, with the goal of better targeting public health efforts to increase screening.
Methods
Prevalence of colorectal cancer screening among Missouri adults between the ages of 50 and 74 was obtained from 2008 and 2010 Behavioral Risk Factor Surveillance System data. We used multilevel logistic regression to generate county-specific estimates. After excluding 77 counties with fewer than 30 respondents, information was available about 3,739 individuals in 37 counties, representing 78.5 % of the state population.
Results
Across counties, the prevalence of being up-to-date with recommended colorectal cancer screening ranged from 25 to 70 %.
Conclusion
State-level information about colorectal cancer screening masks substantial within-state variability. Assessing and monitoring county-level disparities in screening can guide public health efforts to increase screening and reduce colorectal cancer mortality. More complete population survey data will make such analysis possible.
doi:10.1007/s10552-013-0311-0
PMCID: PMC3888950  PMID: 24146228
Colorectal cancer; Screening; Primary prevention; Healthcare disparities; Missouri; Community health planning
13.  Tobacco Smoking, NBS1 Polymorphisms, and Survival in Lung and Upper Aerodigestive Tract Cancers with Semi-Bayes Adjustment for Hazard-ratio Variation 
Cancer causes & control : CCC  2013;25(1):11-23.
Purpose
Although single nucleotide polymorphisms (SNPs) of NBS1 have been associated with susceptibility to lung and upper aerodigestive tract (UADT) cancers, their relations to cancer survival and measures of effect are largely unknown.
Methods
Using follow-up data from 611 lung-cancer cases and 601 UADT-cancer cases from a population-based case-control study in Los Angeles, we prospectively evaluated associations of tobacco smoking and 5 NBS1 SNPs with all-cause mortality. Mortality data were obtained from the Social Security Death Index. We used Cox regression to estimate adjusted hazard ratios (HR) for main effects and ratios of hazard ratios (RHR) derived from product terms to assess hazard-ratio variations by each SNP. Bayesian methods were used to account for multiple comparisons.
Results
We observed 406 (66%) deaths in lung-cancer cases and 247 (41%) deaths in UADT-cancer cases with median survival of 1.43 and 1.72 years, respectively. Ever tobacco smoking was positively associated with mortality for both cancers. We observed an upward dose-response association between smoking pack-years and mortality in UADT squamous cell carcinoma. The adjusted HR relating smoking to mortality in non-small cell lung cancer (NSCLC) was greater for cases with the GG genotype of NBS1 rs1061302 than for cases with AA/AG genotypes (semi-Bayes adjusted RHR = 1.97; 95% limits = 1.14, 3.41).
Conclusions
A history of tobacco smoking at cancer diagnosis was associated with mortality among patients with lung cancer or UADT squamous cell carcinoma. The HR relating smoking to mortality appeared to vary with the NBS1 rs1061302 genotype among NSCLC cases.
doi:10.1007/s10552-013-0303-0
PMCID: PMC3889468  PMID: 24166361
Survival; NBS1; Lung cancer; Upper aerodigestive tract (UADT) cancers; Tobacco; Bayesian methods
14.  Circadian pathway genes in relation to glioma risk and outcome 
Cancer causes & control : CCC  2013;25(1):25-32.
Purpose
There is growing evidence that circadian disruption may alter risk and aggressiveness of cancer. We evaluated common genetic variants in the circadian gene pathway for associations with glioma risk and patient outcome in a US clinic-based case-control study.
Methods
Subjects were genotyped for 17 candidate single nucleotide polymorphisms (SNPs) in ARNTL, CRY1, CRY2, CSNK1E, KLHL30, NPAS2, PER1, PER3, CLOCK and MYRIP. Unconditional logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95% confidence intervals (CI) for glioma risk under three inheritance models (additive, dominant and recessive). Proportional hazards regression was used to estimate hazard ratios (HR) for glioma-related death among 441 patients with high grade tumors. Survival associations were validated using a TCGA (The Cancer Genome Atlas) dataset.
Results
A variant in PER1 (rs2289591) was significantly associated with overall glioma risk (per variant allele OR: 0.80; 95% CI: 0.66–0.97; ptrend=0.027). The variant allele for CLOCK rs11133391 under a recessive model increased risk of oligodendroglioma (OR: 2.41; 95% CI: 1.31–4.42; p=0.005), though not other glioma subtypes (p for heterogeneity=0.0033). The association remained significant after FDR adjustment (p=0.008). Differential associations by gender were observed for MYRIP rs6599077 and CSNK1E rs1534891 though differences were not significant after adjustment for multiple testing. No consistent mortality associations were identified. Several of the examined genes exhibited differential expression in GBM versus normal brain in TCGA data (MYRIP, ARNTL, CRY1, KLHL30, PER1, CLOCK, PER3) and expression of NPAS2 was significantly associated with a poor patient outcome in TCGA patients.
Conclusion
This exploratory analysis provides some evidence supporting a role for circadian genes in the onset of glioma and possibly the outcome of glioma.
doi:10.1007/s10552-013-0305-y
PMCID: PMC3947318  PMID: 24135790
Glioma; Single Nucleotide Polymorphism; Genotype
15.  CXCR4 pathway associated with family history of melanoma 
Cancer causes & control : CCC  2013;25(1):125-132.
Purpose
Genetic predisposition plays a major role in the etiology of melanoma, but known genetic markers only account for a limited fraction of family history-associated melanoma cases. Expression microarrays have offered the opportunity to identify further genomic profiles correlated with family history of melanoma. We aimed to distinguish mRNA expression signatures between melanoma cases with and without a family history of melanoma.
Methods
Based on the Nurses’ Health Study, family history was defined as having one or more first-degree family members diagnosed with melanoma. Melanoma diagnosis was confirmed by reviewing pathology reports and tumor blocks were collected by mail from across the United States. Genomic interrogation was accomplished through evaluating expression profiling of formalin-fixed paraffin-embedded tissues from 78 primary cutaneous invasive melanoma cases, on either a 6K or whole-genome (24K) Illumina gene chip. Gene Set Enrichment Analysis was performed for each batch to determine the differentially enriched pathways and key contributing genes.
Results
The CXC chemokine receptor 4 (CXCR4) pathway was consistently up-regulated within cases of familial melanoma in both platforms. Leading edge analysis showed four genes from the CXCR4 pathway, including MAPK1, PLCG1, CRK, and PTK2, were among the core members that contributed to the enrichment of this pathway. There was no association between the enrichment of CXCR4 pathway and NRAS, BRAF mutation, or Breslow thickness of the primary melanoma cases.
Conclusions
We found that the CXCR4 pathway might constitute a novel susceptibility pathway associated with family history of melanoma in first-degree relatives.
doi:10.1007/s10552-013-0315-9
PMCID: PMC4100594  PMID: 24158781
melanoma; genetic pathway analysis; genome-wide expression profiling
16.  Smoking-associated risks of conventional adenomas and serrated polyps in the colorectum 
Cancer Causes & Control  2014;26(3):377-386.
Purpose
Prior studies suggest cigarette smoking is associated with 1.5- to twofold increased risk of colorectal adenomas and possibly a higher risk of serrated polyps. Further clarification of risk differences between adenomas and serrated polyps is needed with regard to co-occurrence and polyp location.
Methods
We conducted a combined analysis of conventional adenoma and serrated polyp occurrence using individual-level data from 2,915 patients participating in three colonoscopy-based clinical trials. All participants had ≥1 adenomas removed at baseline and were followed for up to 4 years. Smoking habits and other lifestyle factors were collected at baseline using questionnaires. We used generalized linear regression to estimate risk ratios and 95 % confidence intervals.
Results
Smokers were at slightly increased risk of adenomas compared to never smokers [current: RR 1.29 (95 % CI 1.11–1.49) and former: RR 1.18 (1.05–1.32)]. Smoking was associated with greater risk of serrated polyps [current: RR 2.01 (1.66–2.44); former: RR 1.42 (1.20–1.68)], particularly in the left colorectum. Associations between current smoking and occurrence of serrated polyps only [RR 2.33 (1.76–3.07)] and both adenomas and serrated polyps [RR 2.27 (1.68–3.06)] were more pronounced than for adenomas only [RR 1.31 (1.08–1.58)]. Results were similar for other smoking variables and did not differ by gender or for advanced adenomas.
Conclusions
Cigarette smoking has only a weak association with adenomas, but is associated with a significantly increased risk of serrated polyps, particularly in the left colorectum. Since a minority of left-sided serrated polyps is thought to have malignant potential, the role of smoking in initiation phases of carcinogenesis is uncertain.
doi:10.1007/s10552-014-0513-0
PMCID: PMC4331601  PMID: 25537738
Smoking; Tobacco; Colorectal; Adenomas; Serrated polyps
17.  The changing patterns of bladder cancer in Egypt over the past 26 years 
Cancer causes & control : CCC  2008;19(4):421-429.
Objective
To evaluate temporal changes in histopathological types of bladder cancer and to assess associated changes in demographic, epidemiologic, and lifestyle risk factors.
Methods
We abstracted data from all available medical records from the National Cancer Institute of Cairo University (NCI-Cairo). Six calendar years representing 5-year periods between 1980 and 2005 were evaluated. Information on demographics, schistosomal infection, clinical symptoms of bladder cancer, and tumor pathology was abstracted.
Results
During this 26-year period, important changes in the frequency of histopathological types of bladder cancer occurred. We found a statistically significant association between time period of diagnosis and histopathological type. Patients diagnosed in 2005 had a sixfold higher odds associated with transitional cell carcinoma compared to those patients diagnosed in 1980 (odds ratio (OR) 6.00 (95% CI 4.00–8.97)).
Conclusions
These data strongly suggest that the histopathological profile of bladder cancer in Egypt has changed significantly over the past 26 years. Historically, squamous cell carcinoma was the predominant form of bladder cancer in Egypt; however transitional cell carcinoma has become the most frequent type. These results corroborate findings from a few small-scale hospital-based studies which conclude that the etiology of bladder cancer in Egypt has changed significantly over the past 26 years.
doi:10.1007/s10552-007-9104-7
PMCID: PMC4274945  PMID: 18188671
Bladder cancer; Schistosomiasis; Histopathology; Epidemiologic trends; Egypt
18.  Human papillomavirus is not associated with colorectal cancer in a large international study 
Cancer causes & control : CCC  2010;21(5):737-743.
Objective of the study
Recent publications have reported an association between colon cancer and human papillomaviruses (HPV), suggesting that HPV infection of the colonic mucosa may contribute to the development of colorectal cancer.
Methods
The GP5+/GP6+ PCR reverse line blot method was used for detection of 37 types of human papilloma-virus (HPV) in DNA from paraffin-embedded or frozen tissues from patients with colorectal cancer (n = 279) and normal adjacent tissue (n = 30) in three different study populations, including samples from the United States (n = 73), Israel (n = 106) and Spain (n = 100). Additionally, SPF10 PCR was run on all samples (n = 279) and the Innogenetics INNO-LiPA assay was performed on a subset of samples (n = 15).
Results
All samples were negative for all types of HPV using both the GP5+/GP6+ PCR reverse line blot method and the SPF10 INNO-LiPA method.
Conclusions
We conclude that HPV types associated with malignant transformation do not meaningfully contribute to adenocarcinoma of the colon.
doi:10.1007/s10552-010-9502-0
PMCID: PMC4269349  PMID: 20087645
Human papillomavirus; Colorectal cancer; International study
19.  Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case–control study 
Cancer Causes & Control  2014;26:205-218.
Purpose
Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer.
Methods
In a nested case–control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1–T2/T3–T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism.
Results
We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04; rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01); there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure.
Conclusion
We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-014-0500-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s10552-014-0500-5
PMCID: PMC4298668  PMID: 25488826
Prostate cancer; Vitamin D; Vitamin D pathway genes; 25 hydroxyvitamin-D; 1,25-dihydroxyvitamin-D
20.  Toenail iron, genetic determinants of iron status and the risk of glioma 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0281-2.
Purpose
Iron is essential for oxygen transport and oxidative metabolism; however, elevated iron stores can trigger overproduction of reactive oxygen species and induce DNA damage. Little is known about the association between body iron stores and glioma risk. This study examined associations of iron levels measured in toenails and genetic variants linked to body iron stores with risk of glioma in a clinic-based case-control study.
Methods
Samples were collected a median of 24 days following glioma diagnosis in the cases (10th-90th percentile range: 10-44 days). Nail iron levels were measured in 300 cases and 300 controls using neutron-activation analysis. A total of 24 genetic variants associated with iron status were genotyped in 622 cases and 628 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for glioma risk according to toenail iron and the examined genotypes.
Results
No association was observed between toenail iron and glioma risk when restricting to cases with nails collected within ~3 weeks of diagnosis (OR=0.93; 95% CI: 0.46, 1.87 comparing those with high (≥ 14 μg/g) versus low (<6 μg/g) iron levels). In contrast, an inverse association with increasing iron was observed after restricting to cases with a delay of 3 weeks or greater (OR=0.42; 95% CI: 0.19, 0.95) reflecting potentially insidious effects of advancing disease on iron levels among the cases. No associations were observed for any of the examined genetic variants.
Conclusion
The results do not support a role for body iron stores as a determinant of glioma risk.
doi:10.1007/s10552-013-0281-2
PMCID: PMC3823695  PMID: 23996192
glioma; iron; single nucleotide polymorphism; case-control
21.  Circulating cytokines and gastric cancer risk 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0284-z.
Purpose:
Chronic inflammation has been hypothesized to play a significant role in the etiology of cancer, including gastric cancer. In the present study we sought to examine pre-diagnostic systemic cytokine levels in plasma, which can be seen as markers of aggregate inflammation, and risk of distal gastric cancer in a case-control study nested within the prospective Shanghai Men’s Health Study.
Methods:
Circulating levels of eight inflammation-related cytokines were measured in the plasma collected at baseline for 180 incident cases of distal gastric cancer and 358 matched controls. Helicobacter pylori sero-positivity was assessed using multiplex serology. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals.
Results:
Individuals with IL-8 levels above the lowest quartile were at two-fold increased odds of gastric cancer [OR 1.91 (95% CI 1.05-3.46), OR 2.10 (95% CI 1.19-3.74), and OR 2.30 (95% CI 1.26-4.19), for the second through fourth quartiles, respectively]. While there were suggestions of an increase in risk with increased level of many of the other cytokines measured (IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ), no significant associations were found at the p<0.05 level. Infection with CagA-positive H. pylori did not modify these associations.
Conclusions:
In a population with high gastric cancer incidence and high H. pylori prevalence, increased circulating levels of IL-8 may indicate increased risk of gastric cancer. These findings add to our understanding of the disease, and further efforts to uncover biomarkers of disease risk.
doi:10.1007/s10552-013-0284-z
PMCID: PMC3828746  PMID: 24052422
inflammation; cytokines; gastric cancer; epidemiology
22.  Plasma C-reactive protein, genetic risk score, and risk of common cancers in the Atherosclerosis Risk in Communities study 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0285-y.
Purpose
Many studies, including the Atherosclerosis Risk in Communities (ARIC) cohort, reported a positive association between plasma C-reactive protein (CRP) – a biomarker of low-grade chronic inflammation – and colorectal cancer risk, although it is unclear if the association is causal. Our aims were to assess the associations of a CRP genetic risk score (CRP-GRS) created from single nucleotide polymorphisms (SNPs) with colorectal cancer risk, as well as examine plasma CRP and CRP-GRS in relation to common cancers in the ARIC cohort.
Methods
Cox proportional hazards models were used to prospectively estimate hazard ratios (HR) and (95% confidence interval, CI) of total, colorectal, lung, prostate, and breast cancers in relation to: 1) CRP-GRS among 8,657 Whites followed in 1987–2006 and 2) log-transformed plasma CRP among 7,603 Whites followed in 1996–2006. A weighted CRP-GRS was comprised of 20 CRP-related SNPs located in/near CRP, APOC1, HNF1A, LEPR and 16 other genes that were identified in genome-wide association studies.
Results
After multivariable adjustment, one standard deviation increment of the CRP-GRS was associated with colorectal cancer risk (HR=1.19; 95% CI, 1.03–1.37) but not with any other cancer. One unit of log-transformed plasma CRP was associated with the risk of total, colorectal, lung, and breast cancers: HRs (95% CIs) were 1.08 (1.01–1.15), 1.24 (1.01–1.51), 1.29 (1.08–1.54), and 1.27 (1.07–1.51), respectively. HRs remained elevated, although lost statistical significance for all but breast cancer, after excluding subjects with <2 years of follow-up.
Conclusions
The study corroborates a causative role of chronic low-grade inflammation in colorectal carcinogenesis.
doi:10.1007/s10552-013-0285-y
PMCID: PMC3836434  PMID: 24036889
inflammation; CRP; cancer risk; genetic risk score; genetic polymorphism; ARIC cohort
23.  Are HPV vaccination services accessible to high-risk communities?: A spatial analysis of HPV-associated cancer and Chlamydia rates and safety-net clinics 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0286-x.
Purpose
While HPV vaccines can greatly benefit adolescents and young women from high-risk areas, little is known about whether safety-net immunization services are geographically accessible to communities at greatest risk for HPV-associated diseases. We explore the spatial relationship between areas with high HPV risk and proximity to safety-net clinics from an ecologic perspective.
Methods
We used cancer registry data and Chlamydia surveillance data to identify neighborhoods within Los Angeles County with high risk for HPV-associated cancers. We examined proximity to safety-net clinics among neighborhoods with the highest risk. Proximity was measured as the shortest distance between each neighborhood center and the nearest clinic and having a clinic within 3 miles of each neighborhood center.
Results
The average 5-year non-age-adjusted rates were 1,940 cases per 100,000 for Chlamydia and 60 per 100,000 for HPV-associated cancers. A large majority, 349 of 386 neighborhoods with high HPV-associated cancer rates and 532 of 537 neighborhoods with high Chlamydia rates had a clinic within 3 miles of the neighborhood center. Clinics were more likely to be located within close proximity to high-risk neighborhoods in the inner city. High-risk neighborhoods outside of this urban core area were less likely to be near accessible clinics.
Conclusions
The majority of high-risk neighborhoods were geographically near safety-net clinics with HPV vaccination services. Due to low rates of vaccination, these findings suggest that while services are geographically accessible, additional efforts are needed to improve uptake. Programs aimed to increase awareness about the vaccine and to link underserved groups to vaccination services are warranted.
doi:10.1007/s10552-013-0286-x
PMCID: PMC3842032  PMID: 24043448
human papillomavirus; HPV-associated cancers; HPV vaccine; cancer registry; geographic information systems (GIS)
24.  A prospective study of smoking and breast cancer risk among African American women 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0298-6.
Purpose
Active smoking and passive smoking have been associated with increased risk of breast cancer. The purpose of the present study was to prospectively assess associations of smoking with breast cancer and identify subgroups at higher risk among African American women.
Methods
Based on 1,377 incident cases identified during 14 years of follow-up in the Black Women’s Health Study, we assessed active and passive smoking in relation to breast cancer incidence by menopausal status, estrogen receptor status, and other factors. Incidence rate ratios (IRR) and 95% confidence intervals (CI) for categories of smoking relative to no active or passive smoking were calculated from Cox proportional hazards models, controlling for breast cancer risk factors.
Results
Active smoking was associated with increased risk of premenopausal breast cancer. The IRR was 1.21 (95% CI 0.90–1.62) for premenopausal breast cancer overall, and 1.70 (95% CI 1.05–2.75) for premenopausal breast cancer associated with beginning smoking before age 18 together with accumulation of ≥ 20 pack years. The positive association with premenopausal breast cancer was most apparent for estrogen receptor positive cancer. Passive smoking was also associated with increased risk of premenopausal breast cancer (IRR=1.42, 95% CI 1.09–1.85), based on information on passive smoking at home and work. Neither active nor passive smoking was associated with increased risk of postmenopausal breast cancer.
Conclusion
These results strengthen the evidence that both active and passive smoking increase the incidence of premenopausal breast cancer.
doi:10.1007/s10552-013-0298-6
PMCID: PMC3855285  PMID: 24085586
African American; female; breast cancer; smoking
25.  Association of prediagnostic physical activity with survival following breast cancer diagnosis: influence of TP53 mutation status 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0294-x.
Purpose
Physical activity both before and after breast cancer diagnosis has been associated with improved survival. However, it is not clear whether this association differs by molecular features of the tumor or by recency of the physical activity to the time of diagnosis.
Methods
We examined the association of prediagnostic physical activity with survival in a cohort of 1,170 women with primary, incident, and histologically confirmed breast cancer, examining tumor molecular subtypes. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).
Results
Mean follow-up time was 87.4 months after breast cancer diagnosis; there were 170 deaths identified. Compared with inactive patients (<3 hours/ week), women with higher average lifetime physical activity (>6 hours/ week) had reduced risk of all-cause mortality (adjusted HR = 0.61, 95% CI, 0.40-0.95; p trend = 0.04). There were no clear differences in the associations for lifetime and more recent physical activity. Lifetime physical activity was also weakly associated with decreased risk of breast cancer-specific mortality. Higher lifetime physical activity was associated with reduced risk of all-cause mortality among women with ER-positive tumors (HR = 0.52, 95% CI, 0.29-0.93), and mutant TP53 tumors (HR = 0.22, 95% CI, 0.06-0.72); however, no statistically significant interactions were observed for ER or TP53 status.
Conclusions
Our study further supports that prediagnostic physical activity improves overall survival following breast cancer, and suggests that the associations of prediagnostic physical activity with survival following breast cancer may vary by molecular features of the tumor, particularly ER and TP53 status.
doi:10.1007/s10552-013-0294-x
PMCID: PMC3860883  PMID: 24068557
physical activity; breast cancer survival; TP53 mutation; epidemiology

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