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1.  Genes Associated with Prostate Cancer Are Differentially Expressed in African American and European American Men 
Background
Despite more aggressive screening across all demographics and gradual declines in mortality related to prostate cancer (PCa) in the United States, disparities among populations persist. A substantial proportion of African American men (AAM) have a higher overall incidence, earlier age of onset, increased proportion of clinically advanced disease, and increased bone metastases and mortality from PCa compared to European American men (EAM). Limited early evidence indicates that underlying causes for disparities may be observed in tumor-specific gene expression programs.
Methods
This study used microarray-based methods to measure expression levels for 517 genes that were previously associated with PCa in archived formalin-fixed paraffin embedded (FFPE) specimens; testing the hypothesis that gene expression features of functional consequence to cancer distinguish PCa from AAM and EAM. A t test was conducted comparing AAM to EAM expression levels for each probe on the array.
Results
Analysis of 639 tumor samples (270 AAM, 369 EAM) showed that 95 genes were overexpressed specifically in PCa from AAM relative to EAM and 132 were overexpressed in PCa from EAM relative to AAM. Furthermore, systems-level analyses highlight the relevant signaling pathways and functions associated with the EAM- or AAM-specific overexpressed gene sets, for example, inflammation and lipid metabolism.
Conclusions
Results here bring further understanding to the potential for molecular differences for PCa in AAM versus EAM.
Impact
The results support the notion that therapeutic benefits will be realized when targeted treatments are designed to acknowledge and address a greater spectrum of PCa subtypes and molecular distinctions.
doi:10.1158/1055-9965.EPI-12-1238
PMCID: PMC4097306  PMID: 23515145
2.  Loss of PTEN Is Associated with Aggressive Behavior in ERG-Positive Prostate Cancer 
Background
The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables.
Methods
The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements.
Results
ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects.
Conclusions
A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor.
Impact
Interaction of PTEN and ERG pathways warrants further studies.
doi:10.1158/1055-9965.EPI-13-0333-T
PMCID: PMC4086660  PMID: 24083995
3.  Recurrent Prostate Cancer Genomic Alterations Predict Response to Brachytherapy Treatment 
Background
This study aimed to evaluate the association of recurrent molecular alterations in prostate cancer, such as ERG rearrangements and phosphatase and tensin homolog gene (PTEN) deletions, with oncologic outcomes in patients with prostate cancer treated with brachytherapy.
Methods
Ninety-two men underwent I-125 brachytherapy with a 145 Gy delivered dose between 2000 and 2008. Pretreatment prostate biopsies were analyzed by immunohistochemistry (IHC) and FISH for ERG rearrangement and overexpression, PTEN deletion, and expression loss. Univariable and multivariable Cox-regression analyses evaluated association of ERG and PTEN status with biochemical recurrence (BCR).
Results
Within a median follow-up of 73 months, 11% of patients experienced BCR. Of 80 samples with both IHC and FISH performed for ERG, 46 (57.8%) demonstrated rearrangement by FISH and 45 (56.3%) by IHC. Of 77 samples with both IHC and FISH for PTEN, 14 (18.2%) had PTEN deletion by FISH and 22 (28.6%) by IHC. No significant associations were found between ERG, PTEN status, and clinicopathologic features. Patients with concurrent ERG rearrangement and PTEN deletion demonstrated significantly worse relapse-free survival rates compared with those with ERG or PTEN wild type (P < 0.01). In multivariable Cox regression analysis adjusted for the effects of standard clinicopathologic features, combined ERG rearranged and PTEN deletion was independently associated with BCR (HR = 2.6; P = 0.02).
Conclusions
Concurrent ERG rearrangement and PTEN loss was independently associated with time to BCR in patients undergoing brachytherapy. Future studies are needed to validate prostate cancer molecular subtyping for risk stratification.
Impact
Identifying patients in the ERG-rearranged/PTEN-deleted molecular subclass may improve treatment personalization.
doi:10.1158/1055-9965.EPI-13-1180
PMCID: PMC4083705  PMID: 24515272
5.  Active and involuntary tobacco smoking and upper-aerodigestive-tract cancer risks in a multicenter case-control study 
Introduction
Several important issues for the established association between tobacco smoking and upper-aerodigestive tract (UADT) cancer risks include the associations with smoking by cancer subsite, by type of tobacco, and among never alcohol drinkers, and the associations with involuntary smoking among nonsmokers. Our aim was to examine these specific issues in a large scale case-control study in Europe.
Methods
Analysis was performed on 2,103 UADT squamous cell carcinoma cases and 2,221 controls in the Alcohol-Related Cancers and Genetic Susceptibility in Europe (ARCAGE) project, a multicenter case-control study in 10 European countries. Unconditional logistic regression was performed to obtain odds ratios (OR) and 95% confidence intervals (CI).
Results
Compared to never tobacco smoking, current smoking was associated with UADT cancer risks (OR=6.72, 95% CI 5.45–8.30 for overall; 5.83, 4.50–7.54 for oral cavity and oropharynx; 12.19, 8.29–17.92 for hypopharynx and larynx; 4.17, 2.45–7.10 for esophagus). Among never drinkers, dose-response relationships with tobacco smoking packyears were observed for hypopharyngeal and laryngeal cancers (ptrend = 0.01), but not for oral cavity and oropharyngeal cancers (ptrend = 0.282). Among never smokers, ever exposure to involuntary smoking was associated with an increased risk of UADT cancers (OR=1.60, 95% CI 1.04–2.46).
Conclusion
Our results corroborate that tobacco smoking may play a stronger role in the development of hypopharyngeal and laryngeal cancers than that of oral cavity and oropharyngeal cancers among never drinkers and that involuntary smoking is an important risk factor for UADT cancers. Public health interventions to reduce involuntary smoking exposure could help reduce UADT cancer incidence.
doi:10.1158/1055-9965.EPI-09-0910
PMCID: PMC4085143  PMID: 19959682
Active tobacco smoking; involuntary smoking; upper-aerodigestive-tract cancer
6.  Meat-Related Mutagens and Pancreatic Cancer: null results from a clinic-based case-control study 
Background
Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case-control design.
Methods
There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus.
Results
Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer.
Conclusion
The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies.
Impact
These data contribute to evidence regarding pancreatic cancer and potentially carcinogenic compounds in meat.
doi:10.1158/1055-9965.EPI-13-0343
PMCID: PMC3702664  PMID: 23632817
7.  Decisional Outcomes of Maternal Disclosure of BRCA1/2 Genetic Test Results to Children 
Background
Although BRCA1/2 genetic testing is discouraged in minors, mothers may disclose their own results to their children. Factors affecting patients’ disclosure decisions and patient outcomes of disclosure are largely unknown.
Methods
Mothers (N = 221) of children ages 8-21 enrolled in this prospective study of family communication about cancer genetic testing. Patients underwent BRCA1/2 genetic counseling and testing, and completed standardized behavioral assessments prior to and 1-month following receipt of their results.
Results
Most patients (62.4%) disclosed BRCA1/2 test results to their child. Patients were more likely to disclose if they received negative or uninformative vs. positive results (OR = 3.11; 95% CI = 1.11 - 8.71; P = .03), their child was ≥ 13 years of age vs. younger (OR = 5.43; 95% CI = 2.18 - 13.53; P < .001), and as the ratio of patients’ perceived benefits of disclosure outweighed potential risks (OR = 2.40; 95% CI = 1.63 - 3.54; P < .001). Post-decision satisfaction about disclosure was lowest among nondisclosing patients (P < .001) and those reporting greater decisional conflict (P < .001).
Conclusions
Patients commonly discuss their BRCA1/2 results with their teenage and young adult children, especially if the information is perceived as beneficial. Satisfaction with disclosure decision-making remains lowest among nondisclosing and conflicted patients. Family communication decision support adjuncts to genetic counseling are needed to help ameliorate these effects.
Impact
This study describes the prevalence of family communication about maternal BRCA1/2 genetic testing with minor children, and decisions and outcomes of disclosure.
doi:10.1158/1055-9965.EPI-13-0198
PMCID: PMC3703861  PMID: 23825307
8.  Identification of Novel Variants in Colorectal Cancer Families by High-Throughput Exome Sequencing 
Background
Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants.
Methods
We completed exome sequencing on 40 affected cases from 16 multi-case pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single nucleotide variants (SNVs) predicted to be benign.
Results
We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or non-coding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively.
Conclusions
Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in colorectal cancer susceptibility.
Impact
Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.
doi:10.1158/1055-9965.EPI-12-1226
PMCID: PMC3704223  PMID: 23637064
colorectal cancer; familial and hereditary cancers; exome sequencing; rare variants; family study design
9.  Genome-wide association study identifies possible genetic risk factors for colorectal adenomas 
Background
Colorectal cancer (CRC) is the second leading cause of cancer-related death, and most CRC usually arises from colorectal adenomas. Removal of polyps reduces mortality from CRC. Colorectal adenomas are known to aggregate in families; however the genetic determinants for risk of polyps are largely unknown.
Methods
In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We performed logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis.
Results
No SNP achieved a genome-wide significant p-value; however, the most significantly associated SNPs were either previously associated with CRC in GWAS, such as rs10505477 in the gene POU5F1 (odds ratio [OR] = 0.87, 95% confidence interval [CI] 0.81–0.94, p-value = 4.4×10−4), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene HDAC9 OR = 1.32, 95% CI 1.18–1.47, p-value = 1.1×10−6).
Conclusions
This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies.
Impact
These results suggest that some known CRC genetic risk factors are necessary but not sufficient for carcinogenesis.
doi:10.1158/1055-9965.EPI-12-1437
PMCID: PMC3716448  PMID: 23677573
Colorectal adenoma; genetic association
10.  Determinants of breast cancer treatment delay differ for African American and White women 
Background
Timeliness of care may contribute to racial disparities in breast cancer mortality. African American women experience greater treatment delay than White women in most, but not all studies. Understanding these disparities is challenging since many studies lack patient-reported data and use administrative data sources that collect limited types of information. We used interview and medical record data from the Carolina Breast Cancer Study (CBCS) to identify determinants of delay and assess whether disparities exist between White and African American women (n=601).
Methods
The CBCS is a population-based study of North Carolina women. We investigated the association of demographic and socioeconomic characteristics, healthcare access, clinical factors, and measures of emotional and functional well-being with treatment delay. The association of race and selected characteristics with delays of >30 days were assessed using logistic regression.
Results
Household size, losing a job due to one’s diagnosis, and immediate reconstruction were associated with delay in the overall population and among White women. Immediate reconstruction and treatment type were associated with delay among African American women. Racial disparities in treatment delay were not evident in the overall population. In the adjusted models, African American women experienced greater delay than White women for younger age groups: odds ratio (OR), 3.34; 95% confidence interval (CI), 1.07–10.38 for ages 20–39, and OR, 3.40; 95% CI, 1.76–6.54 for ages 40–49.
Conclusions
Determinants of treatment delay vary by race. Racial disparities in treatment delay exist among women <50 years old.
Impact
Specific populations need to be targeted when identifying and addressing determinants of treatment delay.
doi:10.1158/1055-9965.EPI-12-1432
PMCID: PMC3719384  PMID: 23825306
breast cancer; disparities; treatment delay; Carolina Breast Cancer Study
11.  New Breast Cancer Risk Variant Discovered at 10q25 in East Asian Women 
Background
Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations.
Methods
We evaluated nine of those non-replication loci in East Asians in order to identify new risk variants for breast cancer in these regions. First, we analyzed single nucleotide polymorphisms (SNPs) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (Stage 1). In each region we selected a SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (Stage 2). Logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants.
Results
Two SNPs were replicated in Stage 2 at P < 0.05: rs1419026 at 6q14 (per allele OR = 1.07, 95% CI: 1.03-1.12, P = 3.0×10−4) and rs941827 at 10q25 (OR = 0.92, 95% CI: 0.89-0.96, P = 5.3×10−5). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR = 0.88, 95% CI: 0.82-0.97, P = 5.3×10−5).
Conclusion
We identified a new breast cancer risk variant at 10q25 in East Asian women.
Impact
Results from this study improve the understanding of the genetic basis for breast cancer.
doi:10.1158/1055-9965.EPI-12-1393
PMCID: PMC3720126  PMID: 23677579
breast cancer; genetic susceptibility; GWAS replication; single nucleotide polymorphism
12.  Plasma levels of nitrate and risk of prostate cancer: a prospective study 
Background
Nitrate and nitrite supplements have recently been shown to improve cardiovascular health, but there is concern that these supplements could contribute to the development of cancer.Previous small, cross-sectional studies reported positive associations between circulating nitrate/nitrite levels and cancer. Prospective studies examining the association between plasma nitrate and cancer, especially prostate cancer (PCa), are lacking.
Methods
We conducted a nested case-control study within the Health Professionals Follow-up Study. Baseline blood samples were collected in 1994, and incident cases of PCa were identified from 1997–2005. Baseline plasma levels of nitrate were measured in the 630 cases and 630 matched controls.
Results
We have found that baseline levels of plasma nitrate were not associated with risk of PCa. Compared to quintile 1, the relative risk from quintiles 2–5 were 1.13 (95% CI, 0.78–1.63), 0.93 (95% CI, 0.63–1.38), 0.95 (95% CI, 0.65–1.39), and 0.99 (95% CI, 0.68–1.48); p for trend was 0.9 after adjustment of multivariate risk factors. When analyses were restricted to men fasting more than 6 hrs, the trend was similar. Further, plasma nitrate appeared to be inversely associated with advanced-stage PCa. The relative risk across extreme quartiles was 0.44 (95% CI, 0.17–1.12; p for trend = 0.07) for the whole data set and 0.30 (95% CI, 0.09–0.99; p for trend = 0.05) for the fasting data set.
Conclusions
In summary, we did not find an increased risk of PCa associated with higher plasma nitrate levels. A potential protective association between nitrate and aggressive forms of PCa requires confirmation.
Impact
Nitrate-nitrite-nitric oxide pathway has emerged as a new therapeutic pathway for chronic diseases. The results of this study certainly merit replications in other prospective studies.
doi:10.1158/1055-9965.EPI-13-0134
PMCID: PMC3743658  PMID: 23677578
13.  Single nucleotide polymorphisms in genes encoding for CC chemokines were not associated with the risk of Non-Hodgkin Lymphoma 
Background
Chemokines play a pivotal role in immune regulation and response, and previous studies suggest an association between immune deficiency and Non-Hodgkin lymphoma (NHL).
Methods
We evaluated the association between NHL and polymorphisms in 18 genes (CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL18, CCL20, CCL24, CCL26, CCR1, CCR3, CCR4, CCR6, CCR7, CCR8 and CCR9) encoding for the CC chemokines using data from a population-based case-control study of NHL conducted in Connecticut women.
Results
CCR8 was associated with diffuse large B-cell lymphoma (DLBCL) (p = 0.012) and CCL13 was associated with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (p = 0.003) at gene level. After adjustment for multiple comparisons, none of the genes or SNPs were associated with risk of overall NHL or NHL subtypes.
Conclusions
Our results suggest that the genes encoding for CC chemokines are not significantly associated with the risk of NHL, and further studies are needed to verify these findings.
Impact
Our data indicate that CC chemokine genes were not associated with NHL risk.
doi:10.1158/1055-9965.EPI-13-0328
PMCID: PMC3753095  PMID: 23640258
Non-Hodgkin lymphoma; CC chemokine gene; Single nucleotide polymorphism
14.  Circulating adipokine levels and endometrial cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial 
Background
Circulating adipokine levels may be associated with endometrial cancer risk, yet few studies have evaluated these markers prospectively.
Methods
We conducted a nested case-control study of postmenopausal women in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n=78,216), including 167 incident endometrial cancer cases and 327 controls that were matched on age, study center, race, study year of diagnosis, year of blood draw, time of day of blood draw and menopausal hormone therapy (MHT) use. Adipokine and estradiol levels were categorized into tertiles (T). Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of adiponectin, leptin and visfatin with endometrial cancer risk were estimated by conditional logistic regression, adjusting for known endometrial cancer risk factors, including body mass index (BMI) and circulating estradiol levels.
Results
Adiponectin levels were inversely associated with risk of endometrial cancer [OR T3vsT1=0.48 (95%CI: 0.29-0.80); p-trend<0.01], whereas elevated leptin levels showed a positive association [2.77 (1.60-4.79); p-trend<0.01]. These results remained significant after adjustment for estradiol, but not after further adjustment for BMI. When analyses were restricted to non-MHT users, associations of adiponectin and leptin were stronger and remained significant after adjustment for estradiol and BMI [0.27 (0.09-0.80); p-trend=0.01 and 4.29 (1.07-17.15); p-trend=0.02, respectively]. Non-significant positive associations were observed for visfatin.
Conclusion
Adipokines may influence endometrial cancer risk through pathways other than estrogen-mediated cell growth in postmenopausal women not currently on MHT.
Impact
Understanding how adipokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity-endometrial cancer association.
doi:10.1158/1055-9965.EPI-13-0258
PMCID: PMC3819202  PMID: 23696194
endometrial cancer risk; adiponectin; leptin; visfatin; obesity
15.  C-Reactive Protein, Lipid-soluble Micronutrients, and Survival in Colorectal Cancer Patients 
Background
Identification of biomarkers associated with survival in cancer patients is important for elucidating the underlying mechanisms of cancer progression and identifying possible interventions to reduce cancer morbidity and mortality.
Methods
Using stored patient plasma samples from a multiethnic population-based case-control study of invasive colorectal cancer, we measured post-treatment blood levels of C-reactive protein (CRP) and lipid-soluble micronutrients. Patients (n=368) were followed after phlebotomy (mean of 8 years), during which time 47% died (25% colorectal cancer-specific). Hazard ratios (HR) were estimated by Cox proportional hazards regression with adjustment for stage, age at diagnosis, ethnicity, sex, smoking status, and month of blood draw.
Results
A positive association with overall risk of death was observed for CRP (HR for highest vs. lowest quintile: 1.80; 95% CI: 1.07-3.04; Ptrend=0.01) whereas, inverse associations were generally observed for retinol and carotenoids (HRs for overall risk of death for the highest quintile ranging from 0.5-0.8); these associations were significant for retinol (Ptrend=0.0002), α-carotene (Ptrend=0.02), and total carotenoids (Ptrend=0.02) and were generally consistent across subgroups (sex, ethnicity, cancer anatomical subtype, and stage). Hazard ratios for retinol and carotenoids were attenuated somewhat after adjustment for CRP. Similar trends for CRP were observed for colorectal cancer-specific deaths (HR for highest vs. lowest tertile: 2.06; 95% CI: 1.18-3.61; Ptrend=0.01) as for deaths from all other causes (Pheterogeneity=0.78).
Conclusion
These observations are consistent with a direct relationship between circulating CRP and overall survival among colorectal cancer patients.
Impact
These results, if reproduced, suggest that reduction of inflammation should be explored as a potential complementary treatment strategy.
doi:10.1158/1055-9965.EPI-13-0199
PMCID: PMC3834261  PMID: 23677577
Survival; colorectal cancer; carotenoids; coenzyme Q10; C-reactive protein
16.  Circulating Soluble Cytokine Receptors and Colorectal Cancer Risk 
Background
Soluble cytokine receptors and receptor antagonist of proinflammatory cytokines can modify cytokine signaling and may affect cancer risk.
Methods
In a case-cohort study nested within the Women’s Health Initiative cohort of postmenopausal women, we assessed the associations of plasma levels of IL-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-1 (sIL-1R2), IL-6 (sIL-6R and sgp130), and TNF (sTNFR1 and sTNFR2) with risk of colorectal cancer in 433 cases and 821 subcohort subjects. Baseline levels of estradiol, insulin, leptin, IL-6, and TNF-α measured previously were also available for data analysis.
Results
After adjusting for significant covariates – including age, race, smoking, colonoscopy history, waist circumference, and levels of estrogen, insulin, and leptin – relatively high levels of sIL-6R and sIL-1R2 were associated with reduced colorectal cancer risk [hazard ratios comparing extreme quartiles (HRQ4-Q1) for sIL-6R = 0.56, 95% CI = 0.38–0.83; HRQ4-Q1 for sIL-1R2 = 0.44, 95% CI = 0.29–0.67]. The associations with IL-1Ra, sgp130, sTNFR1, and sTNFR2 were null. The inverse association of sIL-1R2 with colorectal cancer risk persisted in cases diagnosed ≤5 and >5 years from baseline blood draw; the association with sIL-6R, however, was not evident in the latter group, possibly indicating that relatively low levels of sIL-6R in cases might be due to undiagnosed cancer at the time of blood draw.
Conclusions
High circulating levels of sIL-1R2 may be protective against colorectal carcinogenesis and/or be a marker of reduced risk for the disease.
Impact
sIL-1R2 has potential to be a chemopreventive and/or immunotherapeutic agent in inflammation-related diseases.
doi:10.1158/1055-9965.EPI-13-0545
PMCID: PMC3947182  PMID: 24192010
soluble cytokine receptor; receptor antagonist; colorectal cancer; IL-1; IL-6; TNF
17.  Nonsteroidal Anti-inflammatory Drugs and Change in Mammographic Density: A Cohort Study Using Pharmacy Records on Over 29,000 Postmenopausal Women 
Background
Use of nonsteroidal anti-inflammatory drugs (NSAID) has been associated with a decrease in breast cancer risk, but it is unknown if they also reduce mammographic density, a strong intermediate marker of breast cancer risk.
Methods
We investigated NSAID use and mammographic density in 29,284 postmenopausal women who had two screening mammograms at Group Health in Seattle. We used pharmacy records to classify women as NSAID nonusers, continuers, initiators, or discontinuers based on use between the two mammograms and nine separate prescription and nonprescription NSAID classes. Using unordered polytomous logistic regression methods, we modeled the odds ratio (OR) of staying not dense, decreasing density, or increasing density relative to remaining dense based on Breast Imaging Reporting Data System classification of density.
Results
There was no association with density change from initiation or continuation of NSAIDs. However, both initiators and continuers of any NSAIDs were more likely to stay not dense than stay dense [OR, 1.12; 95% confidence interval (95% CI), 1.04-1.20; OR, 1.25; 95% CI, 1.05-1.49, respectively]. This association with staying not dense for initiators and continuers of any NSAID use was observed primarily among women ages <65 years at first mammogram (OR, 1.24; 95% CI, 1.12-1.36; OR, 1.48; 95% CI, 1.14-1.93, respectively).
Conclusions
Initiation of NSAID use did not reduce mammographic density over the short term. Continuers of NSAID use were more likely to stay not dense compared with nonusers, suggesting that it is plausible that longer-term use of NSAIDs may be needed to reduce density.
doi:10.1158/1055-9965.EPI-07-2836
PMCID: PMC4072457  PMID: 18483330
18.  Elevated 4-Aminobiphenyl and 2, 6-Dimethylaniline Hemoglobin Adducts and Increased Risk of Bladder Cancer among Lifelong Nonsmokers - The Shanghai Bladder Cancer Study 
Background
4-Aminobiphenyl (ABP) is an established human bladder carcinogen, with tobacco smoke being a major source of human exposure. Other arylamine compounds, including 2,6-dimethylaniline (2,6-DMA), have been implicated as possible human bladder carcinogens. Hemoglobin adducts of 4-ABP and 2,6-DMA are validated biomarkers of exposure to those compounds in humans.
Methods
The Shanghai Bladder Cancer Study enrolled 581 incident bladder cancer cases and 604 population controls. Each participant was solicited for his/her history of tobacco use and other lifestyle factors, and donation of blood and urine specimens. Red blood cell lysates were used to quantify both hemoglobin adducts of 4-ABP and 2,6-DMA. Urine samples were used to quantify total cotinine. Odds ratios (ORs) and 95% confidence intervals (CIs) for bladder cancer were estimated using unconditional logistic regression methods.
Results
Among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for low (below median of positive values) and high versus undetectable levels of 2,6-DMA hemoglobin adducts were 3.87 (1.39-10.75) and 6.90 (3.17-15.02), respectively (Ptrend<0.001). Similarly, among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for 3rd and 4th versus 1st/2nd quartiles of 4-ABP hemoglobin adducts was 1.30 (0.76-2.22) and 2.29 (1.23-4.24), respectively (Ptrend=0.00). The two associations were independent of each other.
Conclusion
Hemoglobin adducts of 4-ABP and 2,6-DMA were significantly and independently associated with increased bladder cancer risk among lifelong nonsmokers in Shanghai, China.
Impact
The findings of the present study in China with previous data in Los Angeles, California strongly implicate arylamines as potential causal agents of human bladder cancer.
doi:10.1158/1055-9965.EPI-12-1447
PMCID: PMC4065796  PMID: 23539508
19.  Functional and Clinical Significance of Variants Localized to 8q24 in Colon Cancer 
Multiple GWAS have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1178 cases and 1009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal OR=0.82, 95% CI=0.072-0.94, Ptrend=0.0037) and rs6983267 (ordinal OR=1.17, 95% CI=1.03-1.32, Ptrend=0.013). Survival analysis was performed using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (N=380) for structural abnormalities at or near the c-MYC locus using FISH analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by FISH, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several SNPs at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not appear to be associated with survival.
doi:10.1158/1055-9965.EPI-09-0362
PMCID: PMC4059694  PMID: 19690179
8q; SNP; association; survival; FISH; fragile site; c-MYC
20.  Patient Navigation Improves Cancer Diagnostic Resolution: An Individually Randomized Clinical Trial in an Underserved Population 
Background
Barriers to timely resolution of abnormal cancer screening tests add to cancer health disparities among low income, uninsured and minority populations. We conducted a randomized trial to evaluate the impact of lay patient navigators on time to resolution and completion of follow-up testing among patients with abnormal screening tests in a medically underserved patient population.
Methods
Denver Health (DH), the safety-net healthcare system serving Denver, is one of ten performance sites participating in the Patient Navigation Research Program (PNRP). Of 993 eligible subjects with abnormal screening tests randomized to navigation and no-navigation (control) arms and analyzed, 628 had abnormal breast screens (66 abnormal clinical breast examinations, 304 BIRADS 0, 200 BIRADS 3, 58 BIRADS 4 or 5) while 235 had abnormal colorectal and 130 had abnormal prostate screens.
Results
Time to resolution was significantly shorter in the navigated group (stratified log rank test, p<0.001). Patient navigation improved diagnostic resolution for patients presenting with mammographic BIRADS 3 (p=0.0003) and BIRADS 0 (p=0.09), but not BIRADS 4/5 or abnormal breast exams. Navigation shortened the time for both colorectal (p=0.0017) and prostate screening resolution (p=0.06). Participant demographics included 72% minority, 49% with annual household income less than $10,000, and 36% uninsured.
Conclusions
Patient navigation positively impacts time to resolution of abnormal screening tests for breast, colorectal and prostate cancers in a medically underserved population.
Impact
By shortening the time to and increasing the proportion of patients with diagnostic resolution patient navigation could reduce disparities in stage at diagnosis and improve cancer outcomes.
doi:10.1158/1055-9965.EPI-12-0513
PMCID: PMC4053249  PMID: 23045537
patient navigation; disparities; cancer; abnormal screening tests
21.  Impact of a Biospecimen Collection Seminar on Willingness to Donate Biospecimens among Chinese Americans: Results from a Randomized, Controlled Community-Based Trial 
Background
Biospecimen collection from diverse populations can advance cancer disparities research, but is currently underrepresented.
Methods
We partnered with a community-based clinic serving Cantonese-speaking Chinese Americans to develop and revise an educational seminar on biospecimen collection. Through a randomized controlled trial (n = 395), the intervention seminar was compared with a control seminar (cancer prevention) on change in willingness to donate biospecimens.
Results
At baseline, many were willing to donate a biospecimen (saliva, urine, hair, toenails, blood, unused cancerous tissue) whether healthy or hypothetically had cancer. Also, many would donate because future generations would benefit, and few had concerns about donation. In logistic regression analyses, there was an intervention effect for willingness to donate: urine if had cancer [OR, 2.2; 95% confidence interval (CI), 1.3–3.7], toenails if healthy (OR, 2.1; 95% CI, 1.4–3.2) or had cancer (OR, 2.3; 95% CI, 2.0–2.7), hair if healthy (OR, 1.8; 95% CI, 1.3–2.5) or had cancer (OR, 2.8; 95% CI, 1.9–4.0), and unused cancerous tissue (OR, 1.8; 95% CI, 1.2–2.9). There was also an intervention effect for donating because future generations would benefit (OR, 2.0; 95% CI, 1.4–3.0), and this attitude was a strong independent predictor for willingness to donate all biospecimens, whether healthy or had cancer (OR, 2.9–4.2).
Conclusion
Cantonese-speaking Chinese American participants of an educational seminar on biospecimen collection showed greater increases in willingness to donate biospecimens and donating for the benefit of future generations, than participants who attended a control seminar.
Impact
Donating for the benefit of future generations is a theme that should be incorporated in messages that encourage biospecimen donation for Chinese Americans.
doi:10.1158/1055-9965.EPI-13-0744
PMCID: PMC4049566  PMID: 24609848
22.  Vitamin D and the Epidemiology of Upper Gastrointestinal Cancers: A Critical Analysis of the Current Evidence 
Prospective analyses have yet to uncover a consistent relationship between vitamin D status and incidence and mortality of rarer cancers including esophageal and upper gastrointestinal cancers. We searched PubMed for literature regarding the epidemiology of upper gastrointestinal cancers and vitamin D published over the last decade and then summarized and critiqued the results of these studies in this review. The search yielded nine relevant studies. Overall, no consistent relationship was reported between serum vitamin D levels or a surrogate and upper gastrointestinal cancers. Four studies reported negative correlations between vitamin D status and upper gastrointestinal cancer, three reported positive correlations, one reported no correlation, and one reported both positive and negative correlations. No relationship has been established based on epidemiological data, but studies examining sun exposure consistently report an inverse association with esophageal cancer. The current literature is limited by the methods used to assess vitamin D status, lack of specific data for the types of upper gastrointestinal cancer, and failure to establish a temporal relationship between vitamin D status assessment and presentation of upper gastrointestinal cancer. It is possible that the lack of a consistent relationship is a consequence of inaccurate and imprecise assessment of vitamin D status.
doi:10.1158/1055-9965.EPI-13-0085
PMCID: PMC3681828  PMID: 23563888
Cancer; Epidemiology; Esophagus; Gastrointestinal; Vitamin D
23.  Physical Activity, Tumor PTGS2 Expression, and Survival in Patients with Colorectal Cancer 
Background
Higher levels of physical activity are associated with lower colorectal cancer incidence and mortality, perhaps through influencing energy balance, cellular prostaglandin biosynthesis and systemic inflammation. Although evidence suggests interactive effects of energetics, sedentary lifestyle, and tumor CTNNB1 (β-catenin) or CDKN1B (p27) status on colon cancer prognosis, interactive effects of physical activity and tumor PTGS2 (the official symbol for cyclooxygenase-2) status on clinical outcome remain unknown.
Methods
Utilizing molecular pathological epidemiology database of 605 stage I-III colon and rectal cancers in two prospective cohort studies (the Nurse’s Health Study and the Health Professionals Follow-up Study), we examined patient survival according to post-diagnosis physical activity and tumor PTGS2 status (with 382 PTGS2-positive and 223 PTGS2-negative tumors by immunohistochemistry). Cox proportional hazards models were used to calculate colorectal cancer-specific mortality hazard ratio (HR), adjusting for clinical and other tumor variables including microsatellite instability status.
Results
Among PTGS2-positive cases, compared with the least active first quartile, the multivariate HRs (95% confidence interval) were 0.30 (0.14–0.62) for the second, 0.38 (0.20–0.71) for the third, and 0.18 (0.08–0.41) for the fourth quartile of physical activity level (Ptrend=0.0002). In contrast, among PTGS2-negative cases, physical activity level was not significantly associated with survival (Ptrend =0.84; Pinteraction=0.024, between physical activity and tumor PTGS2 status).
Conclusions
Post-diagnosis physical activity is associated with better survival among patients with PTGS2-positive tumors, but not among patients with PTGS2-negative tumors.
Impact
Immunohistochemical PTGS2 expression in colorectal carcinoma may serve as a predictive biomarker in pathology practice, which may predict stronger benefit from exercise.
doi:10.1158/1055-9965.EPI-13-0108
PMCID: PMC3681847  PMID: 23629521
colorectal carcinoma; survivorship; lifestyle; tumor behavior; molecular pathological epidemiology
24.  Smokeless and Dual Tobacco Use among Males Surviving Childhood Cancer: A report from the Childhood Cancer Survivor Study 
Cancer survivors experience treatment-related complications that can be exacerbated by tobacco use. This study reports the prevalence of smokeless (ST) and dual tobacco (DT) use, compares these rates to the US population, and examines tobacco risk factors among males surviving childhood cancer. Data from the Childhood Cancer Survivor Study (CCSS) 2007 survey were used (N = 3378). Standardized incidence ratios (SIR) were obtained by comparing CCSS data to the National Survey on Drug Use and Health. Logistic regression was used to evaluate associations between risk factors and tobacco use. Among male survivors, 8.3% and 2.3% were current ST and DT users, respectively. Survivors were less likely than population males to report ST (SIR = 0.64, 95% CI = 0.57 – 0.72) or DT (SIR = 0.37, CI = 0.29 – 0.46) use; however, non-white survivors aged 35–49 years were more likely to use ST (SIR = 2.32, CI = 1.27 – 3.90). ST use was associated (p < 0.05) with younger age at diagnosis, lower education, being married or divorced/separated, and not living in the Northeastern US, while history of cardiovascular- and/or pulmonary-toxic treatment was protective. DT use was associated with younger age at diagnosis, lower education, divorce/separation, and high psychological distress. Having active heart or circulatory conditions was protective. Although ST/DT use is generally low among childhood cancer survivors, these findings suggest that tobacco use screening should be expanded to include ST use and that ST-specific education and cessation interventions should be provided to users. Screening and intervening for ST/DT use in childhood cancer survivors will reduce tobacco-related morbidity and mortality.
doi:10.1158/1055-9965.EPI-12-1302
PMCID: PMC3681858  PMID: 23580700
smokeless tobacco; dual tobacco; cancer survivors; health behaviors
25.  Reduced Nicotine Content Cigarettes and Nicotine Patch 
Background
Reduced nicotine content (RNC) cigarettes have led to smoking fewer cigarettes, withdrawal relief, and facilitation of cessation. The aim of this study is to examine the effects RNC cigarettes with and without nicotine patch and patch alone on smoking behavior, toxicant exposure, withdrawal discomfort and as an exploratory analysis, on long-term abstinence.
Methods
This study involved a randomized, parallel arm design and six weeks of: 1) 0.05-0.09 mg nicotine yield cigarettes (N=79); 2) 21 mg nicotine patch (N=80) or 3) 0.05-0.09 nicotine yield cigarettes with 21 mg nicotine patch (N=76); all groups received six weeks of additional behavioral treatment with follow-ups up to six months.
Results
Combination approach led to lower rates of smoking assigned cigarettes and hence lower CO levels than RNC cigarettes alone. Additionally, the combination approach was associated with less withdrawal severity when switching from usual brand to assigned product, and less smoking of usual brand cigarettes during treatment, but not after treatment compared to the other approaches.
Conclusion
Combining very low nicotine content cigarettes with nicotine patch may improve the acute effects resulting from switching to either of these products alone.
Impact
These findings may have implications for smoking cessation treatment or a policy measure to reduce nicotine content in cigarettes.
doi:10.1158/1055-9965.EPI-12-1439
PMCID: PMC3681886  PMID: 23603206
reduced nicotine; cigarettes-nicotine; patch-tobacco; addiction-cigarette; consumption-biomarkers

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