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Cancer causes & control : CCC  2013;24(4):695-704.
Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms.
The National Cancer Institute developed an innovative concept to establish a centers grant mechanism in nutrition, energetics, and physical activity; referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the Centers.
Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes 3 animal studies, 3 cohort studies, 4 randomized clinical trials, 1 cross-sectional study, and 2 modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality.
The NIH Science of Team Science group will evaluate the value-added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk for cancer as well as cancer survivors.
PMCID: PMC3602225  PMID: 23378138
energetics; obesity; diet; physical activity; cancer; transdisciplinary
Cancer causes & control : CCC  2013;24(4):731-739.
The incidence of estrogen receptor positive (ER+) breast cancer is higher among white women relative to black women. In two large prospective cohorts, the Black Women’s Health Study (BWHS) and the Nurses’ Health Study II (NHSII), we investigated whether reproductive factors explain the difference.
During 1,582,083 person-years of follow-up of 140,914 women observed from 1995-2007, 327 ER+ breast cancers were identified among black women in BWHS and NHSII and 1179 among white women in NHSII. Cox proportional hazards regression models, stratified by race and pooled, were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of race, parity, age at first birth, and lactation in relation to risk of ER+ cancer with adjustment for age and other breast cancer risk factors.
Age at first birth differed markedly in the two groups, with 66% of parous black women having their first child before age 25 as compared with 36% of white women. Each additional year of age at first birth was associated with a 4% increased risk of ER+ breast cancer among both racial groups. Relative to nulliparous women, parous women were at decreased risk of ER+ breast cancer (HR 0.59, 95% CI: 0.20, 1.77), in black women and (HR 0.63, 95% CI: 0.45, 0.87) in white women. The HR for the association of black race with ER+ cancer was 0.67 (95% CI: 0.53, 0.84) in a model that adjusted for age only, 0.77 (95% CI: 0.61, 0.99) in a model that controlled for parity, age at first birth, and other reproductive/hormonal factors, and 0.83 (95% CI: 0.70, 0.98) in a model that additionally controlled for other breast cancer risk factors such as alcohol consumption and use of hormone supplements. Similar associations were seen among premenopausal women and in an analysis restricted to ER+PR+ tumors.
Reproductive factors explained some of the higher incidence of ER+ tumors among white women as compared to black women.
PMCID: PMC3602276  PMID: 23380944
breast carcinoma; race; estrogen receptor; reproductive factors; incidence; black; African-American
3.  Circulating Prolactin Levels and Risk of Epithelial Ovarian Cancer 
Cancer causes & control : CCC  2013;24(4):741-748.
Indirect evidence from experimental and epidemiological studies suggests that prolactin may be involved in ovarian cancer development. However, the relationship between circulating prolactin levels and risk of ovarian cancer is unknown.
We conducted a nested case-control study of 230 cases and 432 individually-matched controls within three prospective cohorts to evaluate whether pre-diagnostic circulating prolactin is associated with subsequent risk of ovarian cancer. We also assessed whether lifestyle and reproductive factors are associated with circulating prolactin among controls.
Prolactin levels were significantly lower among post- vs. pre-menopausal women, parous vs. nulliparous women, and past vs. never users of oral contraceptives in our cross-sectional analysis of controls. In our nested case-control study, we observed a non-significant positive association between circulating prolactin and ovarian cancer risk (ORQ4vsQ1: 1.56, 95% CI: 0.94, 2.63, p-trend: 0.15). Our findings were similar in multivariate-adjusted models and in the subgroup of women who donated blood ≥5 years prior to diagnosis. We observed a significant positive association between prolactin and risk for the subgroup of women with BMI ≥25 kg/m2 (ORQ4vsQ1: 3.10, 95% CI: 1.39, 6.90), but not for women with BMI <25 kg/m2 (ORQ4vsQ1: 0.81, 95% CI: 0.40, 1.64).
Our findings suggest that prolactin may be associated with increased risk of ovarian cancer, particularly in overweight/obese women. Factors associated with reduced risk of ovarian cancer, such as parity and use of oral contraceptives, were associated with lower prolactin levels, which suggests that modulation of prolactin may be a mechanism underlying their association with risk.
PMCID: PMC3602319  PMID: 23378139
Prolactin; Ovarian Cancer; Serum; Plasma
4.  Intention to Quit Smoking and Concerns about Household Environmental Risks: Findings from the Health in Common Study in Low-Income Housing 
Cancer causes & control : CCC  2013;24(4):805-811.
To assess the association between intention to quit smoking and perceptions of household environmental risks among racially/ethnically diverse residents of low-income housing.
Baseline data were collected from 2007 to 2009 for the Health in Common Study, which assessed social and physical determinants of cancer risk-related behaviors among residents of 20 low-income housing developments in the Greater Boston metropolitan area. Participants were surveyed about their tobacco use and concerns about household exposures. Household environmental inspections were also conducted to identify conditions associated with increased risk of exposure to indoor environmental agents, including pesticides, mold and cleaning products.
Intention to quit smoking was associated with a greater degree of concern about exposures in the home, yet not with the actual presence of household hazards, as identified by home inspections and survey findings.
An ecological approach targeting multiple levels of influence may help to highlight the importance of both quitting tobacco and reducing potential household environmental exposures as part of comprehensive efforts to promote individual and household health.
PMCID: PMC3602321  PMID: 23334887
Smoking; tobacco use; household hazards; environmental toxins; low-income
5.  Racial differences in the relationship between tobacco, alcohol and squamous cell carcinoma of the head and neck 
Cancer causes & control : CCC  2012;24(4):649-664.
Tobacco and alcohol use are well-known risk factors for squamous cell carcinoma of the head and neck (SCCHN), but there has been little examination of disparities in SCCHN and racial patterns of tobacco and alcohol use, especially for African-Americans. The Carolina Head and Neck Cancer Study, a population-based case-control study, was utilized to determine if relationships between tobacco and alcohol use and SCCHN differed by race.
Using a rapid case ascertainment system, cases were recruited from 46 contiguous counties in North Carolina from 2002–2006. Controls, selected from motor vehicle records, were frequency-matched to cases on age, sex, and race. This analysis was based on 989 white and 351 African-American cases and 1114 white and 264 African-American controls. Analyses were performed using unconditional logistic regression, adjusting for age, sex, race, education and fruit and vegetable consumption.
The association between SCCHN and ever tobacco use among African-Americans (odds ratio (OR) 9.68 95% confidence interval (CI) 4.70, 19.9) was much greater than that observed in whites (OR:1.94 95% CI 1.51, 2.50). Smaller differences were observed when examining ever alcohol use (African-Americans OR: 3.71 CI 1.65, 8.30 Whites OR: 1.31 CI 0.96, 1.78). African-Americans consistently had greater effect measure estimates when examining common levels of duration and intensity metrics of tobacco and alcohol use, both independently and jointly. No racial differences in the effects of environmental (passive) tobacco smoke were observed.
These findings suggest racial differences in SCCHN are not solely explained by differences in consumption patterns, and tobacco and alcohol may have greater impact in African-Americans.
PMCID: PMC3698868  PMID: 22674225
head and neck neoplasms; tobacco; cigarettes; alcohol; etiology
6.  Associations of serum 25-Hydroxyvitamin D with overall and breast cancer-specific mortality in a multi-ethnic cohort of breast cancer survivors 
Cancer causes & control : CCC  2013;24(4):759-767.
Despite limited evidence on the association of vitamin D with outcomes in breast cancer survivors, some clinicians advise breast cancer patients to use vitamin D supplements. More evidence is needed to inform these recommendations.
In the Health, Eating, Activity and Lifestyle Study, we examined associations of post-treatment serum concentrations of 25-hydroxyvitamin D (25(OH)D) on overall and breast-cancer-specific mortality in 585 breast cancer survivors from western Washington State, New Mexico, and Los Angeles County. 25(OH)D was measured in stored blood collected 2 years post-enrollment. Outcomes were ascertained from the Surveillance, Epidemiology, and End Results registries and medical records. Cox proportional hazards models were fit to assess associations of serum 25(OH)D with overall and breast-cancer-specific mortality.
After a median follow-up of 9.2 years; 110 women died, including 48 from breast cancer. Standard cut points classified 211 (31.6%) women as serum 25(OH)D deficient (<20 ng/mL), 189 (32.2%) as insufficient (20–30 ng/mL), and 185 (36.2%) as sufficient (>30 ng/mL). Compared to women with deficient 25(OH)D, those in the sufficient ranges had a decreased risk of overall mortality (age-adjusted HR=0.58; 95%CI 0.36–0.96); however multivariate adjustments attenuated the association (HR=0.90; 95%CI 0.50–1.61). No association was found between serum 25(OH)D and breast-cancer-specific mortality (sufficient: HR=1.21; 95%CI 0.52–2.80) in multivariate models.
In this breast cancer cohort, higher serum 25(OH)D may be associated with improved survival, but results were not statistically significant and must be interpreted with caution. The potential prognostic effect of vitamin D from diet, supplements or both should be evaluated in future larger studies with additional endpoints from breast cancer patients.
PMCID: PMC3731052  PMID: 23361338
25-hydroxyvitamin D; overall mortality; breast-cancer-specific mortality; vitamin D
7.  Carotenoid Intake and Risk of Colorectal Adenomas in a Cohort of Male Health Professionals 
Cancer causes & control : CCC  2013;24(4):705-717.
Carotenoids have been hypothesized to prevent carcinogenesis through their antioxidant and pro-vitamin A properties. We examined associations between intakes of specific carotenoids and risk of colorectal adenomas.
Among 29,363 men who reported having a lower bowel endoscopy between 1986–2006, 3,997 cases of colorectal adenoma were identified in the Health Professionals Follow-up Study. Participants completed food frequency questionnaires every 4 years; dietary information was cumulatively updated. The associations between carotenoid intakes and risk of colorectal adenomas overall and by anatomic site, stage, smoking status and alcohol consumption were investigated using multivariate logistic regression models.
Total β-carotene and dietary β-carotene, lycopene and lutein/zeaxanthin intakes and the total carotenoid score were inversely associated with colorectal adenoma risk. The odds ratios (95% confidence intervals) comparing the highest vs. lowest quintile of intake were 0.78 (0.69–0.88) for total β-carotene, 0.72 (0.64–0.81) for dietary β-carotene, 0.83 (0.74–0.93) for lycopene, 0.86 (0.76–0.96) for lutein/zeaxanthin, and 0.87 (0.77–0.97) for the total carotenoid score. Associations for α-carotene and β-cryptoxanthin intakes were null. We did not find significant differences in the associations between intakes of each carotenoid and risk of colorectal adenoma by anatomic site or stage (all p-values, test for common effects > 0.10). The inverse associations we observed for total β-carotene and dietary β-carotene, lycopene, and lutein/zeaxanthin intakes and the total carotenoid score with adenoma risk also did not vary by smoking status and alcohol consumption.
This study found that a diet high in carotenoids was associated with a reduced risk of colorectal adenomas.
PMCID: PMC3767390  PMID: 23371557
carotenoids; nutrition; colorectal adenomas; colorectal cancer; epidemiology
8.  Correlates of fruit and vegetable consumption among construction laborers and motor freight workers 
Cancer causes & control : CCC  2012;24(4):637-647.
To compare and contrast correlates of fruit and vegetable consumption in two blue-collar populations: construction laborers and motor freight workers.
Cross-sectional data were collected from two groups of male workers: (1) construction laborers (N=1013; response rate = 44%) randomly selected from a national sample, as part of a diet and smoking cessation study; and (2) motor freight workers (N=542; response rate = 78%) employed in eight trucking terminals, as part of a tobacco cessation and weight management study. Data were analyzed using linear regression modeling methods.
For both groups, higher income and believing it was important to eat right because of work were positively associated with fruit and vegetable consumption; conversely, being White was associated with lower intake. Construction laborers who reported eating junk food due to workplace stress and fatigue had lower fruit and vegetable intake. For motor freight workers, perceiving fast food to be the only choice at work and lack of time to eat right were associated with lower consumption.
Comparing occupational groups illustrates how work experiences may be related to fruit and vegetable consumption in different ways as well as facilitates the development of interventions that can be used across groups.
PMCID: PMC3784996  PMID: 22729935
9.  Prediagnostic plasma vitamin B6 (pyridoxal 5′-phosphate) and survival in patients with colorectal cancer 
Cancer causes & control : CCC  2013;24(4):10.1007/s10552-013-0152-x.
Higher plasma pyridoxal 5′-phosphate (PLP) levels are associated with a decreased incidence of colorectal cancer, but the influence of plasma PLP on survival of patients with colorectal cancer is unknown. We prospectively examined whether prediagnostic plasma PLP levels are associated with mortality among colorectal cancer patients.
We included 472 incident cases of colorectal cancer identified in the Nurses’ Health Study, the Health Professionals Follow-up Study, and the Physicians’ Health Study from 1984 to 2002. The patients provided blood samples two or more years before cancer diagnosis. Stratified Cox proportional hazards models were used to calculate hazard ratios (HR) with 95% confidence interval (CI) adjusted for other risk factors for cancer survival.
Higher plasma PLP levels were not associated with a significant reduction in colorectal cancer-specific (169 deaths) or overall mortality (259 deaths). Compared with patients who had less than 45 pmol/ml of plasma PLP (median: 33.6 pmol/ml), those who had 110 pmol/ml or higher levels (median: 158.8 pmol/ml) had multivariable HRs of 0.85 (95% CI 0.50–1.45, P trend = 0.37) and 0.87 (95% CI 0.56–1.35, P trend = 0.24) for colorectal cancer-specific and overall mortality. Higher plasma PLP levels, however, seemed to be associated with better survival among patients who had lower circulating 25-hydroxyvitamin D3 levels(< 26.5 ng/ml) (P interaction ≤ .005).
Higher prediagnostic plasma PLP levels were not associated with an improvement on colorectal cancer survival overall. Further research is needed to clarify the influence of vitamin B6 on colorectal cancer progression and survival.
PMCID: PMC3884510  PMID: 23340905
vitamin B6; pyridoxal 5′ phosphate (PLP); colorectal cancer; mortality; survival; prospective study
10.  Lifetime exposure to arsenic in drinking water and bladder cancer: a population-based case–control study in Michigan, USA 
Cancer causes & control : CCC  2010;21(5):745-757.
Arsenic in drinking water has been linked with the risk of urinary bladder cancer, but the dose–response relationships for arsenic exposures below 100 µg/L remain equivocal. We conducted a population-based case–control study in southeastern Michigan, USA, where approximately 230,000 people were exposed to arsenic concentrations between 10 and 100 µg/L.
This study included 411 bladder cancer cases diagnosed between 2000 and 2004, and 566 controls recruited during the same period. Individual lifetime exposure profiles were reconstructed, and residential water source histories, water consumption practices, and water arsenic measurements or modeled estimates were determined at all residences. Arsenic exposure was estimated for 99% of participants’ person-years.
Overall, an increase in bladder cancer risk was not found for time-weighted average lifetime arsenic exposure >10 µg/L when compared with a reference group exposed to <1 µg/L (odds ratio (OR) = 1.10; 95% confidence interval (CI): 0.65, 1.86). Among ever-smokers, risks from arsenic exposure >10 µg/L were similarly not elevated when compared to the reference group (OR = 0.94; 95% CI: 0.50, 1.78).
We did not find persuasive evidence of an association between low-level arsenic exposure and bladder cancer. Selecting the appropriate exposure metric needs to be thoughtfully considered when investigating risk from low-level arsenic exposure.
PMCID: PMC3962589  PMID: 20084543
Age factors; Arsenicals; Environmental exposure; Residential mobility; Urinary bladder
11.  Risk factors for gastric cancer in Latin-America: a meta-analysis 
Cancer causes & control : CCC  2012;24(2):217-231.
Latin America has among the highest gastric cancer incidence rates in the world, for reasons that are still unknown. In order to identify region-specific risk factors for gastric cancer, we conducted a meta-analysis summarizing published literature.
Searches of PubMed and regional databases for relevant studies published up to December 2011 yielded a total of 29 independent case-control studies. We calculated summary odds ratios (OR) for risk factors reported in at least five studies, including socioeconomic status (education), lifestyle habits (smoking and alcohol use), dietary factors (consumption of fruits, total vegetables, green vegetables, chili pepper, total meat, processed meat, red meat, fish and salt) and host genetic variants (IL1B-511T, IL1B-31C, IL1RN*2, TNFA-308A, TP53 codon 72 Arg and GSTM1 null). Study-specific ORs were extracted and summarized using random-effects models.
Chili pepper was the only region-specific factor reported in at least five studies. Consistent with multifactorial pathogenesis, smoking, alcohol use, high consumption of red meat or processed meat, excessive salt intake and carriage of IL1RN*2 were each associated with a moderate increase in gastric cancer risk. Conversely, higher levels of education, fruit consumption, and total vegetable consumption were each associated with a moderately decreased risk. The other exposures were not significantly associated. No prospective study data were identified.
Risk factor associations for gastric cancer in Latin America are based on case-control comparisons that have uncertain reliability, particularly with regard to diet; the specific factors identified and their magnitudes of association are largely similar to those globally recognized. Future studies should emphasize prospective data collection and focus on region-specific exposures that may explain high gastric cancer risk.
PMCID: PMC3961831  PMID: 23224270
epidemiology; gastric cancer; Latin-America; meta-analysis; risk factors
12.  An Examination of Sexual Orientation Group Patterns in Mammographic and Colorectal Screening in a Cohort of U.S. Women 
Cancer causes & control : CCC  2012;24(3):539-547.
Underutilization of cancer screening has been found especially to affect socially marginalized groups. We investigated sexual orientation group patterns in breast and colorectal cancer screening adherence.
Data on breast and colorectal cancer screening, sexual orientation, and sociodemographics were gathered prospectively from 1989 through 2005 from 85,759 U.S. women in the Nurses' Health Study II. Publicly available data on state-level health care quality and sexual orientation-related legal protections were also gathered. Multivariable models were used to estimate sexual orientation-group differences in breast and colorectal cancer screening, controlling for sociodemographics and state-level health care quality and legal protections for sexual minorities.
Receipt of a mammogram in the past two years was common though not universal and differed only slightly by sexual orientation: heterosexual 84%; bisexual 79%; lesbian 82%. Fewer than half of eligible women had ever received a colonoscopy or sigmoidoscopy, and rates did not differ by sexual orientation: heterosexual 39%; bisexual 39%; lesbian 42%. In fully adjusted models, state-level health care quality score, though not state-level legal protections for sexual minorities, was positively associated with likelihood of being screened for all women regardless of sexual orientation.
Concerns have been raised that unequal health care access for sexual orientation minorities may adversely affect cancer screening. We found small disparities in mammography and none in colorectal screening, though adherence to colorectal screening recommendations was uniformly very low. Interventions are needed to increase screening in women of all sexual orientation groups, particularly in areas with poor health care policies.
PMCID: PMC3959888  PMID: 22729931
breast cancer; colorectal cancer; screening; sexual orientation; bisexual; lesbian
13.  Diabetes and risk of bladder cancer among postmenopausal women in the Iowa Women's Health Study 
Cancer causes & control : CCC  2013;24(3):603-608.
Studies have indicated that diabetes is a risk factor for bladder cancer; however, many failed to adjust for confounding variables. An earlier publication from the Iowa Women's Health Study reported a positive association of baseline diabetes with bladder cancer risk between 1986 and 1998, although the number of cases was small (n=112). We re-examined the diabetes–bladder cancer risk association by accounting for 12 more years of follow-up and assessed whether the association varied by diabetes duration, body mass index or waist-to-hip ratio (WHR).
Proportional hazards regression was used to estimate the hazard ratio (HR) of bladder cancer (n=277) in relation to diabetes (before enrollment and during follow-up) and diabetes duration using a time-dependent approach.
In a multivariate time-dependent analysis, the HR for bladder cancer was 1.69 (95% CI, 1.40-2.41) in relation to diabetes among 37,327 postmenopausal women initially free of cancer. There was an interaction between diabetes and WHR (p =0.01). Bladder cancer HR in diabetic women with WHR>0.9 was 2.5 times higher than expected. There was no dose-response relation of bladder cancer risk with diabetes duration. Compared to no diabetes, HR were 1.77. 2.03, and 1.55 for diabetes durations of ≤5, 6-10, and >10 years, respectively.
We confirmed a positive association between diabetes and bladder cancer risk among white post-menopausal women. We also observed a synergistic interaction between diabetes and high WHR in bladder cancer development that might be explained by increased insulin resistance and inflammation related to abdominal obesity.
PMCID: PMC3574198  PMID: 23296458
Bladder cancer; diabetes; prospective study
14.  Indoor Air Pollution and Risk of Lung Cancer among Chinese Female Non-Smokers 
Cancer causes & control : CCC  2013;24(3):439-450.
To investigate indoor particulate matter (PM) level and various indoor air pollution exposure, and to examine their relationships with risk of lung cancer in an urban Chinese population, with a focus on non-smoking women.
We conducted a case-control study in Taiyuan, China, consisting of 399 lung cancer cases and 466 controls, of which 164 cases and 218 controls were female non-smokers. Indoor PM concentrations, including PM1, PM2.5, PM7, PM10 and TSP, were measured using a particle mass monitor. Unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals after adjusting for age, education, annual income and smoking.
Among non-smoking women, lung cancer was strongly associated with multiple sources of indoor air pollution 10 years ago, including heavy exposure to ETS at work (aOR=3.65), high frequency of cooking (aOR=3.30), and solid fuel usage for cooking (aOR=4.08) and heating (aORcoal stove=2.00). Housing characteristics related to poor ventilation, including single-story, less window area, no separate kitchen, no ventilator and rarely having windows open, are associated with lung cancer. Indoor medium PM2.5 concentration was 68ug/m3, and PM10 was 230ug/m3. PM levels in winter are strongly correlated with solid fuel usage for cooking, heating and ventilators. PM1 levels in cases are more than 3-time higher than that in controls. Every 10 ug/m3 increase in PM1 is associated with 45% increased risk of lung cancer.
Indoor air pollution plays an important role in the development of lung cancer among non-smoking Chinese women.
PMCID: PMC3574203  PMID: 23314675
Indoor air pollution; lung cancer; particulate matter; Chinese non-smoking female
15.  Racial disparities in advanced stage colorectal cancer survival 
Cancer causes & control : CCC  2013;24(3):463-471.
African Americans (AA) have a higher incidence and lower survival from colorectal cancer (CRC) compared to European Americans (EA). In the present study, statewide, population-based data from South Carolina Central Cancer Registry (SCCCR) is used to investigate the relationship between race and age on advanced stage CRC survival.
The study population was comprised of 3865 advanced pathologically documented colon and rectal adenocarcinoma cases diagnosed between 01 January 1996 and 31 December 2006: 2673 (69%) EA and 1192 (31%) AA. Kaplan-Meier methods were used to generate median survival time and corresponding 95% confidence intervals (CI) by race, age, and gender. Factors associated with survival were evaluated by fitting Cox proportional hazards (CPH) regression models to generate Hazard Ratios (HR) and 95% CI.
We observed a significant interaction between race and age on CRC survival (p = 0.04). Among younger patients (< 50 years), AA race was associated with a 1.34 (95% CI 1.06-1.71) higher risk of death compared to EA. Among older patients, we observed a modest increase risk of death among AA men compared to EA (HR 1.16 (95% CI 1.01-1.32) but no difference by race among women (HR 0.94 (95% CI 0.82-1.08)). Moreover, we observed that the disparity in survival has worsened over the past 15 years.
Future studies that integrate clinical, molecular, and treatment-related data are needed for advancing understanding of the racial disparity in CRC survival, especially for those < 50 years old.
PMCID: PMC3574218  PMID: 23296454
African American; survival; metastatic; colon cancer; young-onset
16.  Baseline E2 Levels Are Higher in BRCA2 Mutation Carriers: A Potential Target for Prevention? 
Cancer causes & control : CCC  2012;24(3):421-426.
BRCA gene mutations and elevated serum estradiol (E2) are well-known risk factors for breast cancer. The aim of this study was to investigate the association between BRCA gene mutations and serum E2 level.
We measured baseline (menstrual cycle day 2–3) E2 levels of 96 women with breast cancer who underwent BRCA testing.
The mean age, parity, and age at menarche did not differ between women with and without BRCA1/2 mutations. Basal serum E2 level was significantly higher in women with BRCA2 mutations compared to women with BRCA1 mutations or without BRCA mutations (71.7±41.6 vs. 45.5±20.7 vs. 38.5±12.6 pg/ml in BRCA2 mutation carriers, BRCA1 mutation carriers, and non-carriers, respectively, p-value=0.03). Women with BRCA2 mutations had 3.1 times as great risk for high basal E2 level (>48 pg/ml) as women without BRCA mutations after adjusting for age and BMI (95% confidence interval: 1.3, 7.6). BRCA mutation carriers with high serum E2 level were significantly younger than the carriers with low serum E2 level (31.4±3.1 vs. 34.7±4.9 year, p=0.04).
In this pilot study, we found an association between high basal serum E2 levels and BRCA2 mutations. Our results suggest that increased production of serum E2 may have a role in the pathogenesis of BRCA2-mutation related breast cancer.
PMCID: PMC3583585  PMID: 23271408
BRCA; Breast Cancer; Estradiol
17.  The modifying effect of patient location on stage-specific survival following colorectal cancer using geosurvival models 
Cancer causes & control : CCC  2013;24(3):473-484.
Colorectal cancer (CRC) is the third leading cause of cancer death in the US, and stage at diagnosis is the primary prognostic factor. To date, the interplay between geographic place and individual characteristics such as cancer stage with CRC survival is unexplored. We used a Bayesian geosurvival statistical model to evaluate whether the spatial patterns of CRC survival at the census tract level varies by stage at diagnosis (in situ/local, regional, distant), controlling for patient characteristics, surveillance test use, and treatment using linked 1991–2005 SEER-Medicare data of patients ≥ 66 years old in two US metropolitan areas. The spatial pattern of survival varied by stage at diagnosis for both cancer sites and registries. Significant spatial effects were identified in all census tracts for colon cancer and the majority of census tracts for rectal cancer. Geographic disparities appeared to be highest for distant-stage rectal cancer. Compared to those with in situ/local stage in the same census tracts, patients with distant-stage cancer were at most 7.73 times and 4.69 times more likely to die of colon and rectal cancer, respectively. Moreover, frailty areas for CRC at in situ/local stage more likely have a higher relative risk at regional stage, but not at distant stage. We identified geographic areas with excessive risk of CRC death and demonstrated that spatial patterns varied by both cancer type and cancer stage. More research is needed to understand the moderating pathways between geographic and individual-level factors on CRC survival.
PMCID: PMC3617359  PMID: 23306551
Colorectal cancer; Diagnosis stage; Geosurvival model; Geographic disparity
18.  Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome 
Cancer causes & control : CCC  2009;20(9):1769-1777.
Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ-line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell-cycle related genes on age of onset for Lynch syndrome using a tree-model.
Experimental Design
We evaluated polymorphisms in a panel of cell-cycle related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1 and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree-modeling (Classification and Regression Tree), to the analysis of data on Lynch syndrome patients to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell-cycle genes.
We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats ≥19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age. While the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeats ≥19, E2F2 wild-type genotype and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset.
Polymorphisms in these cell-cycle related genes work together to modify the age at onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.
PMCID: PMC3917505  PMID: 19690970
Tree model; cell cycle pathway; Polymorphisms; Lynch syndrome; Age of onset
19.  Body mass index, tumor characteristics, and prognosis following diagnosis of early stage breast cancer in a mammographically-screened population 
Cancer causes & control : CCC  2012;24(2):305-312.
Many studies suggest increased body mass index (BMI) is associated with worse breast cancer outcomes, but few account for variability in screening, access to treatment, and tumor differences. We examined the association between BMI and risk of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality, and evaluated whether tumor characteristics differ by BMI among a mammographically-screened population with access to treatment.
Using a retrospective cohort study design, we followed 485 women aged ≥40 years diagnosed with stage I/II breast cancer within 24 months of a screening mammogram occurring between 1988 and 1993 for 10-year outcomes. BMI before diagnosis was categorized as normal (<25 kg/m2), overweight (25–29.9 kg/m2), and obese (≥30 kg/m2). Tumor marker expression was assessed via immunohistochemistry using tissue collected before adjuvant treatment. Medical records were abstracted to identify treatment, recurrence, and mortality. We used Cox proportional hazards to separately model the hazard ratios (HR) of our three outcomes by BMI while adjusting for age, stage, and tamoxifen use.
Relative to normal weight women, obese women experienced increased risk of recurrence (HR-2.43; 95%CI-1.34–4.41) and breast cancer death (HR-2.41; 95%CI-1.00–5.81) within 10 years of diagnosis. There was no association between BMI and all-cause mortality. Obese women had significantly faster growing tumors, as measured by Ki-67.
Our findings add to the growing evidence that obesity may contribute to poorer breast cancer outcomes, and also suggest that increased tumor proliferation among obese women is a pathway that explains part of their excess risk of adverse outcomes.
PMCID: PMC3557530  PMID: 23224272
breast cancer recurrence; breast cancer specific mortality; tumor characteristics; obesity; body mass index
20.  Contribution of diet and physical activity to metabolic parameters among survivors of childhood leukemia 
Cancer causes & control : CCC  2012;24(2):313-321.
Determine the relationship between diet and metabolic abnormalities among adult survivors of childhood acute lymphoblastic leukemia (ALL).
We surveyed 117 adult survivors of childhood ALL using the Harvard Food Frequency Questionnaire. Physical activity energy expenditure (PAEE) was measured with the SenseWear Pro2 Armband. Insulin resistance was estimated using the Homeostasis Model for Insulin Resistance (HOMA-IR). Visceral and subcutaneous adiposity were measured by abdominal CT. Adherence to a Mediterranean diet pattern was calculated using the index developed by Trichopoulou. Subjects were compared using multivariate analysis adjusted for age and gender.
Greater adherence to a Mediterranean diet pattern was associated with lower visceral adiposity (P=0.07), subcutaneous adiposity (P<0.001), waist circumference (P=0.005), and body mass index (P=0.04). For each point higher on the Mediterranean Diet Score, the odds of having the metabolic syndrome fell by 31% (OR 0.69; 95% CI 0.50, 0.94; P = 0.019). Higher dairy intake was associated with higher HOMA-IR (P =0.014), but other individual components of the Mediterranean diet, such as low intake of meat or high intake of fruits and vegetables, were not significant. PAEE was not independently associated with metabolic outcomes, although higher PAEE was associated with lower body mass index.
Adherence to a Mediterranean diet pattern was associated with better metabolic and anthropometric parameters in this cross-sectional study of ALL survivors.
PMCID: PMC3557541  PMID: 23187859
insulin resistance; leukemia; Mediterranean diet; obesity; survivorship
21.  Parental nutrient intake and risk of retinoblastoma resulting from new germline RB1 mutation 
Cancer causes & control : CCC  2012;24(2):343-355.
We conducted a case-control study to examine the role of parents’ nutrient intake before their child’s conception in the child’s risk of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation.
Parents of 206 cases from 9 North American institutions and 269 friend and relative controls participated; fathers of 182 cases and 223 controls and mothers of 202 cases and 260 controls provided useable information in telephone interviews on their diet in the year before the child’s conception. We also asked parents about supplements, a significant source of nutrients in users.
Father’s intake of dairy-associated nutrients and his use of calcium supplements were associated with decreased risk while his intake of copper, manganese, and vitamin E was associated with increased risk. Mother’s use of multivitamins close to conception was associated with lower risk as was her intake of several micronutrients found in these supplements. In analyses to elucidate the primary factor from multiple correlated factors, the most robust findings were for father’s calcium intake (adjusted OR=0.46 – 0.63 for 700 mg increase) and calcium supplement use (OR=0.35 – 0.41) and mother’s multivitamin use (ORs 0.28 – 0.48).
There are few directly relevant studies but some data indirectly support the biologic plausibility of the inverse associations with father’s calcium intake and mother’s use of multivitamins; however, we cannot rule out contributions of bias, confounding, or chance. Our findings provide a starting point for further investigation of diet in the etiology of retinoblastoma and new germline mutation generally.
PMCID: PMC3557550  PMID: 23224327
germline mutation; diet; retinoblastoma; case-control studies; pediatric cancer
22.  Body Size and Risk of Hodgkin Lymphoma by Age and Gender: A Population-based Case-Control Study in Connecticut and Massachusetts 
Cancer causes & control : CCC  2012;24(2):287-295.
Descriptive studies have indicated a rising trend in Hodgkin lymphoma (HL) incidence in young adults, especially females. Increasing evidence has suggested that some risk factors associated with HL may vary by age or gender. Recent studies have reported an increased risk of HL associated with increasing body mass index (BMI), but the results have been inconsistent. The objectives of this study were to examine whether the associations between measures of body size (height, weight, and BMI) and HL risk vary by age and/or gender.
A population-based case-control study was conducted in Connecticut and Massachusetts. A total of 567 HL cases and 679 controls were recruited in 1997–2000. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs).
Among younger women < 35 years old, being overweight (25–29.9 kg/m2) vs. normal weight (18.5–24.9 kg/m2) was significantly associated with an increased risk of HL (OR = 2.1, 95% CI = 1.1–4.0). The risk increased with increasing weight and BMI (P trends < 0.01). Among women ≥ 35 years old, by contrast, higher weight and BMI were associated with a reduced risk of HL (P trends < 0.01). Conversely, there was no significant association between BMI and risk of HL in younger or older males.
These findings show that the associations between body size and risk of HL vary by gender and age, and require confirmation in other populations.
PMCID: PMC3557669  PMID: 23208661
Hodgkin lymphoma; body size; body mass index; height; weight
23.  A Prospective Study of Socioeconomic Status, Prostate Cancer Screening and Incidence Among Men at High Risk for Prostate Cancer 
Cancer causes & control : CCC  2012;24(2):297-303.
Higher socio-economic status (SES) men are at higher risk of prostate cancer (PCa) diagnosis, an association commonly interpreted as a function of higher rates of prostate screening among higher-SES men. However, the extent to which screening explains this association has not been well quantified.
Within a Detroit-area cohort of 6,692 men followed up after a benign prostate procedure, a case-control study was conducted of 494 PCa cases and controls matched on age, race, duration of follow-up, and date of initial benign finding. 2000 Census data were used in a principal component analysis to derive a single factor, labeled the Neighborhood SES Index (NSESI), representing zip code-level SES.
Among cases, higher SES was associated with a younger age at initial biopsy: −1.48 years (95% CI, −2.32, −0.64) per unit NSESI. After adjustment for confounders and duration of follow-up, higher SES was associated with more PSA tests and DRE during follow-up; 9% (95% CI, 2, 16) and 8% (95% CI, 1, 15) more respectively, per unit NSESI. Higher SES was associated with a higher risk of PCa diagnosis during follow-up, multivariable adjusted OR = 1.26 per unit increase in NSESI (95% CI, 1.04, 1.49). Further adjustment for screening frequency somewhat reduced the association between SES and PCa risk (OR = 1.19 per unit NSESI, 95% CI, 0.98, 1.44).
Differences in screening frequency only partially explained the association between higher zip code SES and PCa risk; other health care related factors should also be considered as explanatory factors.
PMCID: PMC3557724  PMID: 23224323
socioeconomic status; prostate cancer; incidence; screening
Cancer causes & control : CCC  2012;24(2):277-285.
Type 2 diabetes mellitus (T2DM) prevalence has increased dramatically in the United States since the early 1970s. Though T2DM is known to be associated with colorectal cancer (CRC), information on racial differences in the relationship between T2DM and CRC is limited.
Using a retrospective cohort design we compared the association between T2DM and CRC, including subsites of the colon, in African Americans (AAs) and European Americans (EAs) in South Carolina, a region with large racial disparities in rates of both diseases. A total of 91,836 individuals who were ≥30 years old on January 1, 1990 and had ≥12 months of South Carolina Medicaid eligibility between January 1, 1990 and December 31, 1995 were included in the analyses. Cancer data from 1996 to 2007, included information on anatomic subsite.
Subjects who had T2DM (n=6,006) were >50% more likely to be diagnosed with colon cancer compared to those without T2DM (n=85,681). The association between T2DM and colon cancer was higher in AAs [odds ratio (OR) = 1.72 (95% Confidence Interval:1.21,2.46); n=47,984] than among EAs (OR = 1.24; 0.73,2.11; n=43,703). Overall, individuals with T2DM were over twice as likely to be diagnosed with in situ or local colon cancer (OR = 2.12; 1.40,3.22; n=191) compared to those without T2DM, with a higher likelihood among AAs (OR = 2.49;1.52,4.09; n=113).
Results from a Medicaid population in a high-risk region of the country, showed an increased likelihood of CRC with T2DM and suggest a racial disparity that disfavors AAs and provides further impetus for efforts aimed at diabetes prevention in this group.
PMCID: PMC3557726  PMID: 23197224
cohort study design; colorectal cancer; diabetes mellitus type II; health status disparities; incidence; South Carolina
25.  Nutrients related to one-carbon metabolism and risk of renal cell cancer 
Cancer causes & control : CCC  2012;24(2):373-382.
Folate, vitamins B6 and B12, methionine, choline, and betaine are nutrients related to one-carbon metabolism and have been hypothesized to decrease cancer risk. Few studies have evaluated dietary intakes of these nutrients in relation to renal cell cancer (RCC).
We conducted prospective follow-up studies of women in the Nurses’ Health Study and men in the Health Professionals Follow-up Study. Diet was assessed repeatedly using a validated semi-quantitative food-frequency questionnaire in both studies.
During follow-up of 24 years among 77,208 women (918,891 person-years) and 22 years among 47,886 men (1,731,752 person-years), we accrued 436 cases of RCC (225 women and 211 men). Intakes of folate, vitamins B6 and B12, methionine, and betaine were not found to be related to RCC risk. Higher intake of free choline, but not other forms of choline, was associated with reduced RCC risk. The results were similar in men and women.
We found little evidence that higher intakes of nutrients related to one-carbon metabolism lower RCC risk. One-carbon metabolism may have little influence on renal carcinogenesis.
PMCID: PMC3557764  PMID: 23242637
one-carbon metabolism; renal cell cancer; folate; prospective study

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