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Find video protocols related to scientific articles indexed in Pubmed.
Effects of estrogen and venlafaxine on menopause-related quality of life in healthy postmenopausal women with hot flashes: a placebo-controlled randomized trial.
Menopause
PUBLISHED: 11-19-2014
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This study aims to evaluate the effects of low-dose estradiol (E2) or venlafaxine on menopause-related quality of life and associated symptoms in healthy perimenopausal and postmenopausal women with hot flashes.
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Red meat intake, NAT2, and risk of colorectal cancer: A pooled analysis of 11 studies.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 10-25-2014
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Background: Red meat intake has been associated with risk of colorectal cancer (CRC), potentially mediated through heterocyclic amines. The metabolic efficiency of N-acetyltransferase 2 (NAT2) required for the metabolic activation of such amines is influenced by genetic variation. The interaction between red meat intake, NAT2 genotype, and CRC has been inconsistently reported. Methods: We used pooled individual-level data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Red meat intake was collected by each study. We inferred NAT2 phenotype based on polymorphism at rs1495741, highly predictive of enzyme activity. Interaction was assessed using multiplicative interaction terms in multivariate-adjusted models. Results: From 11 studies, 8,290 CRC cases and 9,115 controls were included. The highest quartile of red meat intake was associated with increased risk of CRC compared to the lowest quartile (OR 1.41, 95%CI 1.29 - 1.55). However, a significant association was observed only for studies with retrospective diet data, not for studies with diet prospectively assessed before cancer diagnosis. Combining all studies, high red meat intake was similarly associated with CRC in those with a rapid/intermediate NAT2 genotype (OR 1.38, 95%CI 1.20 - 1.59) as with a slow genotype (OR 1.43, 95%CI 1.28 - 1.61) (p- interaction=0.9). Conclusions: We found that high red meat intake was associated with increased risk of CRC only from retrospective case-control studies and not modified by NAT2 enzyme activity. Impact: Our results suggest no interaction between NAT2 genotype and red-meat intake in mediating risk of CRC.
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Cancer Incidence and Mortality during the Intervention and Postintervention Periods of the Women's Health Initiative Dietary Modification Trial.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 09-25-2014
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The Women's Health Initiative (WHI) low-fat (20% kcal) dietary modification (DM) trial (1993-2005) demonstrated a nonsignificant reduction in breast cancer, a nominally significant reduction in ovarian cancer, and no effect on other cancers (mean 8.3 years intervention). Consent to nonintervention follow-up was 83% (n = 37,858). This analysis was designed to assess postintervention cancer risk in women randomized to the low-fat diet (40%) versus usual diet comparison (60%).
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Methods for the design of vasomotor symptom trials: the menopausal strategies: finding lasting answers to symptoms and health network.
Menopause
PUBLISHED: 09-25-2014
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This report describes the Menopausal Strategies: Finding Lasting Answers to Symptoms and Health network and methodological issues addressed in designing and implementing vasomotor symptom trials.
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An analysis of genetic factors related to risk of inflammatory bowel disease and colon cancer.
Cancer Epidemiol
PUBLISHED: 08-15-2014
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Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer than the general population. Genome-wide association studies have identified and replicated several loci associated with risk of IBD; however, it is currently unknown whether these loci are also associated with colon cancer risk.
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Genome-wide association and admixture analysis of glaucoma in the Women's Health Initiative.
Hum. Mol. Genet.
PUBLISHED: 07-15-2014
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We report a genome-wide association study (GWAS) and admixture analysis of glaucoma in 12 008 African-American and Hispanic women (age 50-79 years) from the Women's Health Initiative (WHI). Although GWAS of glaucoma have been conducted on several populations, this is the first to look at glaucoma in individuals of African-American and Hispanic race/ethnicity. Prevalent and incident glaucoma was determined by self-report from study questionnaires administered at baseline (1993-1998) and annually through 2005. For African Americans, there was a total of 658 prevalent cases, 1062 incident cases and 6067 individuals who never progressed to glaucoma. For our replication cohort, we used the WHI Hispanics, including 153 prevalent cases, 336 incident cases and 2685 non-cases. We found an association of African ancestry with glaucoma incidence in African Americans (hazards ratio 1.62, 95% CI 1.023-2.56, P = 0.038) and in Hispanics (hazards ratio 3.21, 95% CI 1.32-7.80, P = 0.011). Although we found that no previously identified glaucoma SNPs replicated in either the WHI African Americans or Hispanics, a risk score combining all previously reported hits was significant in African-American prevalent cases (P = 0.0046), and was in the expected direction in the incident cases, as well as in the Hispanic incident cases. Additionally, after imputing to 1000 Genomes, two less common independent SNPs were suggestive in African Americans, but had too low of an allele frequency in Hispanics to test for replication. These results suggest the possibility of a distinct genetic architecture underlying glaucoma in individuals of African ancestry.
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Gene-environment interaction involving recently identified colorectal cancer susceptibility Loci.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 07-03-2014
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Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer. Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279.
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Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial.
JAMA Intern Med
PUBLISHED: 05-28-2014
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Estrogen therapy is the gold standard treatment for hot flashes and night sweats, but some women are unable or unwilling to use it because of associated risks. The serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride is used widely as a nonhormonal treatment. While the clinical impression is that serotonin-norepinephrine reuptake inhibitors are less effective than estrogen, these medications have not been simultaneously evaluated in one clinical trial to date.
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Genome-wide diet-gene interaction analyses for risk of colorectal cancer.
PLoS Genet.
PUBLISHED: 04-01-2014
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Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
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Pre- to post-diagnosis weight change and associations with physical functional limitations in breast cancer survivors.
J Cancer Surviv
PUBLISHED: 03-19-2014
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We investigated pre- to post-diagnosis weight change and functional limitations in a cohort of breast cancer survivors.
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Race and breast cancer survival by intrinsic subtype based on PAM50 gene expression.
Breast Cancer Res. Treat.
PUBLISHED: 02-22-2014
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To evaluate whether differences in PAM50 breast cancer (BC) intrinsic (Luminal A, Luminal B, Basal-like, and HER2-enriched) subtypes help explain the Black-White BC survival disparity. Utilizing a stratified case-cohort design, this study included 1,635 women from the Pathways and Life After Cancer Epidemiology cohorts, selecting women with tumors based upon IHC classification, recurrences, and deaths.One millimeter punches were obtained from tumor tissue, and expression of the PAM50 genes for molecular subtype was determined by RT-qPCR of extracted RNA. Cox proportional hazards models were used to analyze associations between race and BC outcomes, adjusted for PAM50 BC subtype. All tests of statistical significance were two-sided. Black women had a higher prevalence of the Basal-like BC subtype. Adjusted for potential confounding variables and disease characteristics at diagnosis, Black women had higher risks of recurrence (HR 1.65, 95 % CI 1.06-2.57) and breast cancer-specific mortality (HR 1.71, 95 % CI 1.02-2.86) than White women, but adjusting further for subtype did not attenuate survival disparities. By contrast, Hispanic women had a lower risk of recurrence (HR 0.54, 95 % CI 0.30-0.96) than Whites. Among those with the Basal-like subtype, Black women had a similar recurrence risk as women in other race groups but a higher recurrence risk for all other subtypes. Hispanic women had a lower recurrence risk within each subtype, though associations were not significant, given limited power. Although Black women had a higher risk of the Basal-like subtype, which has poor prognosis, this did not explain the Black-White BC survival disparity.
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Estimating the heritability of colorectal cancer.
Hum. Mol. Genet.
PUBLISHED: 02-21-2014
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A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 × 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 × 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.
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Intrinsic subtypes from the PAM50 gene expression assay in a population-based breast cancer survivor cohort: prognostication of short- and long-term outcomes.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-12-2014
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The PAM50, a gene expression assay to categorize breast tumors into intrinsic subtypes, has not been previously used to examine short- and long-term prognostication in a population-based cohort where treatment patterns and time of initial follow-up vary.
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Better postdiagnosis diet quality is associated with reduced risk of death among postmenopausal women with invasive breast cancer in the women's health initiative.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-03-2014
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Few studies have evaluated whether adherence to dietary recommendations is associated with mortality among cancer survivors. In breast cancer survivors, we examined how postdiagnosis Healthy Eating Index (HEI)-2005 scores were associated with all-cause and cause-specific mortality.
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Effects of physical activity and sedentary time on the risk of heart failure.
Circ Heart Fail
PUBLISHED: 01-23-2014
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Although the benefits of physical activity for risk of coronary heart disease are well established, less is known about its effects on heart failure (HF). The risk of prolonged sedentary behavior on HF is unknown.
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A pragmatic cluster randomized clinical trial of diabetes prevention strategies for women with gestational diabetes: design and rationale of the Gestational Diabetes' Effects on Moms (GEM) study.
BMC Pregnancy Childbirth
PUBLISHED: 01-15-2014
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Women with gestational diabetes (GDM) are at high risk of developing diabetes later in life. After a GDM diagnosis, women receive prenatal care to control their blood glucose levels via diet, physical activity and medications. Continuing such lifestyle skills into early motherhood may reduce the risk of diabetes in this high risk population. In the Gestational Diabetes' Effects on Moms (GEM) study, we are evaluating the comparative effectiveness of diabetes prevention strategies for weight management designed for pregnant/postpartum women with GDM and delivered at the health system level.
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Lifetime Cigarette Smoking and Breast Cancer Prognosis in the After Breast Cancer Pooling Project.
J. Natl. Cancer Inst.
PUBLISHED: 12-07-2013
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There is controversy on whether former smokers have increased risk for breast cancer recurrence or all-cause mortality, regardless of how much they smoked.
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Obesity and mortality after breast cancer by race/ethnicity: the california breast cancer survivorship consortium.
Am. J. Epidemiol.
PUBLISHED: 10-09-2013
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We investigated body size and survival by race/ethnicity in 11,351 breast cancer patients diagnosed from 1993 to 2007 with follow-up through 2009 by using data from questionnaires and the California Cancer Registry. We calculated hazard ratios and 95% confidence intervals from multivariable Cox proportional hazard model-estimated associations of body size (body mass index (BMI) (weight (kg)/height (m)(2)) and waist-hip ratio (WHR)) with breast cancer-specific and all-cause mortality. Among 2,744 ascertained deaths, 1,445 were related to breast cancer. Being underweight (BMI <18.5) was associated with increased risk of breast cancer mortality compared with being normal weight in non-Latina whites (hazard ratio (HR) = 1.91, 95% confidence interval (CI): 1.14, 3.20), whereas morbid obesity (BMI ?40) was suggestive of increased risk (HR = 1.43, 95% CI: 0.84, 2.43). In Latinas, only the morbidly obese were at high risk of death (HR = 2.26, 95% CI: 1.23, 4.15). No BMI-mortality associations were apparent in African Americans and Asian Americans. High WHR (quartile 4 vs. quartile 1) was associated with breast cancer mortality in Asian Americans (HR = 2.21, 95% CI: 1.21, 4.03; P for trend = 0.01), whereas no associations were found in African Americans, Latinas, or non-Latina whites. For all-cause mortality, even stronger BMI and WHR associations were observed. The impact of obesity and body fat distribution on breast cancer patients risk of death may vary across racial/ethnic groups.
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Genetic predictors of circulating 25-hydroxyvitamin d and risk of colorectal cancer.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 08-27-2013
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Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D.
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Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia.
Gut
PUBLISHED: 08-09-2013
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Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer.
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Menopausal quality of life: RCT of yoga, exercise, and omega-3 supplements.
Am. J. Obstet. Gynecol.
PUBLISHED: 07-25-2013
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The purpose of this study was to determine the efficacy of 3 nonhormonal therapies for the improvement of menopause-related quality of life in women with vasomotor symptoms.
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Postdiagnosis cruciferous vegetable consumption and breast cancer outcomes: a report from the After Breast Cancer Pooling Project.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 06-13-2013
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Cruciferous vegetables are a major source of glucosinolate-derived bioactive compounds such as isothiocyanates, which have been shown in animal and in vitro studies to inhibit cancer growth and progression. Few studies have investigated cruciferous vegetable intake after diagnosis and breast cancer outcomes. Using data from the After Breast Cancer Pooling Project, which includes prospective data from U.S. and Chinese breast cancer survivors, we evaluated the association of cruciferous vegetables with breast cancer outcomes. Analyses included 11,390 women diagnosed with stage I-III invasive breast cancer (1990-2006) from four cohorts. Cruciferous vegetable intake (g/day) was assessed using food frequency questionnaires (mean of 22 months postdiagnosis). Study heterogeneity was evaluated by the Q statistic; hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using delayed-entry Cox regression models stratified by study. After a median follow-up of 9.0 years, 1,725 deaths and 1,421 recurrences were documented. In pooled analyses using study-specific quartiles, cruciferous vegetable intake was not associated with breast cancer outcomes, adjusting for known clinical prognostic factors and selected lifestyle factors. HRs (95% CIs) by increasing quartiles (reference = lowest quartile) were 1.08 (0.93-1.25), 1.01 (0.87-1.18), and 1.10 (0.95-1.28) for recurrence (P(trend) = 0.34) and 1.01 (0.88-1.15), 0.97 (0.84-1.11), and 0.99 (0.86-1.13) for total mortality (P(trend) = 0.84). No associations were observed for subgroups defined by estrogen receptor status, stage, or tamoxifen therapy. Cruciferous vegetable intake at approximately two years after diagnosis was not associated with recurrence or mortality. Our results do not support an association between postdiagnosis cruciferous vegetable intake and breast cancer outcomes.
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Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project.
Breast Cancer Res. Treat.
PUBLISHED: 04-22-2013
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Vitamin supplement use after breast cancer diagnosis is common, but little is known about long-term effects on recurrence and survival. We examined postdiagnosis supplement use and risk of death or recurrence in the After Breast Cancer Pooling Project, a consortium of four cohorts of 12,019 breast cancer survivors from the United States and China. Post-treatment supplement use (vitamins A, B, C, D, E, and multivitamins) was assessed 1-5 years postdiagnosis. Associations with risk of recurrence, breast cancer-specific mortality, or total mortality were analyzed in Cox proportional hazards models separately by cohort. Individual cohort results were combined using random effects meta-analysis. Interactions with smoking, treatment, and hormonal status were examined. In multivariate models, vitamin E was associated with a decreased risk of recurrence (RR: 0.88; 95 % CI 0.79-0.99), and vitamin C with decreased risk of death (RR: 0.81; 95 % CI 0.72-0.92). However, when supplements were mutually adjusted, all associations were attenuated. There were no statistically significant associations with breast cancer mortality. The use of antioxidant supplements (multivitamins, vitamin C, or E) was not associated with recurrence, but was associated with a 16 % decreased risk of death (95 % CI 0.72-0.99). In addition, vitamin D was associated with decreased risk of recurrence among ER positive, but not ER negative tumors (p-interaction = 0.01). In this large consortium of breast cancer survivors, post-treatment use of vitamin supplements was not associated with increased risk of recurrence or death. Post-treatment use of antioxidant supplements was associated with improved survival, but the associations with individual supplement were difficult to determine. Stratification by ER status and considering antioxidants as a group may be more clinically relevant when evaluating associations with cancer risk and mortality.
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High- and low-fat dairy intake, recurrence, and mortality after breast cancer diagnosis.
J. Natl. Cancer Inst.
PUBLISHED: 03-14-2013
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Dietary fat in dairy is a source of estrogenic hormones and may be related to worse breast cancer survival. We evaluated associations between high- and low-fat dairy intake, recurrence, and mortality after breast cancer diagnosis.
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Social networks, social support mechanisms, and quality of life after breast cancer diagnosis.
Breast Cancer Res. Treat.
PUBLISHED: 03-06-2013
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We examined mechanisms through which social relationships influence quality of life (QOL) in breast cancer survivors. This study included 3,139 women from the Pathways Study who were diagnosed with breast cancer from 2006 to 2011 and provided data on social networks (the presence of a spouse or intimate partner, religious/social ties, volunteering, and numbers of close friends and relatives), social support (tangible support, emotional/informational support, affection, positive social interaction), and QOL, measured by the FACT-B, approximately 2 months post diagnosis. We used logistic models to evaluate associations between social network size, social support, and lower versus higher than median QOL scores. We further stratified by stage at diagnosis and treatment. In multivariate-adjusted analyses, women who were characterized as socially isolated had significantly lower FACT-B (OR = 2.18, 95 % CI: 1.72-2.77), physical well-being (WB) (OR = 1.61, 95 % CI: 1.27-2.03), functional WB (OR = 2.08, 95 % CI: 1.65-2.63), social WB (OR = 3.46, 95 % CI: 2.73-4.39), and emotional WB (OR = 1.67, 95 % CI: 1.33-2.11) scores and higher breast cancer symptoms (OR = 1.48, 95 % CI: 1.18-1.87) compared with socially integrated women. Each social network member independently predicted higher QOL. Simultaneous adjustment for social networks and social support partially attenuated associations between social networks and QOL. The strongest mediator and type of social support that was most predictive of QOL outcomes was "positive social interaction." However, each type of support was important depending on outcome, stage, and treatment status. Larger social networks and greater social support were related to higher QOL after a diagnosis of breast cancer. Effective social support interventions need to evolve beyond social-emotional interventions and need to account for disease severity and treatment status.
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COX-1 (PTGS1) and COX-2 (PTGS2) polymorphisms, NSAID interactions, and risk of colon and rectal cancers in two independent populations.
Cancer Causes Control
PUBLISHED: 03-01-2013
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Nonsteroidal anti-inflammatory drugs (NSAIDs) target the prostaglandin H synthase enzymes, cyclooxygenase (COX)-1 and COX-2, and reduce colorectal cancer risk. Genetic variation in the genes encoding these enzymes may be associated with changes in colon and rectal cancer risk and in NSAID efficacy.
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Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia.
Genes Chromosomes Cancer
PUBLISHED: 02-12-2013
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Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation-associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with nonsteroidal anti-inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population-based case-control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had a decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wild type = 5, OR>5/?5 = 0.42, 95% CI 0.20-0.92; P = 0.01). Four SNPs in FLAP (rs17239025), ALOX12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at P ? 0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in ALOXs may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia.
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The California Breast Cancer Survivorship Consortium (CBCSC): prognostic factors associated with racial/ethnic differences in breast cancer survival.
Cancer Causes Control
PUBLISHED: 02-08-2013
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Racial/ethnic disparities in mortality among US breast cancer patients are well documented. Our knowledge of the contribution of lifestyle factors to disease prognosis is based primarily on non-Latina Whites and is limited for Latina, African American, and Asian American women. To address this knowledge gap, the California Breast Cancer Survivorship Consortium (CBCSC) harmonized and pooled interview information (e.g., demographics, family history of breast cancer, parity, smoking, alcohol consumption) from six California-based breast cancer studies and assembled corresponding cancer registry data (clinical characteristics, mortality), resulting in 12,210 patients (6,501 non-Latina Whites, 2,060 African Americans, 2,032 Latinas, 1,505 Asian Americans, 112 other race/ethnicity) diagnosed with primary invasive breast cancer between 1993 and 2007. In total, 3,047 deaths (1,570 breast cancer specific) were observed with a mean (SD) follow-up of 8.3 (3.5) years. Cox proportional hazards regression models were fit to data to estimate hazards ratios (HRs) and 95 % confidence intervals (CIs) for overall and breast cancer-specific mortality. Compared with non-Latina Whites, the HR of breast cancer-specific mortality was 1.13 (95 % CI 0.97-1.33) for African Americans, 0.84 (95 % CI 0.70-1.00) for Latinas, and 0.60 (95 % CI 0.37-0.97) for Asian Americans after adjustment for age, tumor characteristics, and select lifestyle factors. The CBCSC represents a large and racially/ethnically diverse cohort of breast cancer patients from California. This cohort will enable analyses to jointly consider a variety of clinical, lifestyle, and contextual factors in attempting to explain the long-standing disparities in breast cancer outcomes.
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African American race but not genome-wide ancestry is negatively associated with atrial fibrillation among postmenopausal women in the Womens Health Initiative.
Am. Heart J.
PUBLISHED: 02-05-2013
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Atrial fibrillation (AF) is the most common arrhythmia in women and is associated with higher rates of stroke and death. Rates of AF are lower in African American subjects compared with European Americans, suggesting European ancestry could contribute to AF risk.
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Phospholipase A2G1B polymorphisms and risk of colorectal neoplasia.
Int J Mol Epidemiol Genet
PUBLISHED: 01-01-2013
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Pancreatic phospholipase A2, product of PLA2G1B, catalyzes the release of fatty acids from dietary phospholipids.Diet is the ultimate source of arachidonic acid in cellular phospholipids, precursor of eicosanoid signaling molecules, linked to inflammation, cell proliferation and colorectal carcinogenesis. We evaluated the association of PLA2G1B tagging single-nucleotide polymorphisms with colorectal neoplasia risk. A linkage-disequilibrium-based tagSNP algorithm (r(2)=0.90, MAF?4%) identified three tagSNPs. The SNPs were genotyped on the Illumina platform in three population-based, case-control studies: colon cancer (1424 cases/1780 controls); rectal cancer (583/775); colorectal adenomas (485/578). Evaluating gene-wide associations, principal-component and haplotype analysis were conducted, individual SNPs were evaluated by logistic regression. Two PLA2G1B variants were statistically significantly associated with reduced risk of rectal cancer (rs5637, 3702 G>A Ser98Ser, p-trend=0.03; rs9657930, 1593 C>T, p-trend=0.01); principal component analysis showed that genetic variation in the gene overall was statistically significantly associated with rectal cancer (p=0.02). NSAID users with the rs2070873 variant had a reduced rectal cancer risk (P-inter=0.02). Specific associations were observed with tumor subtypes (TP53/KRAS). The results suggest that genetic polymorphisms in PLA2G1B affect susceptibility to rectal cancer.
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Pre-diagnosis body mass index and survival after breast cancer in the After Breast Cancer Pooling Project.
Breast Cancer Res. Treat.
PUBLISHED: 12-01-2011
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Obese and underweight women who develop breast cancer may have poorer survival compared with normal-weight women. However, the optimal weight for best prognosis is still under study. We conducted a prospective investigation of pre-diagnosis body mass index (BMI) and mortality among 14,948 breast cancer patients in the After Breast Cancer Pooling Project. Breast cancer patients diagnosed from 1990 to 2006 with AJCC Stage I-III breast tumors were drawn from four prospective cohorts. Hazard ratios (HR) and 95% confidence intervals (CI) representing the associations of BMI categories (World Health Organization international classifications) with recurrence and mortality were estimated using delayed entry Cox proportional hazards models. Obese (30 to < 35 kg/m(2)), severely obese (35 to < 40 kg/m(2)), and morbidly obese (? 40 kg/m(2)) were examined. After a mean follow-up of 7.8 years, 2,140 deaths and 2,065 recurrences were documented. Both underweight (HR = 1.59; 95% CI: 1.18, 2.13) and morbidly obese women (HR = 1.81; 95% CI: 1.42, 2.32) had the greatest risk of overall mortality compared with normal weight (18.5-24.9 kg/m(2)) women. Severe obesity (HR = 1.09; 95% CI: 0.88, 1.36) and obesity (HR = 1.11; 95% CI: 0.97, 1.27) were related to small non-significant increased risks. Overweight (25.0-29.9 kg/m(2)) was not associated with any excess risk compared with normal weight. Similar associations were found for breast cancer death and non-breast cancer death but not recurrence. Women who were underweight and morbidly obese before breast cancer diagnosis were at the greatest risk of all-cause mortality. Morbidly obese women were also at increased risk of death from breast cancer. These results suggest that degree of obesity confers differential risk on survival.
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Diet and colorectal cancer: analysis of a candidate pathway using SNPS, haplotypes, and multi-gene assessment.
Nutr Cancer
PUBLISHED: 10-14-2011
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There is considerable biologic plausibility to the hypothesis that genetic variability in pathways involved in insulin signaling and energy homeostasis may modulate dietary risk associated with colorectal cancer. We utilized data from 2 population-based case-control studies of colon (n = 1,574 cases, 1,970 controls) and rectal (n = 791 cases, 999 controls) cancer to evaluate genetic variation in candidate SNPs identified from 9 genes in a candidate pathway: PDK1, RP6KA1, RPS6KA2, RPS6KB1, RPS6KB2, PTEN, FRAP1 (mTOR), TSC1, TSC2, Akt1, PIK3CA, and PRKAG2 with dietary intake of total energy, carbohydrates, fat, and fiber. We employed SNP, haplotype, and multiple-gene analysis to evaluate associations. PDK1 interacted with dietary fat for both colon and rectal cancer and with dietary carbohydrates for colon cancer. Statistically significant interaction with dietary carbohydrates and rectal cancer was detected by haplotype analysis of PDK1. Evaluation of dietary interactions with multiple genes in this candidate pathway showed several interactions with pairs of genes: Akt1 and PDK1, PDK1 and PTEN, PDK1 and TSC1, and PRKAG2 and PTEN. Analyses show that genetic variation influences risk of colorectal cancer associated with diet and illustrate the importance of evaluating dietary interactions beyond the level of single SNPs or haplotypes when a biologically relevant candidate pathway is examined.
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Meeting the physical activity guidelines and survival after breast cancer: findings from the after breast cancer pooling project.
Breast Cancer Res. Treat.
PUBLISHED: 08-31-2011
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The 2008 Physical Activity (PA) Guidelines recommend engaging in at least 2.5 h (10 MET-hours/week) of moderate intensity PA per week (defined as 4 METs) to reduce risk of morbidity and mortality. This analysis was conducted to investigate whether this recommendation can be extended to breast cancer survivors. Data from four studies of breast cancer survivors measuring recreational PA from semi-quantitative questionnaires a median of 23 months post-diagnosis (interquartile range 18-32 months) were pooled in the After Breast Cancer Pooling Project (n = 13,302). Delayed entry Cox proportional hazards models were applied in data analysis with adjustment for age, post-diagnosis body mass index, race/ethnicity, menopausal status, TNM stage, cancer treatment, and smoking history. Engaging in at least 10 MET-hours/week of PA was associated with a 27% reduction in all-cause mortality (n = 1,468 events, Hazard Ratio (HR) = 0.73, 95% CI, 0.66-0.82) and a 25% reduction in breast cancer mortality (n = 971 events, HR = 0.75, 95% CI 0.65-0.85) compared with women who did not meet the PA Guidelines (<10 MET-hours/week). Risk of breast cancer recurrence (n = 1,421 events) was not associated with meeting the PA Guidelines (HR = 0.96, 95% CI, 0.86-1.06). These data suggest that adhering to the PA guidelines may be an important intervention target for reducing mortality among breast cancer survivors.
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The effect of calcium plus vitamin D on risk for invasive cancer: results of the Womens Health Initiative (WHI) calcium plus vitamin D randomized clinical trial.
Nutr Cancer
PUBLISHED: 07-20-2011
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In the Womens Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.
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Genetic variability in EGFR, Src and HER2 and risk of colorectal adenoma and cancer.
Int J Mol Epidemiol Genet
PUBLISHED: 07-17-2011
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The EGFR signaling pathway is involved in carcinogenesis at multiple sites, particularly colorectal cancer, and is a target of colorectal cancer chemotherapy. EGFR signaling is linked to pro-carcinogenic mechanisms, including cell proliferation, survival, angiogenesis, and more recently prostaglandin synthesis. Genetic variability in this pathway has not yet been studied in relation to colorectal carcinogenesis. In three case-control studies of colorectal adenoma (n=485 cases/578 controls), colon cancer (n=1424 cases/1780 controls) and rectal cancer (n=583 cases/775 controls), we investigated associations between candidate SNPs, tagSNPs and haplotypes in EGFR signaling (EGFR, Src, and HER2) and risk. We also examined associations with tumor subtypes: TP53 and KRAS2 mutations, CpG island methylator phenotype, and microsatellite instability. All three studies were genotyped using an identical Illumina GoldenGate assay, allowing thorough investigation of genetic variability across stages and locations of colorectal neoplasia. The EGFR tagSNP 142572T>C (rs3752651) CC genotype was associated with a suggested increased risk for both colon (OR: 1.40; 95% CI: 1.00-1.96; p-trend=0.04) and rectal cancer (OR: 1.39; 95% CI: 0.81-2.41; p-trend=0.65). In tumor subtype analyses, the association was limited to TP53-mutated colon tumors. Using the Chatterjee 1 df Tukey test to assess gene-gene interactions, we observed a statistically significant (p<0.01) interaction between SNPs in EGFR and Src for colorectal adenoma risk. The association with EGFR 142572 should be investigated in additional studies and the significant gene-gene interaction between EGFR and Src in relation to adenoma risk suggests that these two genes are jointly affecting early stages in colorectal carcinogenesis and requires further follow-up.
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Evaluation and comparison of food records, recalls, and frequencies for energy and protein assessment by using recovery biomarkers.
Am. J. Epidemiol.
PUBLISHED: 07-15-2011
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The food frequency questionnaire approach to dietary assessment is ubiquitous in nutritional epidemiology research. Food records and recalls provide approaches that may also be adaptable for use in large epidemiologic cohorts, if warranted by better measurement properties. The authors collected (2007-2009) a 4-day food record, three 24-hour dietary recalls, and a food frequency questionnaire from 450 postmenopausal women in the Womens Health Initiative prospective cohort study (enrollment, 1994-1998), along with biomarkers of energy and protein consumption. Through comparison with biomarkers, the food record is shown to provide a stronger estimate of energy and protein than does the food frequency questionnaire, with 24-hour recalls mostly intermediate. Differences were smaller and nonsignificant for protein density. Food frequencies, records, and recalls were, respectively, able to "explain" 3.8%, 7.8%, and 2.8% of biomarker variation for energy; 8.4%, 22.6%, and 16.2% of biomarker variation for protein; and 6.5%, 11.0%, and 7.0% of biomarker variation for protein density. However, calibration equations that include body mass index, age, and ethnicity substantially improve these numbers to 41.7%, 44.7%, and 42.1% for energy; 20.3%, 32.7%, and 28.4% for protein; and 8.7%, 14.4%, and 10.4% for protein density. Calibration equations using any of the assessment procedures may yield suitable consumption estimates for epidemiologic study purposes.
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The After Breast Cancer Pooling Project: rationale, methodology, and breast cancer survivor characteristics.
Cancer Causes Control
PUBLISHED: 06-17-2011
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The After Breast Cancer Pooling Project was established to examine the role of physical activity, adiposity, dietary factors, supplement use, and quality of life (QOL) in breast cancer prognosis. This paper presents pooled and harmonized data on post-diagnosis lifestyle factors, clinical prognostic factors, and breast cancer outcomes from four prospective cohorts of breast cancer survivors (three US-based and one from Shanghai, China) for 18,314 invasive breast cancer cases diagnosed between 1976 and 2006. Most participants were diagnosed with stage I-II breast cancer (84.7%). About 60% of breast tumors were estrogen receptor (ER)+/progesterone receptor (PR)+; 21% were ER-/PR-. Among 8,118 participants with information on HER-2 tumor status, 74.8% were HER-2- and 18.5% were HER-2+. At 1-2 years post-diagnosis (on average), 17.9% of participants were obese (BMI ? 30 kg/m2), 32.6% were overweight (BMI 25-29 kg/m2), and 59.9% met the 2008 Physical Activity Guidelines for Americans (? 2.5 h per week of moderate activity). During follow-up (mean = 8.4 years), 3,736 deaths (2,614 from breast cancer) and 3,564 recurrences have been documented. After accounting for differences in year of diagnosis and timing of post-diagnosis enrollment, five-year overall survival estimates were similar across cohorts. This pooling project of 18,000 breast cancer survivors enables the evaluation of associations of post-diagnosis lifestyle factors, QOL, and breast cancer outcomes with an adequate sample size for investigation of heterogeneity by hormone receptor status and other clinical predictors. The project sets the stage for international collaborations for the investigation of modifiable predictors for breast cancer outcomes.
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Genetic variability in IL23R and risk of colorectal adenoma and colorectal cancer.
Cancer Epidemiol
PUBLISHED: 05-11-2011
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Inflammatory processes, including, specifically, the inflammatory conditions Crohns disease (CD) and ulcerative colitis (UC) predispose to colorectal cancer. Interleukin-23 is involved in pro-inflammatory signaling; genetic variation in the interleukin-23 receptor (IL23R) has been consistently associated with CD and UC risk. In three case-control studies of colorectal adenoma (n=485 cases/578 controls), colon cancer (n=1424 cases/1780 controls) and rectal cancer (n=583 cases/775 controls), we investigated associations with 18 candidate and tagSNPs in IL23R. The three studies used an identical Illumina GoldenGate assay, allowing thorough investigation across stages and locations of colorectal neoplasia. We further explored associations with molecular cancer subtypes (MSI+, CIMP+, KRAS2mut, TP53mut). In this comprehensive study of genetic variability in IL23R across the spectrum of colorectal carcinogenesis, as well as within colon and rectal tumor molecular subtypes, we observed associations between SNPs in IL23R and risk of rectal cancer: the 88413 C>A (rs10889675) and 69450 C>A (rs7542081) polymorphisms were associated with decreased rectal cancer risk overall (p-trend=0.04 and 0.05 respectively), and specifically with rectal tumors bearing a TP53 mutation (88413 CA/AA vs. CC OR: 0.66; 95% CI: 0.46-94; 69450 CA/AA vs. CC OR: 0.60; 95% CI: 0.37-0.98). However, none of associations remained statistically significant after correction for multiple testing. These data provide some evidence that genetic variability in IL23R may contribute to rectal cancer risk and should be evaluated in additional studies.
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Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
Cancer
PUBLISHED: 04-21-2011
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There is concern that antioxidant supplement use during chemotherapy and radiation therapy may decrease treatment effects, yet the effects of such supplements on recurrence and survival are largely unknown.
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Meta-analysis of new genome-wide association studies of colorectal cancer risk.
Hum. Genet.
PUBLISHED: 04-18-2011
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Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.
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Nutrients in folate-mediated, one-carbon metabolism and the risk of rectal tumors in men and women.
Nutr Cancer
PUBLISHED: 04-05-2011
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In an investigation of rectal tumors characterized by CpG island methylator phenotype (CIMP), KRAS2 mutation, and TP53 mutation, we examined associations with dietary and supplemental folate, riboflavin, vitamins B(6) and B(12), and methionine, nutrients involved in folate-mediated 1-carbon metabolism. We also examined folate intake and common MTHFR polymorphisms in relation to CIMP. Data from a population-based study of 951 cases (750 with tumor markers) and 1,205 controls were evaluated using multiple logistic regression models and generalized estimating equations. Reduced risk of methylated tumors was suggested in women with the upper tertile of folate intake (?0.42 mg/day) vs. the lower tertile: OR = 0.6, 95%CI = 0.3-1.2. In men, a significant 3-fold increased risk of CIMP+ tumor was observed for the upper tertile of folate (?0.75 mg/day) vs. the lower tertile (<0.44 mg/day): OR = 3.2, 95%CI = 1.5-6.7. These men consumed a greater proportion of folic acid fortified foods relative to natural, primarily plant-based sources (52% vs. 48%) than women with CIMP+ tumors (22% vs. 78%). MTHFR 1298A>C influenced folate in male CIMP+ risk (P interaction < 0.01). Our findings suggest folate supplementation effects may differ between genders, perhaps due to variation in MTHFR and/or endogenous/exogenous hormones, and may be important in the initiation and progression of methylated rectal tumors in men.
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Multivitamin use and breast cancer outcomes in women with early-stage breast cancer: the Life After Cancer Epidemiology study.
Breast Cancer Res. Treat.
PUBLISHED: 04-01-2011
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Little is known about the relation of multivitamin use to breast cancer outcomes. 2,236 women diagnosed from 1997 to 2000 with early-stage breast cancer (Stage I ? 1 cm, II, or IIIA) were enrolled about 2 years post-diagnosis, primarily from the Kaiser Permanente Northern California Cancer Registry (83%). Multivitamin use pre-diagnosis and post-diagnosis was assessed via mailed questionnaire. Outcomes were ascertained yearly by self-report and verified by medical record review. Delayed-entry Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for sociodemographic, tumor, and lifestyle factors. Overall, 54 and 72% of the cohort reported using multivitamins pre- and post-diagnosis, respectively. A total of 380 recurrences, 212 breast cancer deaths, and 396 total deaths were confirmed. Compared to never use, multivitamin use after diagnosis was not associated with any outcome (recurrence HR = 0.92; 95% CI: 0.71, 1.20; total mortality HR = 0.92; 95% CI: 0.71, 1.19). Compared to never use, persistent use of multivitamins from pre- to post-diagnosis was associated with a non-significant decreased risk of recurrence (HR = 0.76; 95% CI: 0.54, 1.06) and total mortality (HR = 0.79; 95% CI: 0.56, 1.12). The protective associations were limited to women who had been treated by radiation only (P for trend = 0.048 and 0.083 for recurrence and total mortality, respectively) and both radiation and chemotherapy (P for trend = 0.015 and 0.095 for recurrence and total mortality, respectively). In stratified analyses, women who consistently used multivitamins before and after diagnosis and ate more fruits/vegetables (P for trend = 0.008) and were more physically active (P for trend = 0.034) had better overall survival. Multivitamin use along with practice of other health-promoting behaviors may be beneficial in improving breast cancer outcomes in select groups of survivors.
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Examining the influence of beta blockers and ACE inhibitors on the risk for breast cancer recurrence: results from the LACE cohort.
Breast Cancer Res. Treat.
PUBLISHED: 04-01-2011
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There is increasing interest in the relationship between host lifestyle factors and the outcomes of cancer treatment. Behavioral factors, comorbid conditions, and non-cancer-related pharmaceutical exposures may affect breast cancer (BC) outcomes. We used observational data from the LACE Study cohort (women with early stage BC from the Kaiser Permanente Northern California Cancer Registry) to examine the association between beta blockers (BBs) and/or angiotensin-converting enzyme inhibitors (ACEi) and BC recurrence, BC-specific mortality, and overall mortality. Among 1,779 women, there were 292 BC recurrences, 174 BC deaths, and 323 total deaths. 23% were exposed to either a BB and/or an ACEi. These drugs were associated with older age, postmenopausal status, tamoxifen therapy, greater pre-diagnosis BMI, hypertension, and diabetes. In Cox proportional hazards models, ACEi exposure was associated with BC recurrence (HR 1.56, 95% CI 1.02, 2.39, P = 0.04), but not cause-specific or overall mortality. Combined ACEi and BB were associated with overall mortality (HR 1.94, 95% CI 1.22, 3.10, P = 0.01). BB exposure was associated with lower hazard of recurrence and cause-specific mortality. However, there was no evidence of a dose response with either medication. For recurrence and cause-specific mortality, BB combined with ACEi was associated with a lower HR for the outcome than when ACEi alone was used. These hypothesis generating findings suggest that BC recurrence and survival were associated with exposure to two commonly used classes of anti-hypertensive medications. These observations need to be confirmed and suggest that greater attention should focus on the potential role of these commonly used medications in BC outcomes.
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Variation in the CYP19A1 gene and risk of colon and rectal cancer.
Cancer Causes Control
PUBLISHED: 03-31-2011
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CYP19A1, or aromatase, influences estrogen-metabolizing enzymes and may influence cancer risk. We examine variation in the CYP19A1 gene and risk of colorectal cancer using data from population-based case-control studies (colon n = 1,574 cases, 1,970 controls; rectal n = 791 cases, 999 controls). Four SNPs were statistically significantly associated with colon cancer and four were associated with rectal cancer. After adjustment for multiple comparisons, the AA genotype of rs12591359 was associated with an increased risk of colon cancer (OR 1.44 95% CI 1.16-1.80) and the AA genotype of rs2470144 was associated with a reduced risk of rectal cancer (OR 0.65 95% CI 0.50-0.84). Variants of CYP19A1 were associated with CIMP+ and CIMP+/KRAS2-mutated tumors. CT/TT genotypes of rs1961177 were significantly associated with an increased likelihood of a MSI+ colon tumor (OR 1.77 95% CI 1.26-2.37). We observed statistically significant interactions between genetic variation in NF?B1 and CYP19A1 for both colon and rectal cancer. Our data suggest the importance of CYP19A1 in the development of colon and rectal cancer and that estrogen may influence risk through an inflammation-related mechanism.
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Genetic variation in bone morphogenetic protein and colon and rectal cancer.
Int. J. Cancer
PUBLISHED: 03-14-2011
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Bone morphogenetic proteins (BMP) are part of the TGF-?-signaling pathway; genetic variation in these genes may be involved in colorectal cancer. In this study, we evaluated the association between genetic variation in BMP1 (11 tagSNPs), BMP2 (5 tagSNPs), BMP4 (3 tagSNPs), BMPR1A (9 tagSNPs), BMPR1B (21 tagSNPs), BMPR2 (11 tagSNPs) and GDF10 (7 tagSNPs) with risk of colon and rectal cancer and tumor molecular phenotype. We used data from population-based case-control studies (colon cancer n = 1,574 cases, 1,970 controls; rectal cancer n = 791 cases, 999 controls). We observed that genetic variation in BMPR1A, BMPR1B, BMPR2, BMP2 and BMP4 was associated with risk of developing colon cancer, with 20 to 30% increased risk for most high-risk genotypes. A summary of high-risk genotypes showed over a twofold increase in colon cancer risk at the upper risk category (OR = 2.49 95% CI = 1.95, 3.18). BMPR2, BMPR1B, BMP2 and GDF10 were associated with rectal cancer. BMPR2 rs2228545 was associated with an almost twofold increased risk of rectal cancer. The risk associated with the highest category of the summary score for rectal cancer was 2.97 (95% CI = 1.87, 4.72). Genes in the BMP-signaling pathway were consistently associated with CIMP+ status in combination with both KRAS-mutated and MSI tumors. BMP genes interacted statistically significantly with other genes in the TGF-?-signaling pathway, including TGF?1, TGF?R1, Smad 3, Smad 4 and Smad 7. Our data support a role for genetic variation in BMP-related genes in the etiology of colon and rectal cancer. One possible mechanism is via the TGF-?-signaling pathway.
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Soy food consumption and breast cancer prognosis.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-25-2011
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Contrary to earlier clinical studies suggesting that soy may promote breast tumor growth, two recent studies show that soy-containing foods are not adversely related to breast cancer prognosis. We examined, using data from the Womens Healthy Eating and Living (WHEL) study, the effect of soy intake on breast cancer prognosis.
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Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial.
JAMA
PUBLISHED: 01-20-2011
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Concerns regarding the risks associated with estrogen and progesterone to manage menopausal symptoms have resulted in its declining use and increased interest in nonhormonal treatments with demonstrated efficacy for hot flashes.
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Genetic variation in the transforming growth factor-? signaling pathway and survival after diagnosis with colon and rectal cancer.
Cancer
PUBLISHED: 01-12-2011
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The transforming growth factor-? (TGF-?) signaling pathway is involved in many aspects of tumorigenesis, including angiogenesis and metastasis. The authors evaluated this pathway in association with survival after a diagnosis of colon or rectal cancer.
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IGF1 and risk of additional breast cancer in the WHEL study.
Endocr. Relat. Cancer
PUBLISHED: 01-01-2011
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IGF1, IGF-binding protein-3 (IGFBP-3), IGFBP-1, insulin, leptin, and adiponectin have been inconsistently associated with breast cancer incidence. We explore how these factors are related to breast cancer recurrence and how tamoxifen treatment is related to IGF1 levels among breast cancer survivors in the Womens Healthy Eating and Living (WHEL) study. A nested case-control design was used to match breast cancer cases (who had an additional breast cancer event) to controls. Baseline blood samples from 510 matched cases and controls were analyzed for IGF1 levels; a subset of 188 pairs were analyzed for five other hormones and binding proteins. Median follow-up was 7.3 years. Matching was on recruitment site, cancer stage, age at cancer diagnosis, dates of cancer diagnosis, and randomization. Cox proportional hazards regression models, stratified on case-control pair, were used to assess the associations. Insulin, IGFBP-1, IGFBP-3, leptin, and adiponectin did not significantly predict recurrence of breast cancer. IGF1 was positively, but not significantly, associated with recurrence (hazard ratio (HR): 1.33 (95% confidence interval (CI) 0.98-1.81)) in the unadjusted analyses. Adjusting for menopausal status and tamoxifen use attenuated the HR to 1.07 (95% CI 0.76-1.40). Analyses of case-control pairs with discordant tamoxifen use show opposing HR: IGF1 predicts higher risk of recurrence if cases did not receive tamoxifen treatment. In conclusion, no significant association was found between IGF1 levels, or other related factors, and risk of additional breast cancer among breast cancer survivors. Tamoxifen can confound analysis of IGF1 and recurrence. This supports re-evaluating significance of IGF1 to breast cancer recurrence.
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Marine fatty acid intake is associated with breast cancer prognosis.
J. Nutr.
PUBLISHED: 12-22-2010
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EPA and DHA, long-chain (n-3) PUFA largely obtained from fish, inhibit the proliferation of breast cancer cells in vitro and reduce the initiation and progression of breast tumors in laboratory animals. Our purpose in this analysis was to examine whether intake of these marine fatty acids (EPA and DHA) were associated with prognosis in a cohort of women who had been diagnosed and treated for early stage breast cancer (n = 3,081). Median follow-up was 7.3 y. Dietary intake was assessed using 24-h recalls (~4 recalls per dietary assessment obtained at 7 time points over 6 y). Survival models with time-dependent covariates were used to examine the association of repeated measures of dietary intake of EPA and DHA from food (i.e., marine sources) and supplements with disease-free survival and overall survival. Women with higher intakes of EPA and DHA from food had an approximate 25% reduced risk of additional breast cancer events [tertile 2: HR = 0.74 (95% CI = 0.58-0.94); tertile 3: HR = 0.72 (95% CI = 0.57-0.90)] compared with the lowest tertile of intake. Women with higher intakes of EPA and DHA from food had a dose-dependent reduced risk of all-cause mortality [tertile 2: HR = 0.75 (95% CI = 0.55-1.04); tertile 3: HR = 0.59 (95% CI = 0.43-0.82)]. EPA and DHA intake from fish oil supplements was not associated with breast cancer outcomes. The investigation indicates that marine fatty acids from food are associated with reduced risk of additional breast cancer events and all-cause mortality.
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Characterization of the association between 8q24 and colon cancer: gene-environment exploration and meta-analysis.
BMC Cancer
PUBLISHED: 12-04-2010
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Genome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with colorectal cancer susceptibility.
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Associations between genetic variation in RUNX1, RUNX2, RUNX3, MAPK1 and eIF4E and riskof colon and rectal cancer: additional support for a TGF-?-signaling pathway.
Carcinogenesis
PUBLISHED: 11-18-2010
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The Runt-related transcription factors (RUNX), mitogen-activated protein kinase (MAPK) 1 and eukaryotic translation initiation factor 4E (eIF4E) are potentially involved in tumorigenesis. We evaluated genetic variation in RUNX1 (40 tagSNPs), RUNX2 (19 tagSNPs), RUNX3 (9 tagSNPs), MAPK1 (6 tagSNPs), eIF4E (3 tagSNPs), eIF4EBP2 (2 tagSNP) and eIF4EBP3 (2 tagSNPs) to determine associations with colorectal cancer (CRC). We used data from population-based studies (colon cancer n = 1555 cases, 1956 controls; rectal cancer n = 754 cases, 959 controls with complete genotype data). Four statistically significant tagSNPs were identified with colon cancer and three tagSNPs were identified with rectal cancer. Whereas the independent risk estimates for each of the tagSNPs ranged from 1.21 to 1.52, the combined risk was greater than additive for any of the three combined high-risk genotypes {combined risk range 1.98 [95% confidence interval (CI) 1.45, 2.70] for eIF4E, RUNX1 and RUNX3 to 3.32 [95% CI 1.34, 8.23] for eIF43, RUNX2 and RUNX3}. For rectal cancer, the strongest association was detected for the combined genotype of RUNX1 and RUNX3 (odds ratio 1.87 95% CI 1.22, 2.87). Associations with specific molecular tumor phenotypes showed consistent and strong associations for CIMP+/MSI+ tumors where the risk estimates were consistently >10-fold and lower confidence bounds were over 3.00 for high-risk genotypes defined by RUNX1, RUNX2 and RUNX3. For CIMP+/KRAS2-mutated colon tumors, the combined risk for high-risk genotypes of RUNX2, eIF4E and RUNX1 was 7.47 (95% CI 1.58, 35.3). Although the associations need confirmation, the findings and their internal consistency underline the importance of genetic variation in these genes for the etiology of CRC.
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Characterization of 9p24 risk locus and colorectal adenoma and cancer: gene-environment interaction and meta-analysis.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 10-26-2010
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A potential susceptibility locus for colorectal cancer on chromosome 9p24 (rs719725) was initially identified through a genome-wide association study, though replication attempts have been inconclusive.
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Candidate pathway polymorphisms in one-carbon metabolism and risk of rectal tumor mutations.
Int J Mol Epidemiol Genet
PUBLISHED: 09-22-2010
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We examined candidate polymorphisms in genes involved in the folate-mediated, one-carbon metabolism pathway, DNMT1 1311V, MTHFD1 R134K and R653Q, MTHFR R594Q, MTR D919G, MTRR H595Y and I22M, SHMT1 L474F, SLC19A1 H27R, and TDG G199S, and associations with rectal tumor characteristics. We hypothesized that these candidate genes would influence CpG Island Methylator Phenotype and potentially KRAS2 or TP53 tumors. Data from a population-based study of 747 rectal cases (593 with tumor markers) and 956 controls were evaluated using generalized estimating equations. We observed an increased risk of TP53 tumor mutations in homozygous carriers of the MTHFD1 134K allele (0R=2.0, 95%CI 1.2-3.1, P- trend=0.02). In the presence of low folate intake, the R134K variant was associated with increased risk of CIMP+ tumors (OR=2.8, 95%CI 1.04-7.7). The MTRR I22M variant genotype was associated with a modest increased risk of TP53 mutations (OR=1.7, 95%CI 1.2-2.5, P-trend=0.001). Our findings offer limited support that polymorphisms in one-carbon metabolism genes influence rectal tumor phenotype, and that folate may interact with MTHFD1 to alter CIMP+ risk.
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Alcohol consumption and breast cancer recurrence and survival among women with early-stage breast cancer: the life after cancer epidemiology study.
J. Clin. Oncol.
PUBLISHED: 08-30-2010
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To examine the association of alcohol consumption after breast cancer diagnosis with recurrence and mortality among early-stage breast cancer survivors.
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Red wine consumption not associated with reduced risk of colorectal cancer.
Nutr Cancer
PUBLISHED: 07-28-2010
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Red wine contains polyphenol antioxidants that inhibit colorectal cancer (CRC) development in animal studies. We investigated the effect of red wine intake on risk of CRC in the California Mens Health Study (CMHS). CMHS is a prospective, multiethnic cohort of middle-aged men who were members of the Kaiser Permanente (KP) California Health Plans and completed study questionnaires between 2002-2003. Incident CRC were identified from the health plan cancer registries through the end of 2007 (n = 287). To properly account for potential confounding by previous endoscopy screening, we restricted the primary analyses to CMHS men continuously enrolled in KP between 1998-2002 (n = 43,483 and CRC = 176). We used multivariable Cox regression to adjust for important confounders. We did not find an inverse association between moderate red wine intake and risk of CRC. The hazard ratio for consuming >/=1 drink/day (average = 2 drinks/day) was 1.16, 95% confidence intervals 0.56-2.40. There was no linear dose-response. The lack of clear association for red wine intake was consistently observed when we stratified the analyses by CRC stage at diagnosis and cancer site (colon or rectum). Moderate red wine consumption was not associated with reduced risk of colorectal cancer in this population of middle-aged men.
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Alcohol consumption and rectal tumor mutations and epigenetic changes.
Dis. Colon Rectum
PUBLISHED: 07-15-2010
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An association between alcohol and rectal cancer has been reported in the epidemiological literature. In this study we further explore the association by examining specific tumor markers with alcohol consumption as well as types of alcoholic beverages consumed.
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Genetic variation in C-reactive protein in relation to colon and rectal cancer risk and survival.
Int. J. Cancer
PUBLISHED: 05-03-2010
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C-reactive protein (CRP), a biomarker of inflammation, has been shown to be influenced by genetic variation in the CRP gene. In this study, we test the hypothesis that genetic variation in CRP influences both the risk of developing colon and rectal cancer and survival. Two population-based studies of colon cancer (n = 1,574 cases, 1,970 controls) and rectal (n = 791 cases, 999 controls) were conducted. We evaluated four CRP tagSNPs: rs1205 (G > A, 3 UTR); rs1417938 (T > A, intron); rs1800947 (G > C, L184L); and rs3093075 (C > A, 3 flanking). The CRP rs1205 AA genotype was associated with an increased risk of colon cancer (OR 1.3, 95%CI 1.1-1.7), whereas the rs3093075 A allele was associated with a reduced risk of rectal cancer (OR 0.7, 95%CI 0.5-0.9). The strongest association for the rs1205 polymorphism and colon cancer was observed among those with KRAS2 mutations (OR 1.5, 95%CI 1.1-2.0). The CRP rs1205 AA genotype also was associated with an increased risk of CIMP+ rectal tumors (OR 2.5, 95%CI 1.2-5.3); conversely, the rs1417938 A allele was associated with a reduced risk of CIMP+ rectal tumors (OR 0.5, 95%CI 0.3-0.9). We observed interactions between CRP rs1800947 and BMI and family history of CRC in modifying risk of both colon and rectal cancer. These data suggest that genetic variation in the CRP gene influences risk of both colon and rectal cancer development.
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Calcium, vitamin D, VDR genotypes, and epigenetic and genetic changes in rectal tumors.
Nutr Cancer
PUBLISHED: 05-01-2010
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Calcium, vitamin D, exposure to sunshine, and vitamin D receptor (VDR) genotypes have been associated rectal cancer. We used data from 750 rectal tumors and 1,205 population-based controls examine associations with TP53, KRAS2, and CpG Island methylator phenotype (CIMP) markers. Rectal tumors were associated with high levels of calcium overall and with TP53 tumor mutations specifically (OR = 0.6, 95% CI = 0.42-0.84). High levels of sunshine exposure had a borderline protective effect for TP53 tumor mutations (OR = 0.78, 95% CI = 0.59-1.03). A mutation at codon 248 was significantly associated with dietary calcium intake (OR = 0.26, 95% CI = 0.09-0.77); having the Ff/ff genotypes of the FOK1 VDR polymorphism significantly increased the odds of a mutation at codon 245 (OR = 4.74, 95% CI = 1.05-21.39); high levels of dietary vitamin D (OR = 3.42, 95% CI = 1.15-10.17) and the Ff/ff genotypes of FOK1 (OR = 3.34, 95% CI = 1.11-10.02) and the GA/AA genotypes of the CDX2 VDR polymorphism (OR = 2.85, 95% CI = 1.23-6.58) increased the odds of a TP53 mutation at codon 273. These data support an association between calcium and rectal tumors overall as well as specifically with TP53 mutations. However, given the number of comparisons, findings need to be confirmed in other studies.
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Vegetable intake is associated with reduced breast cancer recurrence in tamoxifen users: a secondary analysis from the Womens Healthy Eating and Living Study.
Breast Cancer Res. Treat.
PUBLISHED: 03-25-2010
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The protective effect of vegetables on the risk of breast cancer recurrence is uncertain. We sought to evaluate the association between breast cancer recurrence and vegetable intake including analyses stratified on tamoxifen use. Experimental evidence of anti-carcinogenic activity of phytochemicals in cruciferous vegetables in combination with tamoxifen led to specific evaluation of this class of vegetables as well. To assess the association between vegetable intake and breast cancer recurrence, vegetable intake from repeat 24-h dietary recalls were examined as a secondary analysis of 3,080 breast cancer survivors enrolled in the Womens Healthy Eating and Living (WHEL) Study. At the time of enrollment women were, on average, 23.5 months post-diagnosis. The hazard of recurrence, controlling for relevant and significant clinical and demographic variables, with vegetable intake was assessed overall and separately for women taking tamoxifen. WHEL participants reported mean baseline intakes (?x, SE) of 3.1 ± 0.05 and 0.5 ± 0.02 servings/day of total and cruciferous vegetables, respectively. Baseline vegetable intake in the highest as compared to lowest tertiles was associated with an overall lower adjusted hazard ratios (HR) for recurrence of 0.69, 95% CI 0.55-0.87. Among women taking tamoxifen, the HRs were 0.56, 95% CI 0.41-0.77 for total vegetables and 0.65, 95% CI 0.47-0.89 for cruciferous vegetable intake. The hazard in women using tamoxifen who reported cruciferous vegetable intake above the median and who were within the highest tertile of total vegetable intake was HR 0.48; 95% CI 0.32-0.70. This secondary analysis in over 3,000 breast cancer survivors suggests that baseline vegetable intake may be associated with a reduction in the risk of breast cancer recurrent or new events particularly for those using tamoxifen. Such associations should be explored further as the possibility that vegetable intake is simply a surrogate for other health-promoting behaviors cannot be ruled out.
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Diet, physical activity, and body size associations with rectal tumor mutations and epigenetic changes.
Cancer Causes Control
PUBLISHED: 03-20-2010
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Diet and lifestyle factors have been inconsistently associated with rectal tumors. It is possible that evaluation of specific tumor markers with these factors may help clarify these associations. In this study, we examine energy contributing nutrients, dietary fiber, BMI (kg/m2), and long-term physical activity with TP53 mutations, KRAS2 mutations, and CpG Island Methylator Phenotype (CIMP) in 750 population-based cases of rectal cancer compared to healthy controls. We observed that high levels of physical activity reduced the risk of having TP53 and KRAS2 rectal tumor mutations. Dairy products rich in fat were associated with an increased risk of CIMP+ tumors (OR 1.88 95% CI 0.92, 3.84), while low-fat dairy products reduced risk of CIMP+ tumors (OR 0.56 95% CI 0.29, 1.09). Omega-3 fatty acids were associated with a twofold increased risk of a CIMP+ tumor. High levels of vegetable intake reduced risk of both TP53 mutations (OR 0.73 95% CI 0.54, 1.00; p trend 0.02) and KRAS2 mutations (OR 0.60 95% CI 0.40, 0.89; p trend <0.01). High intake of whole grains reduced the likelihood of a TP53 mutation (OR 0.74 95% CI 0.56, 0.99), while high intake of refined grains increased the likelihood of a TP53 mutation (OR 1.41 95% CI 1.02, 1.96). Dietary fiber also was associated with reduced risk of TP53 and KRAS2 rectal tumor mutations. Overall, a prudent dietary pattern significantly reduced the likelihood of a KRAS2 tumor mutation (OR 0.68 95% CI 0.47, 0.98; p linear trend 0.03). These data suggest that diet and lifestyle factors are associated with specific types of rectal tumor mutations and epigenetic changes. Findings need confirmation in other studies.
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Low to moderate alcohol intake is not associated with increased mortality after breast cancer.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 02-16-2010
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Both alcohol consumption and obesity have been linked with breast cancer morbidity and mortality. An inverse association between alcohol intake and obesity suggests possible confounding between these variables (and perhaps other factors) with breast cancer outcomes.
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Increased risk of colon cancer associated with a genetic polymorphism of SMAD7.
Cancer Res.
PUBLISHED: 02-02-2010
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Genome-wide association studies (GWAS) have identified SMAD7 on 8q21 as being associated with colorectal cancer. We evaluated single nucleotide polymorphisms (SNP) in the SMAD7 gene, including rs4939827, rs12953717, and rs4464148, previously identified from GWAS in a large population-based case-control study of colon cancer. We observed that rs12953717 was associated with a statistically significant increased risk of colon cancer [odds ratio, 1.38; 95% confidence intervals (CI), 1.13-1.68; P linear trend < 0.01] for the TT genotype compared with the CC genotype, whereas the CC genotype of the rs4939827 SNP was inversely associated with colon cancer (0.77; 95% CI, 0.64-0.93) relative to the TT genotype. There were no significant differences in association for either of these polymorphisms when stratified by age, tumor site, sex, or family history. The odds ratios between SMAD7 and colon cancer among individuals reporting recent aspirin/nonsteroidal anti-inflammatory drug use was 0.60 (95% CI, 0.43-0.85) for the CC genotype of the rs4939827 polymorphism and 1.69 (95% CI, 1.20-2.38) for the TT genotype of the rs1295371 polymorphism. This result compares to odds ratios of 0.86 (95% CI, 0.68-1.09) for rs4939827 and 1.22 (95% CI, 0.96-1.56) among individuals who did not use aspirin/nonsteroidal anti-inflammatory drugs. An assessment of SMAD7 genotypes with tumor markers did not reveal any significant differences by KRAS2, TP53, CpG island methylator phenotype, or microsatellite instability status. No significant associations were observed for the rs4464148 SNP or other SNPs evaluated in the SMAD7. These results corroborate the findings of GWAS in colon cancer pointing to SMAD7 and reinforce interest in SNPs in this gene.
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Migraine history and breast cancer risk among postmenopausal women.
J. Clin. Oncol.
PUBLISHED: 01-25-2010
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PURPOSE Both migraine and breast cancer are hormonally mediated. Two recent reports indicate that women with a migraine history may have a lower risk of postmenopausal breast cancer than those who never suffered migraines. This finding requires confirmation; in particular, an assessment of the influence of use of nonsteroidal anti-inflammatory drugs (NSAID) is needed, because many studies indicate that NSAID use also may confer a reduction in breast cancer risk. METHODS We assessed the relationship between self-reported history of migraine and incidence of postmenopausal breast cancer in 91,116 women enrolled on the Womens Health Initiative Observational Study prospective cohort from 1993 to 1998 at ages 50 to 79 years. Through September 15, 2005, there were 4,006 eligible patients with breast cancer diagnosed. Results Women with a history of migraine had a lower risk of breast cancer (hazard ratio [HR], 0.89; 95% CI, 0.80 to 98) than women without a migraine history. This risk did not vary by recent NSAID use. The lower risk was somewhat more pronounced for invasive estrogen-receptor-positive and progesterone-receptor-positive tumors (HR, 0.83; 95% CI, 0.71 to 0.97), as no reduction in risk was observed for invasive ER-negative/PR-negative tumors (HR, 1.16; 95% CI, 0.86 to 1.57), and this difference in risk estimates was borderline statistically significant (P = .06). CONCLUSION This study supports the hypothesis that a history of migraine is associated with a lower risk of breast cancer and that this relationship is independent of recent NSAID use.
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Prostatitis, sexually transmitted diseases, and prostate cancer: the California Mens Health Study.
PLoS ONE
PUBLISHED: 01-15-2010
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Prostatitis and sexually transmitted diseases (STDs) have been positively associated with prostate cancer in previous case-control studies. However, results from recent prospective studies have been inconclusive. METHODOGY/PRINCIPAL FINDINGS: We investigated the association between prostatitis, STDs, and prostate cancer among African American, Asian American, Latino, and White participants of the California Mens Health Study. Our analysis included 68,675 men, who completed a detailed baseline questionnaire in 2002-2003. We identified 1,658 incident prostate cancer cases during the follow-up period to June 30, 2006. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals. Overall, men having a history of prostatitis had an increased risk of prostate cancer than men with no history (RR = 1.30; 95% CI: 1.10-1.54). Longer duration of prostatitis symptoms was also associated with an increased risk of prostate cancer (P trend = 0.003). In addition, among men screened for prostate cancer (1 or 2 PSA tests), a non-significant positive association was observed between prostatitis and prostate cancer (RR = 1.10; 95% CI: 0.75-1.63). STDs were not associated with overall prostate cancer risk. In racial/ethnic stratified analysis, Latinos reporting any STDs had an increased risk of disease than those with no STDs (RR = 1.43; 95% CI: 1.07-1.91). Interestingly, foreign-born Latinos displayed a larger risk associated with STDs (RR = 1.87; 95% CI: 1.16-3.02) than U.S. born Latinos (RR = 1.15; 95% CI: 0.76-3.02).
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