Cornelia M. Ulrich

Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis

BACKGROUND & AIMSnHeritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.nnnMETHODSnWe conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.nnnRESULTSnBased on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).nnnCONCLUSIONSnIn a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

Meta-analysis of New Genome-wide Association Studies of Colorectal Cancer Risk

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 1.8xa0×xa010−8). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at pxa0<xa00.05 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 7.3xa0×xa010−5). 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 1.9xa0×xa010−4). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.

Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial.

Obese and sedentary persons have increased risk for cancer; inflammation is a hypothesized mechanism. We examined the effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in 439 women. Overweight and obese postmenopausal women were randomized to 1-year: caloric restriction diet (goal of 10% weight loss, N = 118), aerobic exercise (225 min/wk of moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). Baseline and 1-year high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA), interleukin-6 (IL-6), leukocyte, and neutrophil levels were measured by investigators blind to group. Inflammatory biomarker changes were compared using generalized estimating equations. Models were adjusted for baseline body mass index (BMI), race/ethnicity, and age. Four hundred and thirty-eight (N = 1 in diet + exercise group was excluded) were analyzed. Relative to controls, hs-CRP decreased by geometric mean (95% confidence interval, P value): 0.92 mg/L (0.53-1.31, P < 0.001) in the diet and 0.87 mg/L (0.51-1.23, P < 0.0001) in the diet + exercise groups. IL-6 decreased by 0.34 pg/mL (0.13-0.55, P = 0.001) in the diet and 0.32 pg/mL (0.15-0.49, P < 0.001) in the diet + exercise groups. Neutrophil counts decreased by 0.31 × 10(9)/L (0.09-0.54, P = 0.006) in the diet and 0.30 × 10(9)/L (0.09-0.50, P = 0.005) in the diet + exercise groups. Diet and diet + exercise participants with 5% or more weight loss reduced inflammatory biomarkers (hs-CRP, SAA, and IL-6) compared with controls. The diet and diet + exercise groups reduced hs-CRP in all subgroups of baseline BMI, waist circumference, CRP level, and fasting glucose. Our findings indicate that a caloric restriction weight loss diet with or without exercise reduces biomarkers of inflammation in postmenopausal women, with potential clinical significance for cancer risk reduction.

Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Genome-wide association studies (GWAS) have identified more than a dozen loci associated with colorectal cancer (CRC) risk. Here, we examined potential effect-modification between single-nucleotide polymorphisms (SNP) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23), rs6983267 at 8q24 (MYC), rs10795668 at 10p14 (FLJ3802842), rs3802842 at 11q23 (LOC120376), rs4444235 at 14q22.2 (BMP4), rs4779584 at 15q13 (GREM1), rs9929218 at 16q22.1 (CDH1), rs4939827 at 18q21 (SMAD7), rs10411210 at 19q13.1 (RHPN2), and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/nonsteroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal P(interaction) = 1.3 × 10(-4); adjusted P = 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption.

Correlates of circulating C-reactive protein and serum amyloid A concentrations in breast cancer survivors

Introduction Inflammatory status may be an important prognostic factor for breast cancer. Correlates of markers of inflammation in breast cancer survivors have not been thoroughly evaluated. Methods Using data from, the Health, Eating, Activity, and Lifestyle (HEAL) Study (a population-based, multiethnic prospective cohort study of female breast cancer patients) we evaluated the associations between circulating markers of inflammation (C-reactive protein [CRP] and serum amyloid A [SAA], measured ∼31xa0months after diagnosis) and several demographic, lifestyle, and clinical characteristics in 741 disease-free breast cancer survivors. Analysis of variance and regression methods were used for statistical analyses of log-transformed values of CRP and SAA. Results After adjusting for age, BMI, ethnicity, and study site, higher concentrations of CRP were associated with increasing concentration of SAA (P-trendxa0<xa00.0001), increasing age (P-trendxa0<xa00.0001), increasing BMI (P-trendxa0<xa00.0001), increasing waist circumference (P-trendxa0<xa00.0001), positive history of heart failure (Pxa0=xa00.0007), decreasing physical activity (P-trendxa0=xa00.005), Hispanic ethnicity (Pxa0=xa00.05xa0vs. non-Hispanic white), and current smoking (Pxa0=xa00.03xa0vs. never smoking). Vitamin E supplementation (Pxa0=xa00.0005), tamoxifen use (Pxa0=xa00.008), and radiation treatment (compared to no chemotherapy or radiation; Pxa0=xa00.04) were associated with reduced CRP. Associations of CRP with clinical characteristics were not significant in the adjusted models. In a multivariate analysis, CRP showed significant associations with waist circumference, BMI, age, history of heart failure, tamoxifen use, and vitamin E supplementation (R2xa0=xa00.35). Similar, yet fewer, associations were observed for SAA (R2xa0=xa00.19). Conclusions This study highlights important correlates of inflammatory status in breast cancer patients. Our results are consistent with those from similar studies of healthy women.

Effect of Exercise on Oxidative Stress: A 12-Month Randomized, Controlled Trial

PURPOSEnThis study examined the effect of a yearlong exercise intervention on F2-isoprostane, a specific marker of lipid peroxidation and a general marker of oxidative stress.nnnMETHODSnIn a randomized, controlled trial, 173 overweight or obese, postmenopausal, sedentary women were randomized either to an aerobic exercise intervention (60%-75% observed maximal HR) for > or =45 min.d-1, 5 d.wk-1 (n = 87), or to a stretching control group (n = 86), on an intent-to-treat basis. Baseline and 12-month measures included urinary F2-isoprostane, maximal O2 uptake, body weight, body fat percentage, waist circumference, and intra-abdominal fat surface area. Urine samples were available from 172 and 168 women at baseline and 12 months, respectively.nnnRESULTSnDuring the 12-month study, controls minimally changed maximal O2 uptake (+0.2%) and body weight (+0.1 kg), whereas exercisers increased maximal O2 uptake (+13.6%; P < 0.0001 vs controls) and decreased body weight (-1.3 kg; P = 0.007 vs controls). F2-isoprostane increased slightly among controls (+3.3%) and decreased in exercisers (-6.2%), although the effect was not statistically significant (P = 0.26). In planned subgroup analyses, F2-isoprostane decreased linearly with gain in maximal O2 uptake (Ptrend = 0.005) relative to controls; exercisers who increased maximal O2 uptake by >15% decreased F2-isoprostane by 14.1% (P = 0.005 vs controls). A borderline statistically significant trend was observed between decreased waist circumference and F2-isoprostane (P = 0.06). Similar subgroup analyses by 12-month changes in body fat percentage, weight, and intra-abdominal fat were not statistically significant.nnnCONCLUSIONSnThese findings suggest that aerobic exercise, when accompanied by relatively marked gains in aerobic fitness, decreases oxidative stress among previously sedentary older women and that these effects occur with minimal change in mass or body composition.

Dietary Weight Loss and Exercise Effects on Insulin Resistance in Postmenopausal Women

BACKGROUNDnComprehensive lifestyle interventions are effective in preventing diabetes and restoring glucose regulation; however, the key stimulus for change has not been identified and effects in older individuals are not established. The aim of the study was to investigate the independent and combined effects of dietary weight loss and exercise on insulin sensitivity and restoration of normal fasting glucose in middle-aged and older women.nnnDESIGNnFour-arm RCT, conducted between 2005 and 2009 and data analyzed in 2010.nnnSETTING/PARTICIPANTSn439 inactive, overweight/obese postmenopausal women.nnnINTERVENTIONSnWomen were assigned to: dietary weight loss (n=118); exercise (n=117); exercise+diet (n=117); or control (n=87). The diet intervention was a group-based reduced-calorie program with a 10% weight-loss goal. The exercise intervention was 45 min/day, 5 days/week of moderate-to-vigorous intensity aerobic activity.nnnMAIN OUTCOME MEASURESn12-month change in serum insulin, C-peptide, fasting glucose, and whole body insulin resistance (HOMA-IR).nnnRESULTSnA significant improvement in HOMA-IR was detected in the diet (-24%, p<0.001) and exercise+ diet (-26%, p<0.001) groups but not in the exercise (-9%, p=0.22) group compared with controls (-2%); these effects were similar in middle-aged (50-60 years) and older women (aged 60-75 years). Among those with impaired fasting glucose (5.6-6.9 mmol/L) at baseline (n=143; 33%), the odds (95% CI) of regressing to normal fasting glucose after adjusting for weight loss and baseline levels were 2.5 (0.8, 8.4); 2.76 (0.8, 10.0); and 3.1 (1.0, 9.9) in the diet, exercise+diet, and exercise group, respectively, compared with controls.nnnCONCLUSIONSnDietary weight loss, with or without exercise, significantly improved insulin resistance. Older women derived as much benefit as did the younger postmenopausal women.nnnTRIAL REGISTRATIONnThis study is registered at Clinicaltrials.govNCT00470119.

Randomized controlled pilot trial of yoga in overweight and obese breast cancer survivors: effects on quality of life and anthropometric measures

PurposeTo obtain estimates of time to recruit the study sample, retention, facility-based class attendance and home practice for a study of yoga in breast cancer survivors, and its efficacy on fatigue, quality of life (QOL), and weight change.MethodsSixty-three post-treatment stages 0–III borderline overweight and obese (body mass index ≥24xa0kg/m2) breast cancer survivors were randomly assigned to a 6-month, facility- and home-based viniyoga intervention (nu2009=u200932) or a waitlist control group (nu2009=u200931). The yoga goal was five practices per week. Primary outcome measures were changes in QOL, fatigue, and weight from baseline to 6xa0months. Secondary outcomes included changes in waist and hip circumference.ResultsIt took 12xa0months to complete recruitment. Participants attended a mean of 19.6 classes and practiced at home a mean of 55.8 times during the 6-month period. At follow-up, 90% of participants completed questionnaires and 87% completed anthropometric measurements. QOL and fatigue improved to a greater extent among women in the yoga group relative to women in the control group, although no differences were statistically significant. Waist circumference decreased 3.1xa0cm (95% CI, −5.7 and −0.4) more among women in the yoga compared with the control group, with no difference in weight change.ConclusionsThis study provides important information regarding recruitment, retention, and practice levels achieved during a 6-month, intensive yoga intervention in overweight and obese breast cancer survivors. Yoga may help decrease waist circumference and improve quality of life; future studies are needed to confirm these results.

Translational cancer research: Balancing prevention and treatment to combat cancer globally

Cancer research is drawing on the human genome project to develop new molecular-targeted treatments. This is an exciting but insufficient response to the growing, global burden of cancer, particularly as the projected increase in new cases in the coming decades is increasingly falling on developing countries. The world is not able to treat its way out of the cancer problem. However, the mechanistic insights from basic science can be harnessed to better understand cancer causes and prevention, thus underpinning a complementary public health approach to cancer control. This manuscript focuses on how new knowledge about the molecular and cellular basis of cancer, and the associated high-throughput laboratory technologies for studying those pathways, can be applied to population-based epidemiological studies, particularly in the context of large prospective cohorts with associated biobanks to provide an evidence base for cancer prevention. This integrated approach should allow a more rapid and informed translation of the research into educational and policy interventions aimed at risk reduction across a population.

B vitamin intakes and incidence of colorectal cancer: results from the Women's Health Initiative Observational Study cohort.

BACKGROUNDnThe role of one-carbon metabolism nutrients in colorectal carcinogenesis is not fully understood. Associations might be modified by mandated folic acid (FA) fortification or alcohol intake.nnnOBJECTIVEnWe investigated associations between intakes of folate, riboflavin, vitamin B-6, and vitamin B-12 and colorectal cancer (CRC) in the Womens Health Initiative Observational Study, stratified by time exposed to FA fortification and alcohol intake.nnnDESIGNnA total of 88,045 postmenopausal women were recruited during 1993-1998; 1003 incident CRC cases were ascertained as of 2009. Quartiles of dietary intakes were compared; HRs and 95% CIs were estimated by Cox proportional hazards models.nnnRESULTSnDietary and total intakes of vitamin B-6 in quartile 4 compared with quartile 1 (HR: 0.80; 95% CI: 0.66, 0.97 and HR: 0.80; 95% CI: 0.66, 0.99, respectively) and total intakes of riboflavin (HR: 0.81; 95% CI: 0.66, 0.99) were associated with reduced risk of CRC overall and of regionally spread disease. In current drinkers who consumed <1 drink (13 g alcohol)/wk, B vitamin intakes were inversely associated with CRC risk (P-interaction < 0.05). Dietary folate intake was positively associated with CRC risk among women who had experienced the initiation of FA fortification for 3 to <9 y (P-interaction < 0.01).nnnCONCLUSIONSnVitamin B-6 and riboflavin intakes from diet and supplements were associated with a decreased risk of CRC in postmenopausal women. Associations of B vitamin intake were particularly strong for regional disease and among women drinkers who consumed alcohol infrequently. Our study provides new evidence that the increased folate intake during the early postfortification period may have been associated with a transient increase in CRC risk.