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Background: Despite the existence of numerous biologic pathways potentially linking increased physical activity to decreased risk of hematologic cancers, the associations between physical activity and subtype-specific hematologic cancers have not been comprehensively quantified.Methods: We conducted a systematic review and meta-analysis of physical activity in relation to subtype-specific hematologic cancers. We summarized the data from 23 eligible studies (15 cohort and eight case–control studies) and estimated summary relative risks (RR) and 95% confidence intervals (CI) using random-effects models.Results: When comparing high versus low physical activity levels, the RR for non-Hodgkin lymphoma was 0.91 (95% CI, 0.82–1.00), for Hodgkin lymphoma it was 0.86 (95% CI, 0.58–1.26), for leukemia it was 0.97 (95% CI, 0.84–1.13), and for multiple myeloma it was 0.86 (95% CI, 0.68–1.09). When focusing on subtypes of non-Hodgkin lymphoma, the RR for diffuse large B-cell lymphoma was 0.95 (95% CI, 0.80–1.14) and for follicular lymphoma it was 1.01 (95% CI, 0.83–1.22). In an exploratory analysis combining all hematologic cancers, high versus low physical activity levels yielded a statistically significant RR of 0.93 (95% CI, 0.88–0.99).Conclusions: Physical activity showed statistically nonsignificant associations with risks of non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, and leukemia. These findings may not represent a true lack of associations given the variation in high versus low physical activity definitions, the quality of physical activity assessments, and the variability in hematologic cancer classification schemes in individual studies.Impact: Physical activity is unrelated to risks of subtype-specific hematologic cancers. Cancer Epidemiol Biomarkers Prev; 23(5); 833–46. ©2014 AACR.

PDF file - 47KB, Funnel plot for the main random-effects meta-analysis including 84 risk estimates.

PDF file - 104KB

PDF file - 70KB, Physical activity and total hematologic cancer - summary risk estimates from random-effects models including 75 risk estimates, stratified by selected study characteristics.

PDF file - 50KB, Flowchart of PubMed literature search results.

PDF file - 163K, Table S1: Comparison of baseline characteristics of the overall cohort including 566,401 participants and our analytic cohort including 203,177 participants in the NIH-AARP Diet and Health Study by gender.: Table S2: Correlations of anthropometric parameters in men and women in the NIH-AARP Diet and Health Study.: Table S3: Means and standard deviations of anthropometry parameters in men and women in the NIH-AARP Diet and Health Study.: Table S4: Hazard ratios and 95% confidence intervals for risk of incident rectal cancer by gender across categories of anthropometric measures in the NIH-AARP Diet and Health Study.: Table S5: Hazard ratios and 95% confidence intervals for risk of incident colon cancer across categories of anthropometric measures in women stratified by age in the NIH-AARP Diet and Health Study.: Table S6: Hazard ratios and 95% confidence intervals for risk of incident colon cancer across categories of anthropometric measures in women stratified by colonic sub-site (distal vs. proximal) in the NIH-AARP Diet and Health Study.: Table S7: Hazard ratio, 95% confidence intervals of colon cancer and Δ HR across waist circumference measures in women with current hormone replacement therapy (HRT) use in the NIH-AARP Diet and Health Study.: Table S8: Hazard ratios and 95% confidence intervals for risk of incident colon cancer across categories of anthropometric measures in women stratified by hormone replacement therapy (HRT) use in the NIH-AARP Diet and Health Study.: Table S9: Hazard ratios and 95% confidence intervals for risk of incident rectal cancer across categories of anthropometric measures in women stratified by hormone replacement therapy (HRT) use in the NIH-AARP Diet and Health Study.: Table S10: Hazard ratios and 95% confidence intervals for risk of incident rectal cancer across categories of anthropometric measures in women stratified by hormone replacement therapy (HRT) use in the NIH-AARP Diet and Health Study.: Table S11: Hazard ratios and 95% confidence intervals for risk of incident colon cancer across categories of anthropometric measures in men and women with exclusion of the first 2 years of follow-up in the NIH-AARP Diet and Health Study.

PDF file - 94KB, Supplementary Table S1a. Physical activity and non-Hodgkin lymphoma. Summary risk estimates from random-effects models including 23 risk estimates, stratified by selected study characteristics. Supplementary Table S1b. Physical activity and Hodgkin lymphoma. summary risk estimates from random-effects models including 6 risk estimates, stratified by selected study characteristics. Supplementary Table S1c. Physical activity and follicular lymphoma. summary risk estimates from random-effects models including 9 risk estimates, stratified by selected study characteristics. Supplementary Table S1d. Physical activity and diffuse large B-cell lymphoma. summary risk estimates from random-effects models including 9 risk estimates, stratified by selected study characteristics. Supplementary Table S1e. Physical activity and leukemia. summary risk estimates from random-effects models including 9 risk estimates, stratified by selected study characteristics. Supplementary Table S1f. Physical activity and chronic lymphocytic lymphoma/small lymphocytic lymphoma. summary risk estimates from random-effects models including 7 risk estimates, stratified by selected study characteristics. Supplementary Table S1g. Physical activity and multiple myeloma. summary risk estimates from random-effects models including 12 risk estimates, stratified by selected study characteristics.

Background: Despite the existence of numerous biologic pathways potentially linking increased physical activity to decreased risk of hematologic cancers, the associations between physical activity and subtype-specific hematologic cancers have not been comprehensively quantified. Methods: We conducted a systematic review and meta-analysis of physical activity in relation to subtype-specific hematologic cancers. We summarized the data from 23 eligible studies (15 cohort and eight case–control studies) and estimated summary relative risks (RR) and 95% confidence intervals (CI) using random-effects models. Results: When comparing high versus low physical activity levels, the RR for non-Hodgkin lymphoma was 0.91 (95% CI, 0.82–1.00), for Hodgkin lymphoma it was 0.86 (95% CI, 0.58–1.26), for leukemia it was 0.97 (95% CI, 0.84–1.13), and for multiple myeloma it was 0.86 (95% CI, 0.68–1.09). When focusing on subtypes of non-Hodgkin lymphoma, the RR for diffuse large B-cell lymphoma was 0.95 (95% CI, 0.80–1.14) and for follicular lymphoma it was 1.01 (95% CI, 0.83–1.22). In an exploratory analysis combining all hematologic cancers, high versus low physical activity levels yielded a statistically significant RR of 0.93 (95% CI, 0.88–0.99). Conclusions: Physical activity showed statistically nonsignificant associations with risks of non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, and leukemia. These findings may not represent a true lack of associations given the variation in high versus low physical activity definitions, the quality of physical activity assessments, and the variability in hematologic cancer classification schemes in individual studies. Impact: Physical activity is unrelated to risks of subtype-specific hematologic cancers. Cancer Epidemiol Biomarkers Prev; 23(5); 833–46. ©2014 AACR.

Background: Physical activity may protect against bladder cancer through several biologic pathways, such as enhanced immune function and decreased chronic inflammation. Physical activity may also indirectly prevent bladder cancer by reducing obesity. A sizeable number of epidemiologic studies have examined the association between physical activity and bladder cancer, but the available evidence has not yet been formally summarised using meta-analysis. Methods: We performed a systematic literature review and meta-analysis of English-language studies published from January 1975 through November 2013. We followed the PRISMA guidelines and used a random effects model to estimate the summary risk estimates for the association between physical activity and bladder cancer. Results: A total of 15 studies with 5 402 369 subjects and 27 784 bladder cancer cases were included. High vs low levels of physical activity were related to decreased bladder cancer risk (summary relative risk (RR)=0.85, 95% confidence interval (CI)=0.74–0.98; I2=83% P-value for heterogeneity across all studies

Increasing evidence indicates that breast cancer pathogenesis is linked with DNA double-strand break (DSB) repair dysfunction. This conclusion is based on advances in the study of functions of breast cancer susceptibility genes such as BRCA1 and BRCA2, on the identification of breast cancer-associated changes regarding the genetics, expression, and localization of multiple DSB repair factors, and on observations indicating enhanced radiation-induced chromosomal damage in cells from predisposed individuals and sporadic breast cancer patients. In this pilot study, we describe a sensitive method for the analysis of DSB repair functions in mammary carcinomas. Using this method we firstly document alterations in pathway-specific DSB repair activities in primary cells originating from familial as well as sporadic breast cancer. In particular, we identified increases in the mutagenic nonhomologous end joining and single-strand annealing mechanisms in sporadic breast cancers with wild-type BRCA1 and BRCA2, and, thus, similar phenotypes to tumors with mutant alleles of BRCA1 and BRCA2. This suggests that detection of error-prone DSB repair activities may be useful to extend the limits of genotypic characterization of high-risk susceptibility genes. This method may, therefore, serve as a marker for breast cancer risk assessment and, even more importantly, for the prediction of responsiveness to targeted therapies such as to inhibitors of poly(ADP-ribose)polymerase (PARP1). © 2008 Wiley-Liss, Inc.

Resveratrol (RV) inhibits tumour initiation, promotion and progression which has mainly been explained by its properties in cell cycle control and apoptosis induction. So far, ambiguous observations have been published regarding its influence on genomic stability. To study RV's effects on DNA double-strand break (DSB) repair, we applied the established enhanced green fluorescent protein (EGFP)- and I-SceI-based assay system on RV-treated lymphoblastoid cell lines (LCLs). We show that RV inhibits both, homologous recombination (HR) and non-homologous end joining (NHEJ) independently of its known growth and death regulatory functions. Using (i) the isogenic cell lines TK6 and WTK1, which differ in their p53 status, (ii) LCLs from patients with ataxia telangiectasia, (iii) shRNA-mediated p53 knockdown and (iv) chemical inhibition of ATM/ATR by caffeine, we established an ATM-p53-dependent pathway of HR inhibition by RV. Additional use of LCLs from Nijmegen breakage syndrome patients furthermore provided evidence for an ATM/ATR-Nbs1-dependent inhibition of microhomology-mediated NHEJ after RV treatment. We propose that activation of ATM and/or ATR is a central effect of RV. Repression of error-prone recombination subpathways could at least partially explain the chemopreventive effects of this natural plant constituent in animal cancer models.

Background: Increased body mass index (BMI) is an established colorectal cancer risk factor. High waist circumference or waist-hip-ratio (WHR) may better reflect an abnormal metabolic state and be more predictive of colorectal cancer risk than BMI. Methods: We examined BMI, waist circumference, WHR, and hip circumference in relation to colorectal cancer risk among 203,177 participants followed for 10 years. We derived standardized colorectal cancer risk estimates for each anthropometric parameter and compared predictive characteristics (Harrell's C-index). In women, we examined whether hormone replacement therapy (HRT) use modified the associations between anthropometric measures and colorectal cancer. Results: We ascertained 2,869 colorectal cancers. In men, increased colon cancer risks were associated with BMI [HR per SD, 1.14; 95% confidence interval (CI), 1.08–1.20], waist circumference (HR per SD, 1.17; 95% CI, 1.08–1.27), and WHR (HR per SD, 1.09; 95% CI, 1.04–1.14). In women, anthropometric variables were unrelated to colon cancer. For men and women, anthropometric variables were unrelated to rectal cancer. Compared with BMI, waist circumference and WHR did not materially influence colon cancer prediction models [C-index changes: −0.0041 and 0.0046 (men); 0.0004 and 0.0005 (women)]. In current HRT users, colon cancer was inversely or suggestively inversely associated with waist circumference (HR per SD, 0.78; 95% CI, 0.63–0.97) and WHR (HR per SD, 0.88; 95% CI, 0.76–1.01), but positively related to hip circumference (HR per SD, 1.39; 95% CI, 1.13–1.71). Conclusion: BMI, waist circumference, and WHR show comparable positive associations with colon cancer in men. Associations between anthropometric measures and colon cancer are weak or null in women, but there is some evidence for effect modification by HRT. Impact: These findings may improve our understanding of the relation of adiposity to colorectal cancer. Cancer Epidemiol Biomarkers Prev; 22(8); 1383–94. ©2013 AACR.

Intriguingly, all 10 breast cancer susceptibility genes known today are directly or indirectly related to DNA double-strand break (DSB) repair suggesting a critical role of DSB repair dysfunction in the etiology of this tumor entity. We and others had previously provided evidence indicating that the breast cancer susceptibility gene product p53 controls DSB repair. Experiments with ectopically expressed proteins showed that oncogenic mutants of p53 deregulate homologous recombination (HR) and possibly also non-homologous end joining (NHEJ). Here, we systematically analyzed the role of different p53 variants endogenously expressed in a series of mammary epithelial cell lines. We provide evidence that endogenous wild-type p53 represses HR, particularly between short homologies that strengthens the idea of a quality control mechanism underlying HR regulation. To a lesser extent, p53 also downregulates microhomology-mediated NHEJ and single-strand annealing. Our data also suggest that repression of NHEJ regulation may require the extreme C-terminus, whereas the oligomerization and core domains are involved in HR regulation. We show that depending on the individual mutation, p53 mutants retain more or less partial DSB repair downregulatory activities when compared with loss of p53. All in all, relative effects on distinct DSB repair pathways and discrimination between HR substrates with perfectly versus imperfectly homologous sequences represent good markers for a p53 defect due to a specific mutation. Thus, advanced DSB repair analysis may serve as a novel assay for the functional classification of p53 mutations.