Adaptive-mixture-categorization (AMC)-based g-computation and its application to trace element mixtures and bladder cancer risk.

Several new statistical methods have been developed to identify the overall impact of an exposure mixture on health outcomes. Weighted quantile sum (WQS) regression assigns the joint mixture effect weights to indicate the overall association of multiple exposures, and quantile-based g-computation is a generalized version of WQS without the restriction of directional homogeneity. This paper proposes an adaptive-mixture-categorization (AMC)-based g-computation approach that combines g-computation with an optimal exposure categorization search using the F statistic. AMC-based g-computation reduces variance within each category and retains the variance between categories to build more powerful predictors. In a simulation study, the performance of association analysis was improved using categorizing by AMC compared with quantiles. We applied this method to assess the association between a mixture of 12 trace element concentrations measured from toenails and the risk of non-muscle invasive bladder cancer. Our findings suggested that medium-level (116.7-145.5 µg/g) vs. low-level (39.5-116.2 µg/g) of toenail zinc had a statistically significant positive association with bladder cancer risk.

Plasma Metabolomics Analysis of Aspirin Treatment and Risk of Colorectal Adenomas.

Despite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time. PREVENTION RELEVANCE: This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how aspirin use reduces the risk of colorectal neoplasia in some individuals. Ultimately, this work could have important implications for optimizing aspirin use in the prevention of colorectal cancer.

Diet quality, common genetic polymorphisms, and bladder cancer risk in a New England population-based study.

PURPOSE: We examined the interaction between common genetic bladder cancer variants, diet quality, and bladder cancer risk in a population-based case-control study conducted in New England. METHODS: At the time of enrollment, 806 bladder cancer cases and 974 controls provided a DNA sample and completed a diet history questionnaire. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010) score. Single nucleotide polymorphisms (SNPs) reported in genome-wide association studies to be associated with bladder cancer risk were combined into a polygenic risk score and also examined individually for interaction with the AHEI-2010. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. RESULTS: A 1-standard deviation increase in polygenic risk score was associated with higher bladder cancer risk (OR, 1.34; 95% CI 1.21-1.49). Adherence to the AHEI-2010 was not associated with bladder cancer risk (OR, 0.99; 95% CI 0.98-1.00) and the polygenic risk score did not appear to modify the association between the AHEI-2010 and bladder cancer risk. In single-SNP analyses, rs8102137 (bladder cancer risk allele, C) modified the association between the AHEI-2010 total score and bladder cancer risk, with the strongest evidence for the AHEI-2010 long chain fat guideline (OR for TT, 0.92; 95% CI 0.87-0.98; OR for CT, 1.02; 95% CI 0.96-1.08; OR for CC, 1.03; 95% CI 0.93-1.14; p for interaction, 0.02). CONCLUSIONS: In conclusion, rs8102137 near the cyclin E1 gene ( CCNE1 ) may be involved in gene-diet interactions for bladder cancer risk.

Association of demographic and health characteristics with circulating oxysterol concentrations.

BACKGOUND: Circulating oxysterols, cholesterol metabolites with important signaling functions, are increasingly being recognized as candidate biomarkers for several diseases, but associations with demographic and health characteristics remain poorly described. OBJECTIVE: This study aims to characterize associations of major circulating oxysterols with sex, age, race/ethnicity, body mass index (BMI), lifestyle factors, and use of common medications. METHODS: We measured plasma concentrations of 27-hydroxycholesterol (27-OHC), 25-hydroxycholesterol (25-OHC), 24(S)-hydroxycholesterol (24(S)-OHC), 7ɑ-hydroxycholesterol (7ɑ-OHC), and 4ß-hydroxycholesterol (4ß-OHC) from 1,440 participants of a completed clinical trial for the chemoprevention of colorectal adenomas. Adjusted percent difference in means were calculated using linear regression. RESULTS: Women had 18% (95% CI, 14%, 22%) lower 27-OHC and 21% (15%, 27%) higher 4ß-OHC than men. Blacks had 15% (7%, 23%) higher 4ß-OHC than Non-Hispanic Whites, and Asian or Pacific Islanders had 19% (2%, 35%) higher 7ɑ-OHC than Non-Hispanic Whites. Individuals of BMI ≥35 kg/m2 had 33% (25%, 41%) lower 4ß-OHC than those <25 kg/m2. Current smokers had 15% (5%, 24%) higher 7ɑ-OHC than never smokers, and daily alcohol drinkers had 17% (10%, 24%) higher 7ɑ-OHC than never drinkers. Statin use was associated with lower concentrations of all 5 oxysterols. Differences in mean <15% were found for characteristics such as age, total dietary energy intake, physical activity, diabetes, and anti-inflammatory drug use. CONCLUSION: Circulating oxysterols are uniquely associated with multiple demographic and health characteristics.

Circulating Sex Hormones and Risk of Colorectal Adenomas and Serrated Lesions in Men.

BACKGROUND: Sex hormones have been implicated in the etiology of colorectal neoplasia in women for over 40 years, but there has been very little investigation of the role of these hormones in men. METHODS: Using data from an adenoma chemoprevention trial, we conducted a secondary analysis to examine serum hormone levels [testosterone, androstenedione, DHEA sulfate (DHEAS), and sex hormone binding globulin (SHBG)] and risk of colorectal precursors in 925 men. Multivariable logistic regression models were fit to evaluate adjusted associations between hormone levels and risk of "low-risk" (single tubular adenoma < 1 cm) and "high-risk" lesions (advanced adenoma or sessile serrated adenoma or right-sided serrated polyp or >2 adenomas of any size). RESULTS: Overall, levels of free testosterone, total testosterone, androstenedione, DHEAS, or SHBG were not associated with either "low-risk" or "high-risk" early precursor lesions in the colorectum. CONCLUSIONS: These findings do not support the role of sex hormones in early colorectal neoplasia among men. IMPACT: This large prospective study address a missing gap in knowledge by providing information on the role of sex hormones in colorectal neoplasia in males.

Diet Quality and Survival in a Population-Based Bladder Cancer Study.

Nutrition may impact bladder cancer survival. We examined the association between diet quality and overall and bladder cancer-specific survival. Bladder cancer cases from a population-based study reported pre-diagnosis diet. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010). Vital status was ascertained from the National Death Index. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards and competing risks regression models. Overall AHEI-2010 adherence was not associated with overall or bladder cancer-specific survival among non-muscle invasive bladder cancer (NMIBC) cases (HR, 1.00; 95% CI, 0.98-1.01; HR, 1.00; 95% CI, 0.97-1.02) or muscle invasive bladder cancer (MIBC) cases (HR, 0.99; 95% CI, 0.96-1.03; HR, 1.01, 95% CI 0.97-1.06). AHEI-2010 sugar-sweetened beverages adherence was associated with poorer overall survival (HR, 1.04; 95% CI, 1.01-1.08) and AHEI-2010 sodium adherence was associated with better overall and bladder cancer-specific survival after NMIBC diagnosis (HR, 0.92, 95% CI, 0.85-1.00; HR, 0.82; 95% CI, 0.68-0.98). AHEI-2010 fruit adherence was associated with poorer overall and bladder cancer-specific survival after MIBC diagnosis (HR, 1.17; 95% CI, 1.02-1.33; HR, 1.26; 95% CI, 1.03-1.55). Consumption of sugar-sweetened beverages, sodium, and fruit, not overall AHEI-2010 adherence, may be associated with bladder cancer survival.

Proliferation, apoptosis and their regulatory protein expression in colorectal adenomas and serrated lesions.

BACKGROUND: Adenomas and serrated lesions represent heterogeneous sets of early precursors in the colorectum with varying malignant potential. They are often distinguished by their histopathologic differences, but little is known about potential differences in regulation of epithelial proliferation and apoptosis. METHODS: We conducted a protein expression analysis using tissue microarrays of 625 colorectal adenomas and 142 serrated lesions to determine potential differences in regulation of epithelial proliferation and apoptosis. We quantitated proliferation with Ki-67; apoptosis with activated caspase-3 (CASP3); up- and down-regulators of proliferation with cyclin D1, p16INK2, and p21Cip1; and apoptosis regulators with BAX, BCL2, and survivin. Linear mixed effects models and circos diagrams were used to determine relationships among expression and lesion characteristics. RESULTS: Adenomas had a significantly higher CASP-3 labeling index (LI) than serrated lesions, resulting in a lower net growth ratio (Ki-67 LI/activated CASP-3 LI, p-value<0.0001). Cyclin D1 LI, p16 LI and p21 LI were lower in adenomas compared to serrated lesions, while expression of both BCL2 and BAX were higher (p <0.001). Among adenomas, cyclin D1 LI and p16 LI levels increased with greater villous component, and the highest BAX expression was detected in adenomas larger than 2 cm (both p<0.0001). Right-sided adenomas had higher CASP3 LI than left colorectal adenomas (p = 0.008). Significant differences in cyclin D1 LI, p21 LI and survivin LI were also observed across histopathologic subtypes of serrated lesions. CONCLUSIONS: Our findings demonstrate different patterns of regulatory protein expression in adenomas than serrated lesions, especially involving apoptosis. ClinicalTrials.gov Identifier: NCT00272324.

Oral Antibiotics and Risk of New Colorectal Adenomas During Surveillance Follow-up.

BACKGROUND: Antibiotics may increase colorectal neoplasia risk by modifying the gut microbiome. It is unknown whether use is associated with the risk of new colorectal adenomas among individuals with prior adenomas. METHODS: We performed a secondary analysis of four randomized clinical trials for the chemoprevention of colorectal adenomas. Participants self-reported all currently used prescription drugs shortly after an initial colorectal adenoma diagnosis and two or three times a year thereafter over 3 to 5 years of follow-up. We estimated adjusted risk ratios (RR) with 95% confidence intervals (CI) for incident adenomas, analyzing the four trials together. RESULTS: Cumulatively, the four trials enrolled 5,174 participants (3,491 men and 1,683 women), of whom 4,769 (92%) completed ≥1 follow-up colonoscopy. A total of 763 (15%) participants reported using oral antibiotics on ≥2 occasions. Overall, 39% of those using oral antibiotics at least twice developed new colorectal adenomas compared with 40% of those with no use or a single report of use (RR, 0.99; 95% CI, 0.90-1.10). No statistically significant associations were found in study-specific analyses, and results were similar for high- and low-risk adenoma findings, antibiotic class, anatomic location of adenomas, and analyses excluding those with interim colorectal exams. CONCLUSIONS: Oral antibiotic use during colonoscopic surveillance after an initial adenoma diagnosis was not associated with risk of these polyps. IMPACT: Any changes to the gut microbiome as a consequence of oral antibiotic use during surveillance may not affect the development of metachronous colorectal adenomas.

Circulating 27-hydroxycholesterol and Risk of Colorectal Adenomas and Serrated Polyps.

The oxysterol 27-hydroxycholesterol (27-OHC) is an endogenous selective estrogen receptor modulator implicated in breast cancer etiology. It is unknown whether circulating 27-OHC is associated with colorectal neoplasia risk. Circulating 27-OHC was measured using LC/MS in fasting plasma collected at baseline from participants of the Vitamin D/Calcium Polyp Prevention Study, a completed randomized clinical trial. Participants were between 45 and 75 years old, recently diagnosed with ≥1 colorectal adenoma, and followed for new colorectal polyps during colonoscopic surveillance. Adjusted risk ratios (RR) with 95% confidence intervals (CI) of new colorectal polyps were estimated for quartiles of circulating 27-OHC using log-linear regression for repeated outcomes. Polyp phenotypes included any adenomas, advanced adenomas, hyperplastic polyps, and sessile serrated adenomas/polyps. Circulating 27-OHC was measured at baseline for 1,246 participants. Compared with participants with circulating 27-OHC below the first quartile (<138 ng/mL), those with circulating 27-OHC at or above the fourth quartile (≥201 ng/mL) had 24% higher risk of adenomas (RR, 1.24; 95% CI, 1.05-1.47) and 89% higher risk of advanced adenomas (RR, 1.89; 95% CI, 1.17-3.06). Stronger associations were observed among participants with advanced adenomas at baseline. Circulating 27-OHC was not associated with risk of hyperplastic polyps (RR, 0.90; 95% CI, 0.66-1.22) or sessile serrated adenomas/polyps (RR, 1.02; 95% CI, 0.50-2.07). Circulating 27-OHC may be a risk factor for colorectal adenomas but not serrated polyps. PREVENTION RELEVANCE: This study found that plasma concentration of 27-hydroxycholesterol, a metabolite of cholesterol that regulates lipid metabolism and acts as a selective estrogen receptor modulator, is associated with the risk of developing precursor lesions for colorectal cancer.

Risk of keratinocyte carcinomas with vitamin D and calcium supplementation: a secondary analysis of a randomized clinical trial.

BACKGROUND: It is unknown whether dietary supplementation with vitamin D or calcium prevents keratinocyte carcinomas, also known as nonmelanoma skin cancers. OBJECTIVES: This study aimed to determine whether daily vitamin D or calcium supplementation alters the risk of basal cell carcinoma (BCC) or invasive cutaneous squamous cell carcinoma (SCC). METHODS: The Vitamin D/Calcium Polyp Prevention Study is a completed multicenter, double-blind, placebo-controlled, partial 2 × 2 factorial, randomized clinical trial of vitamin D, calcium, or both for the prevention of colorectal adenomas. During 2004-2008, a total of 2259 men and women, 45-75 y of age, recently diagnosed with a colorectal adenoma, were randomly assigned to 1000 IU/d of vitamin D3 or placebo and 1200 mg/d of calcium carbonate or placebo for 3 or 5 y, and followed after treatment ended. Reports of incident BCC or SCC were confirmed from pathology records. RESULTS: During a median follow-up of 8 y, 200 (9%) participants were diagnosed with BCC and 68 (3%) participants were diagnosed with SCC. BCC incidence was unrelated to treatment with vitamin D compared with no vitamin D (HR: 0.96; 95% CI: 0.73, 1.26), calcium compared with no calcium (HR: 1.01; 95% CI: 0.74, 1.39), and both agents compared with neither (HR: 0.99; 95% CI: 0.65, 1.51). SCC incidence was unrelated to treatment with vitamin D compared with no vitamin D (HR: 0.79; 95% CI: 0.49, 1.27), but there was suggestive evidence of beneficial treatment effects for calcium compared with no calcium (HR: 0.60; 95% CI: 0.36, 1.01) and both agents compared with neither (HR: 0.42; 95% CI: 0.19, 0.91). CONCLUSIONS: Calcium alone or in combination with vitamin D may reduce the risk of SCC, but not BCC. This trial was registered at clinicaltrials.gov as NCT00153816.

Metabolomics Analysis of Aspirin's Effects in Human Colon Tissue and Associations with Adenoma Risk.

Although substantial evidence supports aspirin's efficacy in colorectal cancer chemoprevention, key molecular mechanisms are uncertain. An untargeted metabolomics approach with high-resolution mass spectrometry was used to elucidate metabolic effects of aspirin treatment in human colon tissue. We measured 10,269 metabolic features in normal mucosal biopsies collected at colonoscopy after approximately 3 years of randomized treatment with placebo, 81 or 325 mg/day aspirin from 325 participants in the Aspirin/Folate Polyp Prevention Study. Linear regression was used to identify aspirin-associated metabolic features and network analysis was used to identify pathways and predict metabolite identities. Poisson regression was used to examine metabolic features associations with colorectal adenoma risk. We detected 471 aspirin-associated metabolic features. Aside from the carnitine shuttle, aspirin-associated metabolic pathways were largely distinct for 81 mg aspirin (e.g., pyrimidine metabolism) and 325 mg (e.g., arachidonic acid metabolism). Among aspirin-associated metabolic features, we discovered three that were associated with adenoma risk and could contribute to the chemopreventive effect of aspirin treatment, and which have also previously been associated with colorectal cancer: creatinine, glycerol 3-phosphate, and linoleate. The last two of these are in the glycerophospholipid metabolism pathway, which was associated with 81 mg aspirin treatment and provides precursors for the synthesis of eicosanoids from arachidonic acid upstream of cyclooxygenase inhibition by aspirin. Conversely, carnitine shuttle metabolites were increased with aspirin treatment and associated with increased adenoma risk. Thus, our untargeted metabolomics approach has identified novel metabolites and pathways that may underlie the effects of aspirin during early colorectal carcinogenesis.

Folic acid supplementation and risk of colorectal neoplasia during long-term follow-up of a randomized clinical trial.

BACKGROUND: The Aspirin/Folate Polyp Prevention Study previously found folic acid increased risk of advanced and multiple colorectal adenomas during a surveillance colonoscopy interval starting about 3 y after randomization. OBJECTIVE: We conducted secondary analyses to evaluate folic acid effects with additional follow-up after treatment was stopped. METHODS: In total, 1021 participants recently diagnosed with colorectal adenomas were randomly assigned to 1 mg/d of folic acid (n = 516) or placebo (n = 505), with or without aspirin, beginning 6 July 1994. The original 3-y treatment period was extended into a subsequent colonoscopy interval, but eventually stopped prematurely on 1 October 2004. With additional post-treatment follow-up, a total of 663 participants who extended treatment completed a second colonoscopic surveillance interval after the initial 3-y follow-up. In addition, 490 participants provided information regarding a subsequent surveillance colonoscopy occurring before completion of follow-up on 31 May 2012, including 325 who had agreed to extended treatment. Study endpoints included conventional adenomas, sessile serrated adenomas/polyps (SSA/Ps), or colorectal cancer, and RRs with 95% CIs were adjusted for baseline characteristics associated with availability of follow-up. RESULTS: Among those who extended treatment, any colorectal neoplasia was found in 118 (36%) participants assigned to placebo and 146 (43%) assigned to folic acid during the second surveillance interval (RR: 1.21; 95% CI: 0.99, 1.47; P = 0.06). Increased risk of SSA/P with extended folic acid supplementation was statistically significant during the second surveillance interval (RR: 1.94; 95% CI: 1.02, 3.68; P = 0.04). There was no evidence of post-treatment effects for any colorectal neoplasia (RR: 1.01; 95% CI: 0.80, 1.28; P = 0.94), and the post-treatment effect for SSA/P was no longer statistically significant (RR: 1.38; 95% CI: 0.59, 3.19; P = 0.46). CONCLUSIONS: Delayed treatment effects were not observed, but folic acid may increase SSA/P risk. This trial was registered at clinicaltrials.gov as NCT00272324.

Body Composition and Aspirin Dose for Colorectal Adenoma Prevention in a Randomized Clinical Trial.

BACKGROUND: Visceral adiposity is a risk factor for colorectal adenomas, and aspirin is an established chemopreventive agent. Evidence from clinical trials suggests the effectiveness of aspirin at preventing cardiovascular disease and cancer may require higher doses for higher body weight. METHODS: Body mass index, body surface area, fat-free mass, and fat mass were calculated from baseline height and weight in 1,121 participants of the Aspirin/Folate Polyp Prevention Study, a double-blind, placebo-controlled, 3 × 2 factorial randomized clinical trial of low-dose (81 mg/day) or high-dose (325 mg/day) aspirin and/or 1 mg/day folic acid to prevent metachronous colorectal adenomas. Participants were treated during a surveillance colonoscopy interval of approximately 3 years. Risk ratios (RR) with 95% confidence intervals (CI) for any colorectal neoplasia and high-risk adenoma (HRA, advanced or ≥3 adenomas) were estimated from log-linear regression. RESULTS: We did not find evidence to suggest aspirin dose-response differed by body composition measurements, including weight alone. Among those weighing ≥ 80 kg, treatment effects for low-dose aspirin (RR for colorectal neoplasia, 0.75; 95% CI, 0.60-0.94; RR for HRA, 0.52; 95% CI, 0.31-0.86) and high-dose aspirin (RR for colorectal neoplasia, 0.88; 95% CI, 0.72-1.08; RR for HRA, 0.68; 95% CI, 0.43-1.09) were not meaningfully different than for those weighing 70-79 kg or <70 kg. CONCLUSIONS: Measurements of body composition calculated from height and weight did not modify aspirin treatment effects for colorectal adenoma prevention. IMPACT: Aspirin dosing strategies accounting for body weight suggested in previous trials of colorectal cancer may not apply to adenomas.

No Evidence for Posttreatment Effects of Vitamin D and Calcium Supplementation on Risk of Colorectal Adenomas in a Randomized Trial.

Vitamin D and calcium supplementation are postulated to have chemopreventive effects against colorectal neoplasia, yet in our previously reported randomized trial, there was no overall efficacy of calcium and/or vitamin D3 against colorectal adenoma recurrence. It is possible vitamin D3 and calcium chemopreventive effects are not detectable until beyond the 3- to 5-year follow-up captured in that trial. Accordingly, we explored possible vitamin D and calcium effects on posttreatment (observational) adenoma occurrence. In this secondary analysis of the observational follow-up phase of the Vitamin D/Calcium Polyp Prevention Study, participants who completed the treatment phase were invited to be followed for one additional surveillance colonoscopy cycle. We evaluated adenoma occurrence risk at surveillance colonoscopy, with a mean of 55 ± 15 months after treatment follow-up, according to randomized treatment with vitamin D versus no vitamin D, calcium versus no calcium, and calcium plus vitamin D versus calcium alone. Secondary outcomes included advanced and multiple adenomas. Among the 1,121 participants with observational follow-up, the relative risk (95% confidence interval, CI) of any adenoma was 1.04 (0.93-1.17) for vitamin D versus no vitamin D; 0.95 (0.84-1.08) for calcium versus no calcium; 1.07 (0.91-1.25) for calcium plus vitamin D versus calcium; and 0.96 (0.81-1.15) for calcium plus vitamin D versus neither. Risks of advanced or multiple adenomas also did not differ by treatment. Our results do not support an association between supplemental calcium and/or vitamin D3 for 3 to 5 years and risk of recurrent colorectal adenoma at an average of 4.6 years after treatment.

Postmenopausal Fracture History and Survival After Reproductive Cancer Diagnosis.

BACKGROUND: Postmenopausal bone fracture's have been proposed as a marker of lifetime estrogen exposure and have been associated with decreased risk of breast and endometrial cancer. It is plausible that prediagnostic fractures may be related to survival of estrogen-sensitive cancers. METHODS: We evaluated a cohort of breast (n = 6411), endometrial (n = 1127), and ovarian (n = 658) cancer cases diagnosed between 1992 and 2010 while participating in the Women's Health Initiative. Postmenopausal fracture history was assessed from baseline reports of fractures after age 55 years and incident fractures that occurred at least one year prior to cancer diagnosis during study follow-up. Using Cox regression, we compared women with and without a history of fractures with respect to overall and cancer-specific survival. Estimates were adjusted for participant factors, including hormone therapy use; hormone receptor status was not included in our analysis. RESULTS: Among women with breast cancer, a history of prediagnostic fractures at any site was associated with poorer overall survival (hazard ratio [HR] = 1.22, 95% confidence interval [CI] = 1.05 to 1.43). A history of hip, forearm, or spine fractures, or hip fracture alone, was associated with increased risk of mortality (HR = 1.26, 95% CI = 1.01 to 1.58, and HR = 2.05, 95% CI = 1.27 to 3.32, respectively). Fracture history was associated neither with cancer-specific survival among breast cancer survivors, nor with overall or disease-specific mortality among endometrial and ovarian cancer survivors. CONCLUSIONS: Postmenopausal breast cancer patients with a history of fractures, especially of the hip, are more likely to die of any cause than breast cancer survivors without a fracture history. Identifying and intervening in fracture risk factors should be standard of care for all women diagnosed with breast cancer.

Identification of Pleiotropic Cancer Susceptibility Variants from Genome-Wide Association Studies Reveals Functional Characteristics.

Background: There exists compelling evidence that some genetic variants are associated with the risk of multiple cancer sites (i.e., pleiotropy). However, the biological mechanisms through which the pleiotropic variants operate are unclear.Methods: We obtained all cancer risk associations from the National Human Genome Research Institute-European Bioinformatics Institute GWAS Catalog, and correlated cancer risk variants were clustered into groups. Pleiotropic variant groups and genes were functionally annotated. Associations of pleiotropic cancer risk variants with noncancer traits were also obtained.Results: We identified 1,431 associations between variants and cancer risk, comprised of 989 unique variants associated with 27 unique cancer sites. We found 20 pleiotropic variant groups (2.1%) composed of 33 variants (3.3%), including novel pleiotropic variants rs3777204 and rs56219066 located in the ELL2 gene. Relative to single-cancer risk variants, pleiotropic variants were more likely to be in genes (89.0% vs. 65.3%, P = 2.2 × 10-16), and to have somewhat larger risk allele frequencies (median RAF = 0.49 versus 0.39, P = 0.046). The 27 genes to which the pleiotropic variants mapped were suggestive for enrichment in response to radiation and hypoxia, alpha-linolenic acid metabolism, cell cycle, and extension of telomeres. In addition, we observed that 8 of 33 pleiotropic cancer risk variants were associated with 16 traits other than cancer.Conclusions: This study identified and functionally characterized genetic variants showing pleiotropy for cancer risk.Impact: Our findings suggest biological pathways common to different cancers and other diseases, and provide a basis for the study of genetic testing for multiple cancers and repurposing cancer treatments. Cancer Epidemiol Biomarkers Prev; 27(1); 75-85. ©2017 AACR.