Colorectal Cancer Risk between Mendelian and Non-Mendelian Inheritance.

Hereditary colorectal cancer has been an area of focus for research and public health practitioners due to our ability to quantify risk and then act based on such results by enrolling patients in surveillance programs. The wide access to genetic testing and whole-genome sequencing has resulted in identifying many low/moderate penetrance genes. Above all, our understanding of the family component of colorectal cancer has been improving. Polygenic scores are becoming part of the risk assessment for many cancers, and the data about polygenic risk scores for colorectal cancer is promising. The challenge is determining how we incorporate this data in clinical care.

Imaging modalities for measuring body composition in patients with cancer: opportunities and challenges.

Body composition assessment (ie, the measurement of muscle and adiposity) impacts several cancer-related outcomes including treatment-related toxicities, treatment responses, complications, and prognosis. Traditional modalities for body composition measurement include body mass index, body circumference, skinfold thickness, and bioelectrical impedance analysis; advanced imaging modalities include dual energy x-ray absorptiometry, computerized tomography, magnetic resonance imaging, and positron emission tomography. Each modality has its advantages and disadvantages, thus requiring an individualized approach in identifying the most appropriate measure for specific clinical or research situations. Advancements in imaging approaches have led to an abundance of available data, however, the lack of standardized thresholds for classification of abnormal muscle mass or adiposity has been a barrier to adopting these measurements widely in research and clinical care. In this review, we discuss the different modalities in detail and provide guidance on their unique opportunities and challenges.

Age is a major determinant for poor prognosis in patients with pilocytic astrocytoma: a SEER population study.

Background Pilocytic astrocytomas (PAs) are central nervous system tumors with variable prognosis and poorly understood risk factors. Little evidence exists regarding the effect of age on mortality in PA. Therefore, we conducted a thorough characterization of PA in the US. Methods We queried the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2018 to extract age-adjusted incidence rate (AAIR), age-adjusted mortality rate (AAMR), and survival data on PA. The age group comparisons for each measure varied depending on available SEER data. We compared trends in AAIR and AAMR by two age groups (children, 0-19 years; adults, 20 + years) and by sex. The cumulative incidence function and the Fine-Gray competing risk model were applied by 0-19, 20-39, 40-59, and 60 + years of age groups. Results This study included 5211 incident PA and 462 PA-specific deaths between 2000 and 2018. Trends in AAIRs and AAMRs were almost constant between 2000 and 2018. Average AAIRs had a sharp peak in 1-4 years of age groups, whereas AAMRs had a gradual peak in 80-84 years of age groups. Age groups, tumor location, and race/ethnicity were significantly associated with PA-specific death, whereas only age was associated with other cause of deaths. Conclusions Trends in AAIRs and AAMRs were constant regardless of age. PAs in older populations, especially over 60 years old, have higher incidence of death than those in younger populations.

Knowledge and perception of cardiovascular disease risk in women of reproductive age.

Objective: Women who experience adverse pregnancy outcomes (APO) are at increased risk for cardiovascular disease (CVD); however, their knowledge of CVD risk is not well characterized. We aimed to evaluate knowledge and perception of CVD risk in young women and to determine whether these factors differ based on experience of an APO. Methods: We conducted a cross-sectional study among women with a recent live birth at an urban medical center. Knowledge and perception of CVD risk were assessed through a self-administered online survey adapted from the American Heart Association Survey of Women's CVD Awareness. Results: Of 5612 individuals contacted between 3/1/21 and 4/18/21, 714 completed the survey; the mean (SD) age was 34 (4) years and 25% reported an APO. While 62% of respondents identified CVD as the leading cause of death in women, there was no significant difference in CVD knowledge scores between participants who reported experiencing an APO and those who did not (6.9 vs 6.8 out of 10; p = 0.51). Participants who reported experiencing an APO had higher perception of personal risk for CVD (adjusted odds ratio, 2.64 [95% CI 1.83-3.80]) compared with participants who did not. Half of participants who experienced an APO reported perceiving average, or below average, risk for CVD and only 41 (22.5%) reported speaking with a healthcare professional about CVD within the past year. Conclusions: Gaps remain in knowledge of CVD risk among young women, particularly after an APO. The peripartum period may represent a unique opportunity for targeted education when healthcare engagement is high.

Interconnected Clinical and Social Risk Factors in Breast Cancer and Heart Failure.

Breast cancer and heart failure share several known clinical cardiovascular risk factors, including age, obesity, glucose dysregulation, cholesterol dysregulation, hypertension, atrial fibrillation and inflammation. However, to fully comprehend the complex interplay between risk of breast cancer and heart failure, factors attributed to both biological and social determinants of health must be explored in risk-assessment. There are several social factors that impede implementation of prevention strategies and treatment for breast cancer and heart failure prevention, including socioeconomic status, neighborhood disadvantage, food insecurity, access to healthcare, and social isolation. A comprehensive approach to prevention of both breast cancer and heart failure must include assessment for both traditional clinical risk factors and social determinants of health in patients to address root causes of lifestyle and modifiable risk factors. In this review, we examine clinical and social determinants of health in breast cancer and heart failure that are necessary to consider in the design and implementation of effective prevention strategies that altogether reduce the risk of both chronic diseases.

Novel Interactive Tool for Breast and Ovarian Cancer Risk Assessment (Bright Pink Assess Your Risk): Development and Usability Study.

BACKGROUND: The lifetime risk of breast and ovarian cancer is significantly higher among women with genetic susceptibility or a strong family history. However, current risk assessment tools and clinical practices may identify only 10% of asymptomatic carriers of susceptibility genes. Bright Pink developed the Assess Your Risk (AYR) tool to estimate breast and ovarian cancer risk through a user-friendly, informative web-based quiz for risk assessment at the population level. OBJECTIVE: This study aims to present the AYR tool, describe AYR users, and present evidence that AYR works as expected by comparing classification using the AYR tool with gold standard genetic testing guidelines. METHODS: The AYR is a recently developed population-level risk assessment tool that includes 26 questions based on the National Comprehensive Cancer Network (NCCN) guidelines and factors from other commonly used risk assessment tools. We included all women who completed the AYR between November 2018 and January 2019, with the exception of self-reported cancer or no knowledge of family history. We compared AYR classifications with those that were independently created using NCCN criteria using measures of validity and the McNemar test. RESULTS: There were 143,657 AYR completions, and most participants were either at increased or average risk for breast cancer or ovarian cancer (137,315/143,657, 95.59%). Using our estimates of increased and average risk as the gold standard, based on the NCCN guidelines, we estimated the sensitivity and specificity for the AYR algorithm-generated risk categories as 100% and 89.9%, respectively (P<.001). The specificity improved when we considered the additional questions asked by the AYR to define increased risk, which were not examined by the NCCN criteria. By race, ethnicity, and age group; we found that the lowest observed specificity was for the Asian race (85.9%) and the 30 to 39 years age group (87.6%) for the AYR-generated categories compared with the NCCN criteria. CONCLUSIONS: These results demonstrate that Bright Pink's AYR is an accurate tool for use by the general population to identify women at increased risk of breast and ovarian cancer. We plan to validate the tool longitudinally in future studies, including the impact of race, ethnicity, and age on breast and ovarian cancer risk assessment.

Fifteen-year trends and differences in mortality rates across sex, age, and race/ethnicity in patients with brainstem tumors.

BACKGROUND: Localization of tumors to the brainstem carries a poor prognosis, however, risk factors are poorly understood. We examined secular trends in mortality from brainstem tumors in the United States by age, sex, and race/ethnicity. METHODS: We extracted age-adjusted incidence-based mortality rates of brainstem tumors from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2018. Trends in age-adjusted mortality rate (AAMR) were compared by sex and race/ethnicity among the younger age group (0-14 years) and the older age group (>15 years), respectively. Average AAMRs in each 5-year age group were compared by sex. RESULTS: This study included 2039 brainstem tumor-related deaths between 2004 and 2018. Trends in AAMRs were constant during the study period in both age groups, with 3 times higher AAMR in the younger age group compared to the older age group. Males had a significantly higher AAMR in the older age group, while no racial differences were observed. Intriguingly, AAMRs peaked in patients 5-9 years of age (0.57 per 100 000) and in patients 80-84 years of age (0.31 per 100 000), with lower rates among middle-aged individuals. Among 5-9 years of age, the average AAMR for females was significantly higher than that of males (P = .017), whereas the reverse trend was seen among those 50-79 years of age. CONCLUSIONS: Overall trends in AAMRs for brainstem tumors were constant during the study period with significant differences by age and sex. Identifying the biological mechanisms of demographic differences in AAMR may help understand this fatal pathology.

Physical activity, dietary calcium to magnesium intake and mortality in the National Health and Examination Survey 1999-2006 cohort.

Calcium and magnesium affect muscle mass and function. Magnesium and calcium are also important for optimal vitamin D status. Vitamin D status modifies the associations between physical activity and risk of incident cardiovascular disease (CVD) and CVD mortality. However, no study examined whether levels of magnesium and calcium and the ratio of dietary calcium to magnesium (Ca:Mg) intake modify the relationship between physical activity and mortality. We included 20,295 National Health and Nutrition Examination Survey participants (1999-2006) aged >20 years with complete dietary, physical activity and mortality data (2,663 deaths). We assessed physical activity based on public health guidelines and sex-specific tertiles of MET-minutes/week. We used Cox proportional hazards models adjusted for potential confounding factors and stratified by the intakes of magnesium, calcium, Ca:Mg ratio. We found higher physical activity was significantly associated with reduced risk of total mortality and cause-specific mortality, regardless of Ca:Mg ratio, magnesium or calcium intake. In contrast, both moderate and high physical activity were significantly associated with substantially reduced risks of mortality due to cancer when magnesium intake was above the RDA level. We also found higher physical activity was significantly associated with a reduced risk of mortality due to cancer only when Ca:Mg ratios were between 1.7 and 2.6, although the interaction was not significant. Overall, dietary magnesium and, potentially, the Ca:Mg ratio modify the relationship between physical activity and cause-specific mortality. Further study is important to understand the modifying effects of the balance between calcium and magnesium intake on physical activity for chronic disease prevention.

Dose-dependent effect of aerobic exercise on inflammatory biomarkers in a randomized controlled trial of women at high risk of breast cancer.

BACKGROUND: Increased levels of inflammation are associated with many diseases, including cancer. Physical activity can lower breast cancer risk as well as levels of inflammation. The Women In Steady Exercise Research (WISER) Sister trial was a randomized controlled trial that investigated the effects of a dosed, moderate to vigorous, aerobic exercise intervention on levels of inflammation in premenopausal women who were at high risk of developing breast cancer. METHODS: Participants were randomized to control (<75 minutes per week; 41 patients), low-dose exercise (150 minutes per week; 38 patients), or high-dose exercise (300 minutes per week; 37 patients) groups. The 5-menstrual cycles-long, home-based treadmill exercise intervention gradually increased in minutes per week and intensity up to a maximum of 80% of the age-predicted maximum heart rate. Blood was collected at baseline and at follow-up and assayed for chemokine (C-C motif) ligand 2 (CCL2), interleukin 10 (IL-10), interleukin 12 (IL-12), and tumor necrosis factor α (TNF-α). RESULTS: A linear dose-response relationship was observed for the proinflammatory biomarkers CCL2 (%Δ of -5.44% in the control group, -0.03% in the low-dose exercise group, and 1.54% in the high-dose exercise group), IL-12 (%Δ of -21.5% in the control group, 38.2% in the low-dose exercise group, and 25.8% in the high-dose exercise group,) and TNF-α (%Δ of -4.69% in the control group, 9.51% in the low-dose exercise group, and 15.7% in the high-dose exercise group) but not for the anti-inflammatory biomarker IL-10 (%Δ of 5.05% in the control group, 6.05% in the low-dose exercise group, and 10.6% in the high-dose exercise group). For IL-12 and TNF-α, the percentage change was significantly higher in the low-dose (IL-12: P < .001; and TNF-α: P = .01) and high-dose (IL-12: P < .001; and TNF-α: P < .001) exercise groups compared with the control group. CONCLUSIONS: Moderate to vigorous aerobic exercise appeared to increase levels of proinflammatory biomarkers in a dose-dependent manner in a population of healthy women at high risk of developing breast cancer. The results of the current study suggest that for healthy premenopausal women, the mechanism of reduced breast cancer risk observed in physically active individuals may not be a result of reduced levels of inflammation.

Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation.

BACKGROUND: Studies demonstrate the impact of diet and physical activity on epigenetic biomarkers, specifically DNA methylation. However, no intervention studies have examined the combined impact of dietary and activity changes on the blood epigenome. The objective of this study was to examine the impact of the Make Better Choices 2 (MBC2) healthy diet and activity intervention on patterns of epigenome-wide DNA methylation. The MBC2 study was a 9-month randomized controlled trial among adults aged 18-65 with non-optimal levels of health behaviors. The study compared three 12-week interventions to (1) simultaneously increase exercise and fruit/vegetable intake, while decreasing sedentary leisure screen time; (2) sequentially increase fruit/vegetable intake and decrease leisure screen time first, then increase exercise; (3) increase sleep and decrease stress (control). We collected blood samples at baseline, 3 and 9 months, and measured DNA methylation using the Illumina EPIC (850 k) BeadChip. We examined region-based differential methylation patterns using linear regression models with the false discovery rate of 0.05. We also conducted pathway analysis using gene ontology (GO), KEGG, and IPA canonical pathway databases. RESULTS: We found no differences between the MBC2 population (n = 340) and the subsample with DNA methylation measured (n = 68) on baseline characteristics or the impact of the intervention on behavior change. We identified no differentially methylated regions at baseline between the control versus intervention groups. At 3 versus 9 months, we identified 154 and 298 differentially methylated regions, respectively, between controls compared to pooled samples from sequential and simultaneous groups. In the GO database, we identified two gene ontology terms related to hemophilic cell adhesion and cell-cell adhesion. In IPA analysis, we found pathways related to carcinogenesis including PI3K/AKT, Wnt/ß-catenin, sonic hedgehog, and p53 signaling. We observed an overlap between 3 and 9 months, including the GDP-L-fucose biosynthesis I, methylmalonyl metabolism, and estrogen-mediated cell cycle regulation pathways. CONCLUSIONS: The results demonstrate that the MBC2 diet and physical activity intervention impacts patterns of DNA methylation in gene regions related to cell cycle regulation and carcinogenesis. Future studies will examine DNA methylation as a biomarker to identify populations that may particularly benefit from incorporating health behavior change into plans for precision prevention.

The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma.

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with a median overall survival (mOS) of 16-21 months. Our previous work found a negative association between advanced aging and the survival benefit after treatment with immunotherapy in an experimental brain tumor model. Given the recent phase III clinical success of immunotherapy in patients with many types of cancer, but not for patients with GBM, we hypothesize that aging enhances immunosuppression in the brain and contributes to the lack of efficacy for immunotherapy to improve mOS in patients with malignant glioma. Herein, we compare epidemiological data for the incidence and mortality of patients with central nervous system (CNS) cancers, in addition to immune-related gene expression in the normal human brain, as well as peripheral blood immunological changes across the adult lifespan. Methods: Data were extracted from the National Cancer Institute's surveillance, epidemiology, and end results (SEER)-, the Broad Institute's Genotype Tissue Expression project (GTEx)-, and the University of California San Francisco's 10k Immunomes-databases and analyzed for associations with aging. Results: The proportion of elderly individuals, defined as ≥65 years of age, has predominantly increased for more than 100 years in the United States. Over time, the rise in elderly United States citizens has correlated with an increased incidence and mortality rate associated with primary brain and other CNS cancer. With advanced aging, human mRNA expression for factors associated with immunoregulation including immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO) and programmed death-ligand 1 (PD-L1), as well as the dendritic cell surface marker, CD11c, increase in the brain of normal human subjects, coincident with increased circulating immunosuppressive Tregs and decreased cytolytic CD8+ T cells in the peripheral blood. Strikingly, these changes are maximally pronounced in the 60-69 year old group; consistent with the median age of a diagnosis for GBM. Conclusion: These data demonstrate a significant association between normal human aging and increased immunosuppression in the circulation and CNS; particularly late in life. Our data raise several hypotheses including that, aging: (i) progressively suppresses normal immunosurveillance and thereby contributes to GBM cell initiation and/or outgrowth; (ii) decreases immunotherapeutic efficacy against malignant glioma.

The Inflammatory Potential of Dietary Manganese in a Cohort of Elderly Men.

Manganese is an essential nutrient that may play a role in the production of inflammatory biomarkers. We examined associations between estimated dietary manganese intake from food/beverages and supplements with circulating biomarkers of inflammation. We further explored whether estimated dietary manganese intake affects DNA methylation of selected genes involved in the production of these biomarkers. We analyzed 1023 repeated measures of estimated dietary manganese intakes and circulating blood inflammatory biomarkers from 633 participants in the Normative Aging Study. Using mixed-effect linear regression models adjusted for covariates, we observed positive linear trends between estimated dietary manganese intakes and three circulating interleukin proteins. Relative to the lowest quartile of estimated intake, concentrations of IL-1ß were 46% greater (95% CI - 5, 126), IL-6 52% greater (95% CI - 9, 156). and IL-8 32% greater (95% CI 2, 71) in the highest quartiles of estimated intake. Estimated dietary manganese intake was additionally associated with changes in DNA methylation of inflammatory biomarker-producing genes. Higher estimated intake was associated with higher methylation of NF-κß member activator NKAP (Q4 vs Q1: ß = 3.32, 95% CI - 0.6, 7.3). When stratified by regulatory function, higher manganese intake was associated with higher gene body methylation of NF-κß member activators NKAP (Q4 vs Q1: ß = 10.10, 95% CI - 0.8, 21) and NKAPP1 (Q4 vs Q1: ß = 8.14, 95% CI 1.1, 15). While needed at trace amounts for various physiologic functions, our results suggest estimated dietary intakes of manganese at levels slightly above nutritional adequacy contribute to inflammatory biomarker production.

Interactions between calcium intake and polymorphisms in genes essential for calcium reabsorption and risk of colorectal neoplasia in a two-phase study.

The SLC8A1 (solute carrier family 8, member 1) gene, encoding Na+ /Ca2+ exchanger, is essential in regulating calcium reabsorption and homeostasis. Calcium homeostasis plays a key role in cell proliferation and apoptosis. We hypothesized that polymorphisms in five calcium-regulating genes (SLC8A1, ATP2B1, CALB1, CALB2, and CABP1) interact with calcium intake in relation to the risk of colorectal neoplasia. A two-phase (discovery and replication) study was conducted within the Tennessee Colorectal Polyp Study, including a total of 1275 cases and 2811 controls. In Phase I, we identified six out of 135 SNPs that significantly interacted with calcium intake in relation to adenoma risk. In Phase II, the calcium intake by rs4952490 (SLC8A1) interaction was replicated (Pinteraction = 0.048). We found an inverse association between calcium intake (1000-2000 mg/day) and colorectal adenomas, particularly for multiple/advanced adenomas, among the G-allele carriers but not among homozygous carriers of the common variant (A) in rs4952490. In the joint analysis of SLC8A1, KCNJ1, and SLC12A1 SNPs, carriers of variant alleles in at least two genes and with calcium intake above the DRI (1000 mg/day) were approximately 30-57% less likely to have adenomas than those whose calcium intake was below the DRI. The association was stronger for multiple/advanced adenomas. No association was found among those who did not carry any variant alleles in these genes when calcium intake was below 2500 mg/day. These findings, if confirmed, may provide a new avenue for the personalized prevention of colorectal adenoma and cancer.

Genetic variation in SLC7A2 interacts with calcium and magnesium intakes in modulating the risk of colorectal polyps.

Solute carrier family 7, member 2 (SLC7A2) gene encodes a protein called cationic amino acid transporter 2, which mediates the transport of arginine, lysine and ornithine. l-Arginine is necessary for cancer development and progression, including an important role in colorectal cancer pathogenesis. Furthermore, previous studies found that both calcium and magnesium inhibit the transport of arginine. Thus, calcium, magnesium or calcium:magnesium intake ratio may interact with polymorphisms in the SLC7A2 gene in association with colorectal cancer. We conducted a two-phase case-control study within the Tennessee Colorectal Polyps Study. In the first phase, 23 tagging single-nucleotide polymorphisms in the SLC7A2 gene were included for 725 colorectal adenoma cases and 755 controls. In the second phase conducted in an independent set of 607 cases and 2113 controls, we replicated the significant findings in the first phase. We observed that rs2720574 significantly interacted with calcium:magnesium intake ratio in association with odds of adenoma, particularly multiple/advanced adenoma. In the combined analysis, among those with a calcium:magnesium intake ratio below 2.78, individuals who carried GC/CC genotypes demonstrated higher odds of adenoma [OR (95% CI):1.36 (1.11-1.68)] and multiple/advanced adenoma [OR (95% CI): 1.68 (1.28, 2.20)] than those who carried the GG genotype. The P values for interactions between calcium:magnesium intake ratio and rs2720574 were .002 for all adenomas and <.001 for multiple/advanced adenoma. Among those with the GG genotype, a high calcium:magnesium ratio was associated with increased odds of colorectal adenoma [OR (95% CI): 1.73 (1.27-2.36)] and advanced/multiple adenomas [1.62 (1.05-2.50)], whereas among those with the GC/CC genotypes, high calcium:magnesium ratio was related to reduced odds of colorectal adenoma [0.64 (0.42-0.99)] and advanced/multiple adenomas [0.55 (0.31-1.00)].

Greater Adherence to Cancer Prevention Guidelines Is Associated with Higher Circulating Concentrations of Vitamin D Metabolites in a Cross-Sectional Analysis of Pooled Participants from 2 Chemoprevention Trials.

Background: Several lifestyle factors targeted by the American Cancer Society (ACS) Nutrition and Physical Activity Cancer Prevention Guidelines are also associated with circulating concentrations of vitamin D metabolites. This suggests that greater adherence to the ACS guidelines may be related to better vitamin D status.Objective: We examined the relation between adherence to the ACS guidelines and circulating concentrations of 2 vitamin D metabolites, 25-hydroxycholecalciferol [25(OH)D] and 1α,25-dihydroxyvitamin D [1,25(OH)2D].Methods: We conducted cross-sectional analyses of pooled participants from the Wheat Bran Fiber (n = 503) and Ursodeoxycholic Acid (n = 854) trials. A cumulative adherence score was constructed with the use of baseline data on body size, diet, physical activity, and alcohol consumption. Continuous vitamin D metabolite concentrations and clinically relevant categories were evaluated with the use of multiple linear and logistic regression models, respectively.Results: The most adherent participants were more likely to be older, white, and nonsmokers than were the least adherent. A statistically significant association was observed between guideline adherence and concentrations of circulating 25(OH)D (means ± SEs-high adherence: 32.0 ± 0.8 ng/mL; low adherence: 26.4 ± 0.7 ng/mL; P-trend < 0.001). For 1,25(OH)2D concentrations, high adherence was again significantly related to greater metabolite concentrations, with mean ± SE concentrations of 36.3 ± 1.3 pg/mL and 31.9 ± 1.0 pg/mL for high- and low-adherers, respectively (P-trend = 0.008). Furthermore, the odds of attaining a sufficient 25(OH)D status were 4.37 times higher for those most adherent than for those least adherent (95% CI: 2.47, 7.71 times).Conclusion: These findings demonstrate that greater adherence to the ACS guidelines is associated with higher circulating concentrations of both of 25(OH)D and 1,25(OH)2D.

Bone loss after oophorectomy among high-risk women: an NRG oncology/gynecologic oncology group study.

OBJECTIVE: Women undergoing premenopausal oophorectomy for a variety of reasons, including to reduce ovarian or breast cancer risk were evaluated for accelerated bone loss. METHODS: The Gynecologic Oncology Group (GOG)-0215 randomized phase-II trial of zoledronic acid was initiated to determine if postoophorectomy bisphosphonate therapy could prevent this bone loss. The study was closed after slow accrual prevented evaluation of the primary study endpoint. We analyzed changes in bone mineral density (BMD) among the 80 women randomized to the observation arm of this study, as measured 3, 9, and 18 months postenrollment. RESULTS: The mean change in BMD from baseline to 18 months was -0.09 (95% CI, -0.12 to -0.07), -0.05 (95% CI, -0.07 to -0.03), and -0.06 (95% CI, -0.07 to -0.05) g/cm across the lumbar spine, right hip, and left hip, respectively. This represents a BMD decrease of -8.5% for the lumbar spine and -5.7% for both the right and left hips from baseline to 18 months' observation. CONCLUSIONS: These results demonstrate that premenopausal women undergoing oophorectomy clearly experience bone loss, an adverse effect of oophorectomy, which requires attention and active management. BMD should be monitored postoophorectomy, and treated per standard practice guidelines. Future studies will be required to determine if early treatment can mitigate fracture risk, and to test promising therapeutic interventions and novel prevention strategies, such as increased physical activity or alternative medications, in randomized trials.

Prospective changes in global DNA methylation and cancer incidence and mortality.

BACKGROUND: Methylation of repetitive elements Alu and LINE-1 in humans is considered a surrogate for global DNA methylation. Previous studies of blood-measured Alu/LINE-1 and cancer risk are inconsistent. METHODS: We studied 1259 prospective methylation measurements from blood drawn 1-4 times from 583 participants from 1999 to 2012. We used Cox regression to evaluate time-dependent methylation as a biomarker for cancer risk and mortality, and linear regression to compare mean differences in methylation over time by cancer status and analyse associations between rate of methylation change and cancer. RESULTS: Time-dependent LINE-1 methylation was associated with prostate cancer incidence (HR: 1.38, 95% CI: 1.01-1.88) and all-cancer mortality (HR: 1.41, 95% CI: 1.03-1.92). The first measurement of Alu methylation (HR: 1.39, 95% CI: 1.08-1.79) was associated with all-cancer mortality. Participants who ultimately developed cancer had lower mean LINE-1 methylation than cancer-free participants 10+ years pre-diagnosis (P<0.01). Rate of Alu methylation change was associated with all-cancer incidence (HR: 3.62, 95% CI: 1.09-12.10). CONCLUSIONS: Our results add longitudinal data on blood Alu and LINE-1 methylation and cancer, and potentially contribute to their use as early-detection biomarkers. Future larger studies are needed and should account for the interval between blood sample collection and cancer diagnosis.

Calcium/magnesium intake ratio, but not magnesium intake, interacts with genetic polymorphism in relation to colorectal neoplasia in a two-phase study.

Some studies suggest that the calcium to magnesium ratio intakes modify the associations of calcium or magnesium with risk of colorectal adenoma, adenoma recurrence, and cancer. Parathyroid hormone (PTH) plays a key role in the regulation of homeostasis for both calcium and magnesium. We hypothesized that polymorphisms in PTH and 13 other genes may modify the association between the calcium/magnesium intake ratio and colorectal neoplasia risk. We conducted a two-phase study including 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study. In Phase I, we identified 19 SNPs that significantly interacted with the calcium/magnesium intake ratio in adenoma risk. In Phase II, rs11022858 in PTH was replicated. In combined analysis of phases I and II, we found high calcium/magnesium intake ratio tended to be associated with a reduced risk of colorectal adenoma (P for trend, 0.040) among those who carried the TT genotype in rs11022858. In stratified analyses, calcium intake (≥ 1000 mg/d) was significantly associated with 64% reduced adenoma risk (OR = 0.36 (95% CI : 0.18-0.74)) among those homozygous for the minor allele (TT genotype) (P for trend, 0.012), but not associated with risk in other genotypes (CC/TC). Conversely, we found that highest magnesium intake was significantly associated with 27% reduced risk (OR = 0.73 (95% CI : 0.54-0.97)) of colorectal adenoma (P for trend, 0.026) among those who possessed the CC/TC genotypes, particularly among those with the TC genotype, whereas magnesium intake was not linked to risk among those with the TT genotype. These findings, if confirmed, will help for the development of personalized prevention strategies for colorectal cancer. © 2015 Wiley Periodicals, Inc.