Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk.

Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Coffee Consumption and the Risk of Colorectal Cancer.

BACKGROUND: Coffee contains several bioactive compounds relevant to colon physiology. Although coffee intake is a proposed protective factor for colorectal cancer, current evidence remains inconclusive. METHODS: We investigated the association between coffee consumption and risk of colorectal cancer in 5,145 cases and 4,097 controls from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study in northern Israel. We also examined this association by type of coffee, by cancer site (colon and rectum), and by ethnic subgroup (Ashkenazi Jews, Sephardi Jews, and Arabs). Coffee data were collected by interview using a validated, semi-quantitative food frequency questionnaire. RESULTS: Coffee consumption was associated with 26% lower odds of developing colorectal cancer [OR (drinkers vs. non-drinkers), 0.74; 95% confidence interval (CI), 0.64-0.86; P < 0.001]. The inverse association was also observed for decaffeinated coffee consumption alone (OR, 0.82; 95% CI, 0.68-0.99; P = 0.04) and for boiled coffee (OR, 0.82; 95% CI, 0.71-0.94; P = 0.004). Increasing consumption of coffee was associated with lower odds of developing colorectal cancer. Compared with <1 serving/day, intake of 1 to <2 servings/day (OR, 0.78; 95% CI, 0.68-0.90; P < 0.001), 2 to 2.5 servings/day (OR, 0.59; 95% CI, 0.51-0.68; P < 0.001), and >2.5 servings/day (OR, 0.46; 95% CI, 0.39-0.54; P < 0.001) were associated with significantly lower odds of colorectal cancer (Ptrend < 0.001), and the dose-response trend was statistically significant for both colon and rectal cancers. CONCLUSIONS: Coffee consumption may be inversely associated with risk of colorectal cancer in a dose-response manner. IMPACT: Global coffee consumption patterns suggest potential health benefits of the beverage for reducing the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 634-9. ©2016 AACR.

The risk of all-cause mortality is inversely related to serum 25(OH)D levels.

CONTEXT AND OBJECTIVES: Vitamin D plays a key role in maintaining bone health, but evidence for its nonskeletal effects is inconsistent. This study aims to examine the association between serum 25-hydroxyvitamin D [25(OH)D] levels and all-cause mortality in a large general population cohort. DESIGN, PARTICIPANTS, AND SETTING: Using the computerized database of the largest health care provider in Israel, we identified a cohort of subjects 20 years old or older with serum 25(OH)D levels measured between January 2008 and December 2009. Vital status was ascertained through August 2011. RESULTS: Median follow-up was 28.5 months (interquartile range 23.8-33.5 months); 7,247 of 182,152 participants (4.0%) died. Subjects who died had significantly lower serum 25(OH)D levels (mean 44.8 ± 24.2 nmol/liter) than those alive at the end of follow-up (51.0 ± 23.2 nmol/liter), P < 0.001. After adjustment for age, gender, ethnicity, and seasonality, the hazard ratio (HR) for all-cause mortality was 2.02 [95% confidence interval (CI) 1.89-2.15] for the lowest serum 25(OH)D quartile (<33.8 nmol/liter) compared with the highest. After further adjustment for comorbidity, use of vitamin D supplements and statins, smoking, socioeconomic status, and body mass index, the HR was 1.81 (95% CI 1.69-1.95). This remained, even after adjustment for serum low-density lipoprotein, high-density lipoprotein, calcium level (corrected for serum albumin levels), and glomerular filtration rate, 1.85 (95% CI 1.70-2.01). The fully adjusted HR associated with being in the second 25(OH)D quartile (33.8-49.4 nmol/liter) was 1.25 (95% CI 1.16-1.34). CONCLUSIONS: All-cause mortality is independently and inversely associated with serum 25(OH)D levels at levels less than 50 nmol/liter.

The longitudinal variability of serum 25(OH)D levels.

BACKGROUND: The extent to which a single serum 25(OH)D measurement represents long-term vitamin D status remains unclear. This study aims to assess the variability of serum 25(OH)D between tests taken at different time intervals. METHODS: Using the computerized database of the largest healthcare provider in Israel, we identified subjects in whom a serum 25(OH)D test was performed on at least two different occasions between January 2008 and September 2011 (n = 188,771). For these subjects we selected the first and the last dated tests, then we identified those who were not treated with supplements during the last 6 months before the first and before the last test (n = 94,418). Of these we analyzed subjects in whom the first and the last tests were performed in the same month of the year (n = 8881). RESULTS: The mean serum 25(OH)D level at the first test was 51.7 ± 24.0 nmol/L and was 56.7 ± 24.7 at the last test (P<0.001); the overall correlation was 0.63 (P < 0.001). For vitamin D status in two categories (<50 versus ≥ 50 nmol/L), the percentage of agreement between the first and last tests was 74.4%, and was 50.8% for vitamin D status in four categories (<30, 30-49.9, 50-74.9, and ≥ 75 nmol/L). The correlation decreased with increasing time between the tests ranging from 0.83 for tests done at the same year to 0.55 after 3 years. The more the first levels were higher or lower, the more likely subjects remain in their first category (≥ 50 versus <50 nmol/L). CONCLUSIONS: Long-term month specific serum 25(OH)D levels are relatively stable.

Vitamin D status in primary hyperparathyroidism.

BACKGROUND: Hypovitaminosis D worsens the manifestations of primary hyperparathyroidism (PHPT). Only a few studies have assessed the status of vitamin D in PHPT. The objective of this study was to determine the prevalence of 25(OH)D levels<50 nmol/L in PHPT in comparison to a population without PHPT. METHODS: Subjects with PHPT were identified from the computerized database of the Clalit Health Services in Israel and were included only if they had an available serum 25(OH)D test result in 2009 and were not taking vitamin D supplements in 2008-2009 prior to the 25(OH)D test result. Subjects with renal failure were excluded (included n=1180). All other subjects with an available 25(OH)D value in 2009 constituted the control group (n=184,479). RESULTS: Subjects with PHPT and 25(OH)D<50 nmol/L had higher levels of serum PTH, alkaline phosphatase, and calcium levels compared to those with 25(OH)D levels≥50 nmol/L (P<0.02). The mean serum 25(OH)D level was 47.7±22.5 nmol/L compared to 52.1±24.5 nmol/L in the control group (P<0.001). 59.6% of subjects with PHPT had 25(OH)D levels<50 nmol/L as compared to 49.5% in the control group (P<0.001). Logistic regression, controlling for gender, ethnicity, age, and seasonality, showed that PHPT independently predicted 25(OH)D levels<50 nmol/L; OR=1.61(95% CI, 1.43-1.82). CONCLUSIONS: Serum 25(OH)D levels<50 nmol/L are frequent in PHPT, are more common than in controls, and are associated with more severe bone disease based on higher serum PTH and bone turnover biomarkers.

Vitamin D Status in Israeli subjects before the initiation and after the cessation of vitamin D supplements.

Vitamin D supplements are often recommended to restore sufficiency, although the adherence to treatment is low. This study assessed vitamin D status at different time intervals following the cessation of treatment. The database of Clalit-Health-Services (CHS), a not-for-profit HMO covering more than half of the Israeli population, was retrospectively searched for all members with available serum 25OHD test results in 2009 (245,493). We then identified those who filled any cholecalciferol prescription in 2008-2009 (121,817). Subjects were included in the final analysis only if they started treatment in 2009, had serum 25OHD < 50 nmol/l before the first prescription in 2009, and had at least one additional test result after the last dated prescription in 2009 (5,461). Serum 25OHD increased from 32 ± 11 nmol/l at baseline to 58.6 ± 22.3 nmol/l after treatment (P < 0.001). The proportion of subjects with sufficient vitamin D after treatment increased with increasing cholecalciferol daily dose and treatment duration (P < 0.001) and decreased with increasing time from cessation of treatment (P < 0.001). The effect of time from treatment cessation persisted after controlling for baseline serum 25OHD, daily cholecalciferol dose, treatment duration, seasonality, gender, age, ethnicity, and BMI; the ORs for sufficient vitamin D were 2.02 (95% CI 1.66-2.45), 1.67 (1.39-2.01), and 1.23 (1.04-1.47) for >30-60, 61-99, and 100-155 days compared to >155 days, respectively. Long-term vitamin D treatment is needed to maintain sufficient levels in those with baseline serum 25OHD below 50 nmol/l.

Use of bisphosphonates and risk of postmenopausal breast cancer.

PURPOSE: Bisphosphonates are commonly used for the treatment of osteoporosis and for prevention and treatment of skeletal lesions due to malignancy. However, the association between the use of bisphosphonates and the risk of developing breast cancer has not been reported. PATIENTS AND METHODS: The Breast Cancer in Northern Israel Study is a population-based case-control study in northern Israel of patients with breast cancer and age-, clinic-, and ethnic-group matched controls. Use of bisphosphonates was assessed in 4,039 postmenopausal patients and controls, members of Clalit Health Services, using pharmacy records. RESULTS: The use of bisphosphonates for longer than 1 year before diagnosis, but not for shorter than 1 year, was associated with a significantly reduced relative risk of breast cancer (odds ratio [OR], 0.61; 95% CI, 0.50 to 0.76). This association remained significant after adjustment for age, fruit, and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, use of calcium supplements, hormone replacement therapy use, number of pregnancies, months of breast feeding, and age at first pregnancy (OR, 0.72; 95% CI, 0.57 to 0.90). Breast cancer risk did not change further if bisphosphonates were used for more years. Breast tumors identified in bisphosphonates users were more often estrogen receptor positive and less often poorly differentiated. CONCLUSION: The use of bisphosphonates for longer than 1 year was associated with a 28% relative reduction in the risk of postmenopausal breast cancer. Tumors developing under bisphosphonates treatment tended to have a favorable prognostic factors profile.

Gene expression patterns in mismatch repair-deficient colorectal cancers highlight the potential therapeutic role of inhibitors of the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway.

PURPOSE: High-frequency microsatellite-instable (MSI-H) tumors account for approximately 15% of colorectal cancers. Therapeutic decisions for colorectal cancer are empirically based and currently do not emphasize molecular subclassification despite an increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI colorectal cancers using combined gene expression data sets. EXPERIMENTAL DESIGN: Three expression/query signatures (discovery data set) characterizing MSI-H colorectal cancer were matched with information derived from changes induced in cell lines by 164 compounds using the systems biology tool "Connectivity Map." A series of sequential filtering and ranking algorithms were used to select the candidate compounds. Compounds were validated using two additional expression/query signatures (validation data set). Cytotoxic, cell cycle, and apoptosis effects of validated compounds were evaluated in a panel of cell lines. RESULTS: Fourteen of the 164 compounds were validated as targeting MSI-H cell lines using the bioinformatics approach; rapamycin, LY-294002, 17-(allylamino)-17-demethoxygeldanamycin, and trichostatin A were the most robust candidate compounds. In vitro results showed that MSI-H cell lines due to hypermethylation of MLH1 are preferentially targeted by rapamycin (18.3 versus 4.4 mumol/L; P = 0.0824) and LY-294002 (15.02 versus 10.37 mumol/L; P = 0.0385) when compared with microsatellite-stable cells. Preferential activity was also observed in MSH2 and MSH6 mutant cells. CONCLUSION: Our study shows that the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway is of special relevance in mismatch repair-deficient colorectal cancer. In addition, we show that amalgamation of gene expression information across studies provides a robust approach for selection of potential therapies corresponding to specific groups of patients.

Prevention and early detection of colorectal cancer--new horizons.

Colorectal cancer is potentially one of the most preventable malignancies. Nutritional awareness (low fat, low red meat, high fruits and vegetables) and regular physical activity have major potential for primary prevention of this malignancy, while early detection technologies have the potential of both influencing mortality from colorectal cancer as well as enhancing primary prevention through detection and removal of lesions that could potentially develop into cancer. While the potential for prevention is large, its materialization is far from being optimal. The large-scale lifestyle changes in the population necessary to reduce colorectal cancer rates are hard to achieve, and most of the early detection technologies are either invasive or otherwise nonappealing to the population. Thus, without abandoning the proven prevention methods, new avenues need to be investigated to deal with this malignancy, which carries both high morbidity and high mortality. Such new avenues can now be followed, both in prevention and detection. Chemoprevention, or the use of medications to prevent disease, has now been extensively explored in colorectal cancer. Some of these interventions, such as supplemental fibers, have failed to demonstrate the anticipated effect, while others such as calcium supplementation have been shown to reduce formation of premalignant lesions, polyps, or adenomas. Data accumulating in recent years have suggested that aspirin, nonsteroidal anti-inflammatory drugs, and selective COX-II inhibitors all have a potential to reduce both colorectal cancer and colorectal adenomas. Issues of safety and therapeutic indexes have recently come up as barriers to the use of COX-II inhibitors, and have again drawn attention to aspirin as a potential drug of choice. Association studies have also shown a major potential role for statins in colorectal cancer prevention. New methodologies in cancer detection involve the introduction of colonography or virtual colonoscopy, and the development of methods of detection of genetic somatic mutations in feces or peripheral blood. While radiological techniques currently avoid the need for premedication and are less invasive, they currently still require similar gut cleansing to colonoscopy, can also lead to perforation, are costly, and carry a non-negligible exposure to radiation. Genetic analysis of the stool for mutations in tumor cells is evolving as a promising technique, struggling to achieve both high sensitivity and high specificity with the right combination of mutations sought. With all of these developments taking place, the near future will undoubtedly bring about the expected reduction in colorectal cancer mortality.

Sustained effect of short-term calcium supplementation on bone mass in adolescent girls with low calcium intake.

BACKGROUND: The effect of short-term calcium supplementation on peak bone mass in adolescent girls is not completely defined. In our previous double-blind, placebo-controlled, calcium-supplementation study (1000 mg calcium carbonate/d), we showed that calcium supplementation of postmenarcheal girls with low calcium intakes enhances bone mineral acquisition. OBJECTIVE: The objective of this follow-up study, conducted 3.5 y after the end of calcium supplementation, was to investigate the sustained effect of calcium supplementation on bone mineral mass. DESIGN: Anthropometric data, nutrient intakes, and bone variables were reassessed in 96 of the 100 adolescent girls whose data had been studied at the end of the supplementation period. Bone mineral content and bone mineral density (BMD) of the total body, lumbar spine, and femoral neck were determined by dual-energy X-ray absorptiometry. RESULTS: The calcium-supplemented group tended to have a greater accretion of total-body BMD (TBBMD) than did the control group 3.5 y after the end of supplementation. The finding was statistically significant in the active-treatment cohort (n = 17 in the calcium-supplemented group and 28 in the placebo group), who had a compliance rate of > or =75% during the intervention study. In a multivariate linear-regression analysis, TBBMD accretion from the beginning of the intervention study to the follow-up study in the active-treatment cohort was attributed to calcium supplementation and to the time since inclusion in the initial study. CONCLUSION: Calcium supplementation for 1 y in postmenarcheal girls with low calcium intakes may provide a sustained effect on the basis of TBBMD measurements in participants with compliance rates of > or =75%.

Calcium supplementation provides an extended window of opportunity for bone mass accretion after menarche.

BACKGROUND: High calcium intakes during adolescence may increase bone acquisition. The magnitude of the effect of dietary calcium supplementation and the timing of its administration to achieve significant effects on bone health are still incompletely defined. OBJECTIVE: The objective of this study was to assess the effect of calcium supplementation on bone mass accretion in postmenarcheal adolescent girls with low calcium intakes. DESIGN: A double-blind, placebo-controlled calcium supplementation study was implemented. One hundred girls with a mean (+/- SD) age of 14 +/- 0.5 y with habitual calcium intakes < 800 mg/d completed a 12-mo protocol. The treatment group received a daily supplement containing 1000 mg elemental calcium. Bone mineral density (BMD) and bone mineral content (BMC) of the total body, lumbar spine, and femoral neck were determined at inclusion, 6 mo, and 12 mo. Also measured were serum concentrations of biochemical markers of bone turnover (osteocalcin and deoxypyridinoline), parathyroid hormone, and vitamin D. RESULTS: The calcium-supplemented group had greater accretion of total-body BMD and lumbar spine BMD but not BMC than did the control group. Calcium supplementation appeared selectively beneficial for girls who were 2 y postmenarcheal. Calcium supplementation significantly decreased bone turnover and decreased serum parathyroid hormone concentrations. CONCLUSION: Calcium supplementation of postmenarcheal girls with low calcium intakes enhances bone mineral acquisition, especially in girls > 2 y past the onset of menarche.

Clustering women's health behaviors.

This study attempts to characterize health lifestyles by subgrouping women with similar behavior patterns. Data on background, health behaviors, and perceptions were collected via phone interview from 1,075 Israeli women aged 50 to 74. From a cluster analysis conducted on health behaviors, three clusters emerged: a "health promoting" cluster (44.1%), women adhering to recommended behaviors; an "inactive" cluster (40.3%), women engaging in neither health-promoting nor compromising behaviors; and an "ambivalent" cluster (15.4%), women engaging somewhat in both health-promoting and compromising behaviors. Clustering was cross-tabulated by demographic and perceptual variables, further validating the subgrouping. The cluster solution was also validated by predicting another health behavior (mammography screening) for which there was an external validating source. Findings are discussed in comparison to published cluster solutions, culminating in suggestions for intervention alternatives. The concept of lifestyle was deemed appropriate to summarize the clustering of these behavioral, perceptual, and structural variables.