Genome-wide interaction analysis of folate for colorectal cancer risk.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Risk factors for early-onset colorectal cancer: a population-based case-control study in Ontario, Canada.

PURPOSE: There has been an alarming increase in colorectal cancer (CRC) incidence among young adults aged < 50 years, and factors driving this upward trend are unknown. This study investigated associations between various medical, lifestyle, and dietary factors and risk of early-onset CRC (EO-CRC). METHODS: A population-based case-control study was conducted in Ontario, Canada during 2018-2019. EO-CRC cases aged 20-49 years (n = 175) were identified from the Ontario Cancer Registry; sex- and age group-matched controls (n = 253) were recruited through random digit dialing. Data on potential a priori risk factors were collected using a web-based self-reported questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression. RESULTS: Family history of CRC in a first- or second-degree relative (OR 2.37; 95% CI 1.47-3.84), longer sedentary time (≥ 10 vs. < 5 h/day, OR 1.93; 95% CI 1.02-3.65), greater consumption of sugary drinks (≥ 7 vs. < 1 drinks/week, OR 2.99; 95% CI 1.57-5.68), and a more Westernized dietary pattern (quartile 4 vs. 1, OR 1.92; 95% CI 1.01-3.66) were each associated with an increased risk of EO-CRC. Conversely, calcium supplement use (OR 0.53; 95% CI 0.31-0.92), history of allergy or asthma (OR 0.62; 95% CI 0.39-0.98), and greater parity in females (≥ 3 vs. nulliparity, OR 0.29; 95% CI 0.11-0.76) were each associated with a reduced risk. CONCLUSION: Modifiable factors, particularly sedentary behavior and unhealthy diet including sugary drink consumption, may be associated with EO-CRC risk. Our findings, if replicated, may help inform prevention strategies targeted at younger persons.

Iron intake, oxidative stress-related genes and breast cancer risk.

Iron has been suggested to contribute to breast cancer development through oxidative stress generation. Our study investigated associations between iron intake and breast cancer risk, overall and by menopausal and estrogen receptor/progesterone receptor (ER/PR) status, and modification by oxidative stress-related genetic polymorphisms (MnSOD, GSTM1 and GSTT1). A population-based case-control study (3,030 cases and 3,402 controls) was conducted in Ontario, Canada. Iron intake (total, dietary, supplemental, heme, nonheme) was assessed using a validated food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. Interactions between iron intake and genotypes were assessed among 1,696 cases and 1,761 controls providing DNA. Overall, no associations were observed between iron intake and breast cancer risk. Among premenopausal women, total, dietary and dietary nonheme iron were positively associated with ER-/PR- breast cancer risk (all ptrend < 0.05). Among postmenopausal women, supplemental iron was associated with reduced breast cancer risk (OR>18 vs. 0 mg/day = 0.68, 95% CI: 0.51-0.91), and dietary heme iron was associated with an increased risk, particularly the ER-/PR- subtype (ORhighest vs. lowest quintile = 1.69, 95% CI: 1.16-2.47; ptrend = 0.02). Furthermore, GSTT1 and combined GSTM1/GSTT1 polymorphisms modified some of the associations. For example, higher dietary iron was most strongly associated with increased breast cancer risk among women with GSTT1 deletion or GSTM1/GSTT1 double deletions (pinteraction < 0.05). Findings suggest that iron intake may have different effects on breast cancer risk according to menopausal and hormone receptor status, as well as genotypes affecting antioxidant capacity.

Iron intake, body iron status, and risk of breast cancer: a systematic review and meta-analysis.

BACKGROUND: Iron has been shown to promote breast carcinogenesis in animal models through generation of oxidative stress and interaction with estrogen. Heme iron, which is found exclusively in animal-sourced foods, is suggested to have a more detrimental effect. Epidemiological evidence of the association between iron and breast cancer risk remains inconclusive and has not been comprehensively summarized. This systematic review and meta-analysis evaluated associations between both iron intake and body iron status and breast cancer risk. METHODS: Four electronic databases (MEDLINE, EMBASE, CINAHL, and Scopus) were searched up to December 2018 for studies assessing iron intake and/or biomarkers of iron status in relation to breast cancer risk. Using random-effects meta-analyses, pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated comparing the highest vs. lowest category of each iron measure. Dose-response meta-analyses were also performed to investigate linear and nonlinear associations. RESULTS: A total of 27 studies were included in the review, of which 23 were eligible for meta-analysis of one or more iron intake/status measures. Comparing the highest vs. lowest category, heme iron intake was significantly associated with increased breast cancer risk, with a pooled RR of 1.12 (95% CI: 1.04-1.22), whereas no associations were found for dietary (1.01, 95% CI: 0.89-1.15), supplemental (1.02, 95% CI: 0.91-1.13), or total (0.97, 95% CI: 0.82-1.14) iron intake. Associations of iron status indicators with breast cancer risk were generally in the positive direction; however, a significant pooled RR was found only for serum/plasma levels (highest vs. lowest) of iron (1.22, 95% CI: 1.01-1.47), but not for ferritin (1.13, 95% CI: 0.78-1.62), transferrin saturation (1.16, 95% CI: 0.91-1.47), or total iron-binding capacity (1.10, 95% CI: 0.97-1.25). In addition, a nonlinear dose-response was observed for heme iron intake and serum iron (both Pnonlinearity < 0.05). CONCLUSIONS: Heme iron intake and serum iron levels may be positively associated with breast cancer risk. Although associations were modest, these findings may have public health implications given the widespread consumption of (heme) iron-rich foods. In light of methodological and research gaps identified, further research is warranted to better elucidate the relationship between iron and breast cancer risk.

High coffee intake, but not caffeine, is associated with reduced estrogen receptor negative and postmenopausal breast cancer risk with no effect modification by CYP1A2 genotype.

Associations between caffeine and coffee consumption and breast cancer risk are uncertain, with studies suggesting inverse and null associations. Variation in cytochrome P450 1A2 (CYP1A2), a gene responsible for caffeine metabolism, may modify these associations. Cases (n = 3,062) were recruited through the Ontario Cancer Registry and controls (n = 3,427) through random digit dialing. Logistic regression was used to evaluate associations between breast cancer risk and intakes of 7 caffeine-containing items and total caffeine, and examine whether a genetic variant in CYP1A2 (rs762551) modified these associations. Analyses were stratified by estrogen receptor (ER), menopausal, and smoking status. Generally, coffee and caffeine were not associated with breast cancer risk; however, a significant reduction in risk was observed with the highest category of coffee consumption [≥5 cups per day vs. never, multivariate-adjusted odds ratio (MVOR) = 0.71, 95% confidence interval (CI): 0.51, 0.98]. Variant rs762551 did not modify associations. In stratified analyses, high coffee intake was associated with reduced risk of ER- (MVOR = 0.41, 95% CI: 0.19, 0.92) and postmenopausal breast cancer (MVOR = 0.63, 95% CI: 0.43, 0.94). High coffee consumption, but not total caffeine, may be associated with reduced risk of ER- and postmenopausal breast cancers, independent of CYP1A2 genotype. Further studies are needed to replicate these findings.

Phytoestrogen intake from foods, during adolescence and adulthood, and risk of breast cancer by estrogen and progesterone receptor tumor subgroup among Ontario women.

Phytoestrogen intake may reduce breast cancer risk and limited evidence suggests this association may hold for hormone receptor-positive tumors only. The study aims were to assess whether the association between phytoestrogen intake during adolescence and adulthood and breast cancer risk varies by estrogen and progesterone receptor (ERPR) tumor subgroup. Cases were identified from the Ontario Cancer Registry (2002-2003), and ERPR status was ascertained from pathology reports for 81% of cases (n = 2,438). Controls were identified through random digit dialing of Ontario households (n = 3,370). Published phytoestrogen food values were applied to food frequency questionnaire responses to assess isoflavone, lignan and total phytoestrogen intake, during adolescence and adulthood. Polytomous multivariate logistic regression was used to estimate adjusted odds ratios (ORs) for association between phytoestrogen intake and breast cancer risk by hormone receptor ERPR tumor subgroups. Among premenopausal women, few associations were observed for adolescent or adult phytoestrogen intake across all tumor subgroups. Among postmenopausal women, adolescent phytoestrogen intake (isoflavone, lignan and total) was associated with reduced risk across all hormone receptor subgroups; however, statistical significance was most consistent within the ER+PR+ subgroup. For example, ER+PR+ postmenopausal breast cancer risk was associated with adolescent phytoestrogen intake (highest vs. lowest: OR = 0.79; 95% confidence interval: 0.65-0.96). Among all women and postmenopausal women, ORs for high adult lignan intake were all below 1.0 within each tumor subgroup, suggesting reduced breast cancer risk, although none reached statistical significance. In conclusion, adolescent phytoestrogen intake was associated with reduced postmenopausal breast cancer, particularly for ER+PR+ tumor subgroup.

Use of isoflavone supplements is associated with reduced postmenopausal breast cancer risk.

Botanical supplements are widely used and contain diverse ingredients, including isoflavones. Food-based isoflavones have been associated with reduced breast cancer risk. However, no study has comprehensively evaluated supplements identified by isoflavone content and breast cancer risk. Associations between ever use of 28 isoflavone supplements and breast cancer risk in Ontario, Canada were evaluated using cases (n = 3,101) identified in 2002-2003 from the Ontario Cancer Registry and controls (n = 3,471) identified through random digit dialing methods. Multivariate logistic regression was used to estimate age-adjusted odds ratio (AOR) and 95% confidence intervals (CI). Several individual supplements were associated with reduced breast cancer risk (e.g., Natural HRT; AOR = 0.39; 95% CI: 0.22, 0.69; n(users) = 58). Use of any isoflavone supplements was associated with reduced risk when ≥ 3 were ever used (AOR = 0.68; 95% CI: 0.54, 0.86; n(users) = 332; p(trend) = 0.008) or any was taken >5 years (AOR = 0.75; 95% CI: 0.60, 0.94; n(users) = 325; p(trend) = 0.01); high content supplements were consistently associated with reduced risk. Risk reduction was confined to postmenopausal breast cancer for both individual and combined supplements, and was strongest in the latter among high content users who ever took ≥ 3 supplements (AOR = 0.55; 95% CI: 0.38, 0.81; n(users) = 118; p(trend) = 0.04) or any >5 years (AOR = 0.47; 95% CI: 0.27, 0.81; n(users) = 60; p(trend) = 0.03). Associations did not differ by estrogen-progesterone tumor receptor status. In conclusion, isoflavone supplements were associated with decreased postmenopausal breast cancer risk. Further research to examine these novel findings is warranted, given the low supplement use and potential limitations of our results.

Intake of phytoestrogen foods and supplements among women recently diagnosed with breast cancer in Ontario, Canada.

Phytoestrogens are found in foods such as soy (isoflavones) and flaxseed (lignans), and certain botanical supplements. Their role in estrogen receptor positive (ER+) breast cancer recurrence and treatment is controversial, and it is unknown how this affects intake among patients. The Ontario Cancer Registry was used to identify 417 population-based breast cancer cases (mean time from diagnosis was 57 days). A questionnaire was mailed to determine intake of phytoestrogen foods and supplements in the last 2 mo, changes since diagnosis and differences by ER tumor status or hormonal treatment. Of 278 (67%) respondents, 56% consumed soy foods, 39% consumed isoflavone-rich foods (tofu, soybeans, soy milk, soy nuts), and 70% ate lignan-rich foods, including flaxseed (33%). Only soy milk, flaxseed, and flaxseed bread were commonly consumed more than once/wk. Few patients (4%) took isoflavone (soy, red clover, kudzu, licorice, isoflavones) or lignan/flaxseed supplements. Since diagnosis, 17% started or stopped soy foods (most stopped); this was more prevalent among those receiving hormonal treatment (20%; 95% confidence interval (CI): 14, 26) than not (6%; 95% CI: 1, 12). No other differences by ER status or hormonal treatment were observed. Research is needed to confirm this and to explore influencing factors.

Reported intake of selected micronutrients and risk of colorectal cancer: results from a large population-based case-control study in Newfoundland, Labrador and Ontario, Canada.

AIM: The impact of micronutrient intake and colorectal cancer (CRC) risk is poorly understood. The objective of this study was to evaluate the associations of selected micronutrients with risk of incident CRC in study participants from Newfoundland, Labrador (NL) and Ontario (ON), Canada. MATERIALS AND METHODS: We conducted a population-based study among 1760 case participants and 2481 age- and sex-matched control participants. Information on diet and other lifestyle factors were measured using a food frequency questionnaire and a personal history questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, controlling for covariables. RESULTS: Highest compared to lowest quartile intakes of certain micronutrients were associated with lower risk of CRC, including: calcium (from food and supplements (FS), OR=0.59; 95% CI=0.45-0.77, and from food only (FO): OR=0.76, 95% CI=0.59-0.97), vitamin C (FS:OR=0.67; 95%CI:0.51-0.88), vitamin D (FS: OR=0.73; 95% CI: 0.57-0.94, FO: OR=0.79, 95% CI=0.62-1.00), riboflavin (FS: OR=0.61; 95% CI=0.47-0.78, and folate (FS: OR=0.72; 95% CI=0.56-0.92). Higher risk of CRC was observed for iron intake (highest versus lowest quintiles: OR=1.34, 95% CI=1.01-1.78). CONCLUSION: This study presents evidence that dietary intake of calcium, vitamin D, vitamin C, riboflavin and folate are associated with a lower risk of incident CRC and that dietary intake of iron may be associated with a higher risk of the disease.

Calcium and vitamin D and risk of colorectal cancer: results from a large population-based case-control study in Newfoundland and Labrador and Ontario.

BACKGROUND: Previous epidemiological studies have been suggestive but inconclusive in demonstrating inverse associations of calcium, vitamin D, dairy product intakes with risk of colorectal cancer (CRC). We conducted a large population-based comparison of such associations in Newfoundland and Labrador (NL) and Ontario (ON). METHODS: A case control study design was used. Colorectal cancer cases were new CRC patients aged 20-74 years. Controls were a sex and age-group matched random sample of the population in each province. 1760 cases and 2481 controls from NL and ON were analyzed. Information on dietary intake and lifestyle was collected using self-administered food frequency and personal history questionnaires. RESULTS: Controls reported higher mean daily intakes of total calcium and total vitamin D than cases in both provinces. In ON, significant reduced CRC risk was associated with intakes of total calcium (OR of highest vs. lowest quintiles was 0.57, 95% CI 0.42-0.77, p(trend) = 0.03), total vitamin D (OR = 0.73, 95% CI 0.54-1.00), dietary calcium (OR = 0.76, 95% CI 0.60-0.97), dietary vitamin D (OR = 0.77, 95% CI 0.61-0.99), total dairy products and milk (OR = 0.78, 95% CI 0.60-1.00), calcium-containing supplements use (OR = 0.76). In NL, the inverse associations of calcium, vitamin D with CRC risk were most pronounced among calcium- or vitamin D-containing supplement users (OR = 0.67, 0.68, respectively). CONCLUSIONS: Results of this study add to the evidence that total calcium, dietary calcium, total vitamin D, dietary vitamin D, calcium- or vitamin D-containing supplement use may reduce the risk of CRC. The inverse associations of CRC risk with intakes of total dairy products and milk may be largely due to calcium and vitamin D.

Vitamin D intake from food and supplements among Ontario women based on the US block food frequency questionnaire with and without modification for Canadian food values.

OBJECTIVES: To measure and compare dietary vitamin D intake among women in Ontario using a modified Block 1998 (US) food frequency questionnaire (FFQ) before and after modification for Canadian-specific vitamin D food fortification. METHODS: An age-stratified random sample of 3,471 women in Ontario (aged 25-74) was identified using random digit dialing methods. Standard US food values and a modified Canadian-specific vitamin D nutrient analysis were applied to the FFQ. RESULTS: Intake of vitamin D from foods (Canadian nutrient analysis) was 5.3 +/- 3.4 microg/day (mean +/- SD) and 45% of women reported vitamin D intake from supplements. Total vitamin D intakes met the current Adequate Intakes of 5, 10 and 15 microg/day for only 62%, 47%, and 28% of women aged < or = 50, 51-70 and > or = 71, respectively. Relatively high agreement was found between the US and Canadian nutrient analysis methods of measuring vitamin D from food (weighted kappa = 0.74, 95% CI 0.72-0.76). Intake differences (US minus Canadian) ranged from -5.0 microg/day to +2.0 microg/day (1st-99th percentile); however, the mean difference was only -0.54 microg/day (95% CI: -0.58 to -0.50). CONCLUSIONS: Lower than recommended total vitamin D intakes were observed among our study participants which may negatively impact the health status of women. Adjustment for Canadian food fortification and the inclusion of fatty fish had little impact on the measurement of vitamin D from food.

Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women.

BACKGROUND: Some evidence suggests that vitamin D may reduce breast cancer risk. Despite the biological interaction between vitamin D and calcium, few studies have evaluated their joint effects on breast cancer risk. OBJECTIVE: The objective was to evaluate the associations and potential interaction between vitamin D and calcium (from food and supplements) and breast cancer risk in a population-based case-control study. DESIGN: Breast cancer cases aged 25-74 y (diagnosed 2002-2003) were identified through the Ontario Cancer Registry. Controls were identified by using random digit dialing; 3101 cases and 3471 controls completed epidemiologic and food-frequency questionnaires. Adjusted odds ratios (ORs) and 95% CIs were estimated by using multivariate logistic regression. RESULTS: Vitamin D and calcium intakes from food only and total combined intakes (food and supplements) were not associated with breast cancer risk, although the mean intake of vitamin D was low. Vitamin D supplement intake >10 microg/d (400 IU/d) compared with no intake was associated with a reduced risk of breast cancer (adjusted OR: 0.76; 95% CI: 0.59, 0.98). No categories of calcium supplement intake were significantly associated with reduced breast cancer risk, but a significant inverse trend was observed (P = 0.04). There were no significant interactions involving vitamin D, calcium, or menopausal status. CONCLUSIONS: No associations were found between overall vitamin D or calcium intake and breast cancer risk. Vitamin D from supplements was independently associated with reduced breast cancer risk. Further research is needed to investigate the effects of higher doses of vitamin D and calcium supplements.

Genetic variation in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC) and risk for colorectal cancer: results from the Colon Cancer Family Registry.

Epidemiologic evidence supports a role for vitamin D in colorectal cancer (CRC) risk. Variants in vitamin D-related genes might modify the association between vitamin D levels and CRC risk. In this analysis, we did a comprehensive evaluation of common variants in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC; group-specific component) genes using a population-based case-unaffected sibling control design that included 1,750 sibships recruited into the Colon Cancer Family Registry. We also evaluated whether any associations differed by calcium supplement use, family history of CRC, or tumor characteristics. Heterogeneity by calcium and vitamin D intake was evaluated for a subset of 585 cases and 837 sibling controls who completed a detailed food frequency questionnaire. Age- and sex-adjusted associations were estimated using conditional logistic regression. Overall, we did not find evidence for an association between any single-nucleotide polymorphism (SNP) in VDR or GC and risk for CRC (range of unadjusted P values 0.01-0.98 for VDR and 0.07-0.95 for GC). None of these associations was significant after adjustment for multiple comparisons. We also found no evidence that calcium or vitamin D intake (food and supplement) from the food frequency questionnaire modified the association estimates between VDR and GC SNPs and CRC. We did observe associations between SNPs in GC and microsatellite unstable CRC, although these results should be confirmed in additional studies. Overall, our results do not provide evidence for a role of common genetic variants in VDR or GC in susceptibility to CRC.

Lifestyle, dietary, and medical history factors associated with pancreatic cancer risk in Ontario, Canada.

OBJECTIVES: Pancreatic adenocarcinoma has one of the worst survival rates of all the cancers. Established risk factors for this malignancy are smoking, body mass index (BMI) and family history of pancreatic cancer. Findings are inconsistent regarding pancreatitis, diabetes, allergies, intake of fruit, vegetables, red meat, alcohol, caffeine, vitamin C, calcium, and folate supplements. Possible pancreatic cancer risk factors were evaluated within the population-based Ontario Pancreas Cancer Study. METHODS: Pathologically confirmed pancreatic cancer cases (n = 422) were identified from the Ontario Cancer Registry between 2003 and 2007. Controls (n = 312) were recruited through random digit dialing. Data were collected using self-administered questionnaires. Multivariate logistic regression was used to obtain odds ratios. RESULTS: Smoking, BMI, family history of pancreatic cancer, and caffeine were significantly associated with increased pancreatic cancer risk, while fruit intake and allergies significantly decreased risk. No other significant associations were observed in the multivariate model. Effect modification by smoking status was suggested for caffeine, family history of pancreatic cancer, BMI, and fruit. CONCLUSIONS: This study further clarifies the association between several lifestyle, dietary and medical history factors, and pancreatic cancer risk, many of which are potentially modifiable. Possible effect modification by smoking status should be further explored in future etiologic studies.

Dietary phytoestrogen intake--lignans and isoflavones--and breast cancer risk (Canada).

OBJECTIVE: To evaluate whether phytoestrogen intake is associated with reduced breast cancer risk, using a novel phytoestrogen database. METHODS: Population-based breast cancer cases aged 25-74 years (diagnosed 2002-2003) were identified using Ontario Cancer Registry (n = 3,063) and controls (n = 3,430) were an age-stratified random sample of women identified through random digit dialing. An epidemiologic and Block food frequency questionnaire--expanded to include phytoestrogen-containing foods--was mailed to all subjects. The recently published Ontario phytoestrogen database was applied to FFQ responses to estimate intake. Multivariate logistic regression provided odds ratio (OR) estimates, while controlling for confounders. RESULTS: Among all women, lignan intake was associated with a reduced breast cancer risk (Q5 vs. Q1 MVOR: 0.81, 95% CI: 0.65, 0.99); however, following stratification by BMI, this reduction in risk was statistically significant only among overweight (BMI > 25) women. Total phytoestrogen intake was also associated with a risk reduction among overweight women only. Among pre-menopausal women, total phytoestrogen intake was associated with a significant reduction in breast cancer risk among overweight women only (Q5 vs. Q1 MVOR: 0.51, 95% CI: 0.30, 0.87). Among post-menopausal women, no statistically significant association was observed between breast cancer risk and isoflavones or lignans. CONCLUSION: Lignan intake may be associated with reduced breast cancer risk among pre-menopausal women, and our data suggest BMI modifies this association.

Dietary phytoestrogens, including isoflavones, lignans, and coumestrol, in nonvitamin, nonmineral supplements commonly consumed by women in Canada.

Twenty-one nonvitamin, nonmineral dietary supplements commonly consumed by women in Canada were analyzed for isoflavones (formononetin, daidzein, genistein, glycitein), lignans (pinoresinol, lariciresinol, secoisolariciresinol, matairesinol), and coumestrol to complement our previously published food phytoestrogen database. Supplements containing soy or red clover had the highest concentrations of total isoflavones (728.2-35,417.0 ug/g) and total phytoestrogens (1030.1-35,517.7 ug/g) followed by licorice and licorice-containing supplements (41.3-363.3 ug/g isoflavones; 56.5-370.0 ug/g total phytoestrogens). Other supplements had considerably less isoflavones (