Plasma methionine,choline, betaine,and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)

BackgroundDisturbances in one carbon metabolism may contribute to carcinogenesis by affecting methylation and synthesis of DNA. Choline and its oxidation product betaine are involved in this metabolism and can serve as alternative methyl group donors when folate status is low.Patients and methodsWe conducted a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1367 incident CRC cases (965 colon and 402 rectum) and 2323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for CRC risk were estimated by conditional logistic regression, comparing the fifth to the first quintile of plasma concentrations.ResultsOverall, methionine (OR: 0.79, 95% CI: 0.63–0.99, P-trend = 0.05), choline (OR: 0.77, 95% CI: 0.60–0.99, P-trend = 0.07), and betaine (OR: 0.85, 95% CI: 0.66–1.09, P-trend = 0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/l, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95% CI: 0.50–1.00, P-trend = 0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95% CI: 0.43–0.88, P-trend = 0.01). Plasma DMG was not associated with CRC risk.ConclusionsIndividuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of CRC.     

Associations of early life and adulthood adiposity with risk of epithelial ovarian cancer

BackgroundFew studies have evaluated the association between early life adiposity and ovarian cancer risk. Adiposity during different periods of life may be differentially associated with the risk.Patients and methodsWe prospectively followed 133 526 women in the Nurses' Health Study (NHS; 1980–2012) and NHSII (1989–2013). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident ovarian cancer (N = 788) according to validated measures for early life adiposity [body mass index (BMI) at age 10 imputed from somatotype and recalled BMI at age 18) as well as BMI change between age 10 and 18 and after age 18 (current weight assessed on every biennial questionnaire since baseline).ResultsAfter mutual adjustment for BMI at age 10, BMI at age 18 and current BMI, the HR (95% CI) for ovarian cancer risk per 5 kg/m² was 0.84 (0.74–0.96) for BMI at age 10 (P-trend = 0.01), 1.17 (1.03–1.33) for BMI at age 18 (P-trend = 0.02), and 1.06 (0.99–1.14) for current BMI (P-trend = 0.08). However, the inverse association with BMI at age 10 was attenuated after adjusting for BMI change between age 10 and 18 and BMI change after age 18 (HR per 5 kg/m²: 1.04; 95% CI 0.91–1.20; P-trend = 0.55). By contrast, BMI change between age 10 and 18 was strongly positively associated with ovarian cancer risk (HR per 5 kg/m² increase: 1.24; 95% CI 1.11–1.39; P-trend = 0.0002), whereas BMI change since age 18 was only slightly associated with risk (HR per 5 kg/m² increase: 1.06; 95% CI 0.99–1.14; P-trend = 0.10). These associations were in general stronger for premenopausal cases or non-serous tumors.ConclusionEarly life changes in adiposity were more strongly associated with ovarian cancer risk than adulthood changes. The specific mechanisms underlying the associations with adiposity changes during early life warrant further investigation.     

Prognostic significance of Ki-67 labeling index after short-term presurgical tamoxifen in women with ER-positive breast cancer

BackgroundStudies have shown that Ki-67 response after short-term neoadjuvant aromatase inhibitors may predict recurrence in postmenopausal breast cancer, whereas its prognostic effect in premenopausal women is unknown.Patients and methodsWe compared the prognostic and predictive value of baseline and post-treatment Ki-67 in 120 pre- and postmenopausal women with early-stage estrogen receptor-positive breast cancer who participated in a 4-week presurgical trial of tamoxifen.ResultsAfter 7.2 years of follow-up, women with post-treatment Ki-67 in the second (14%–19%), third (20%–29%) and top (≥30%) quartiles had a recurrence hazard ratio of 2.92 [95% confidence interval (CI) 0.95–8.96], 4.37 (1.56–12.25) and 6.05 (2.07–17.65), respectively, as compared with those in the bottom quartile (<14%) (P-trend = 0.001). The risk of invasive disease recurrence was 2.2% (95% CI 0.9–5.0) per point increase in baseline Ki-67 (P-trend = 0.076) and 5.0% (95% CI 2.3–7.7) per point increase in post-tamoxifen Ki-67 (P-trend < 0.001). The risk of death was 5.5 (95% CI 1.26–23.16) times higher in patients with post-drug Ki-67 ≥20% than in those with Ki-67 <20% (P-trend = 0.006).ConclusionsKi-67 response after short-term neoadjuvant tamoxifen is a good predictor of recurrence-free survival and overall survival, further supporting its use as surrogate biomarker to personalize adjuvant treatment and to screen novel drugs cost-effectively.     

Genetic variation in PRL and PRLR, and relationships with serum prolactin levels and breast cancer risk: results from a population-based case-control study in Poland

Introduction

Studies suggest that high circulating levels of prolactin increase breast cancer risk. It is unclear if genetic variations in prolactin (PRL) or prolactin receptor (PRLR) genes also play a role. Thus, we examined the relationship between single nucleotide polymorphisms (SNPs) in PRL and PRLR, serum prolactin levels and breast cancer risk in a population-based case-control study.

Methods

We genotyped 8 PRL and 20 PRLR tag SNPs in 1965 breast cancer cases and 2229 matched controls, aged 20-74, and living in Warsaw or Łódź, Poland. Serum prolactin levels were measured by immunoassay in a subset of 773 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for genotype associations with breast cancer risk were estimated using unconditional logistic regression, adjusted for age and study site. Geometric mean prolactin levels were estimated using linear regression models adjusted for age, study site, blood collection time, and menstrual cycle day (premenopausal women).

Results

Three SNPs were associated with breast cancer risk: in premenopausal women, PRLR rs249537 (T vs. C per-allele OR 1.39, 95% CI 1.07 - 1.80, P = 0.01); and in postmenopausal women, PRLR rs7718468 (C vs. T per-allele OR 1.16, 95% CI 1.03 - 1.30, P = 0.01) and PRLR rs13436213 (A vs. G per-allele OR 1.13 95% CI 1.01 - 1.26, P = 0.04). However, mean serum prolactin levels for these SNPs did not vary by genotype (P-trend > 0.05). Other SNPs were associated with serum prolactin levels: PRLR rs62355518 (P-trend = 0.01), PRLR rs10941235 (P-trend = 0.01), PRLR rs1610218 (P-trend = 0.01), PRLR rs34024951 (P-trend = 0.02), and PRLR rs9292575 (P-trend = 0.03) in premenopausal controls and PRL rs849872 (P-trend = 0.01) in postmenopausal controls.

Conclusions

Our data provide limited support for an association between common variations in PRLR and breast cancer risk. Altered serum prolactin levels were not associated with breast cancer risk-associated variants, suggesting that common genetic variation is not a strong predictor of prolactin-associated breast cancer risk in this population.     

Use of aspirin,other nonsteroidal anti-inflammatory drugs and acetaminophen and risk of endometrial cancer: the Epidemiology of Endometrial Cancer Consortium

BackgroundRegular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited.Patients and methodsWe pooled individual-level data from seven cohort and five case–control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7120 women with endometrial cancer and 16 069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses, we used mixed-effects logistic regression with study as a random effect.ResultsAt least weekly use of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR = 0.86 [95% CI 0.76–0.98] and 0.86 [95% CI 0.76–0.97], respectively, for aspirin; 0.87 [95% CI 0.76–1.00] and 0.84 [0.74–0.96], respectively, for non-aspirin NSAIDs). There was no association among women of normal weight (body mass index < 25 kg/m², P_{heterogeneity} = 0.04 for aspirin, P_{heterogeneity} = 0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2–6 times/week (OR = 0.81, 95% CI 0.68–0.96) than for daily use (0.91, 0.80–1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen.ConclusionOur pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.     

Metabolic syndrome is associated with colorectal cancer in men

Aim of the studyWe assessed the relation between metabolic syndrome (MetS) and its components and colorectal cancer.MethodsWe analysed data from a multicentre case–control study conducted in Italy and Switzerland, including 1378 cases of colon cancer, 878 cases of rectal cancer and 4661 controls. All cases were incident and histologically confirmed. Controls were subjects admitted to the same hospitals as cases with acute non-malignant conditions. MetS was defined according to the International Diabetes Federation criteria. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated by multiple logistic regression models, including terms for major identified confounding factors for colorectal cancer.ResultsWith reference to each component of the MetS, the ORs of colorectal cancer in men were 1.27 (95% CI, 0.95–1.69) for diabetes, 1.24 (95% CI, 1.03–1.48) for hypertension, 1.14 (95% CI, 0.93–1.40) for hypercholesterolaemia and 1.26 (95% CI, 1.08–1.48) for overweight at age 30. The corresponding ORs in women were 1.20 (95% CI, 0.82–1.75), 0.87 (95% CI, 0.71–1.06), 0.83 (95% CI, 0.66–1.03) and 1.06 (95% CI, 0.86–1.30). Colorectal cancer risk was increased in men (OR = 1.86; 95% CI, 1.21–2.86), but not in women (OR = 1.13; 95% CI, 0.66–1.93), with MetS. The ORs were 2.09 (95% CI, 1.38–3.18) in men and 1.15 (95% CI, 0.68–1.94) in women with ?3 components of the MetS, as compared to no component. Results were similar for colon and rectal cancers.ConclusionThis study supports a direct association between MetS and both colon and rectal cancers in men, but not in women.     

Adolescent dietary fiber,vegetable fat,vegetable protein,and nut intakes and breast cancer risk

The importance of early-life exposures in breast cancer development is increasingly recognized. However, limited research has evaluated the relationship between adolescent diet and subsequent risk of breast cancer and reported inconsistent results. This population-based case–control study investigated the associations of dietary fiber, vegetable protein, vegetable fat, and nuts consumed during adolescence with adult breast cancer risk. Women, ages 25–74 years, who were diagnosed with first primary breast cancer between 2002 and 2003, were identified using the Ontario Cancer Registry. Controls were identified through random-digit dialing and age-frequency matched to cases. Diet at ages 10–15 was assessed with a 55-item food frequency questionnaire among 2,865 cases and 3,299 controls. Logistic regression was performed to estimate odds ratios (ORs) and 95 % confidence intervals (CIs). Inverse associations were found between intakes of dietary fiber, vegetable protein, vegetable fat, and nuts during adolescence and breast cancer risk, which persisted after controlling for adult intakes. The ORs (95 % CI) for the highest versus the lowest quintile of intake were 0.66 (0.55–0.78; P _trend < 0.0001) for fiber, 0.80 (0.68–0.95; P _trend = 0.01) for vegetable protein, 0.74 (0.63–0.87; P _trend = 0.002) for vegetable fat, and 0.76 (0.61–0.95 for ≥1 serving/day vs. <1 serving/month intake; P _trend = 0.04) for nuts. The reduced risk for adolescent intakes of fiber, vegetable protein, and nuts was largely limited to postmenopausal women (P _interaction ≤ 0.05). Dietary fiber, vegetable protein, vegetable fat, and nuts consumed during adolescence were associated with reduced breast cancer risk.     

Metabolic syndrome and the risk of breast cancer in postmenopausal women

BackgroundOnly a few small studies investigated the association between postmenopausal breast cancer and metabolic syndrome (MetS) as a single entity.Materials and methodsWe analyzed the data of two Italian and Swiss case–control studies conducted between 1983 and 2007, including 3869 postmenopausal women with incident breast cancer and 4082 postmenopausal controls admitted to the same hospitals as cases for acute conditions. MetS was defined as the presence of at least three components among diabetes, drug-treated hypertension, drug-treated hyperlipidemia, and obesity.ResultsThe odds ratios (ORs) of postmenopausal breast cancer were 1.33 [95% confidence interval (CI) 1.09–1.62] for diabetes, 1.19 (95% CI 1.07–1.33) for hypertension, 1.08 (95% CI 0.95–1.22) for hyperlipidemia, 1.26 (95% CI 1.11–1.44) for body mass index ≥30 kg/m², and 1.22 (95% CI 1.09–1.36) for waist circumference ≥88 cm. The risk of postmenopausal breast cancer was significantly increased for women with MetS (OR = 1.75, 95% CI 1.37–2.22, for three or more MetS components, P for trend for increasing number of components < 0.0001) and the risk was higher at older age (OR = 3.04, 95% CI 1.75–5.29, at age ≥70 years for three or more MetS components).ConclusionsThis study supports a direct association between MetS and postmenopausal breast cancer risk.     

Association of plasma concentrations of branched-chain amino acids with risk of colorectal adenoma in a large Japanese population

BackgroundAvailable evidence from animal studies suggests that branched-chain amino acids (BCAAs) may have a protective effect against colorectal carcinogenesis. However, a possible effect of BCAAs against colorectal neoplasia has not been evaluated in humans. Here, we aimed to evaluate whether plasma concentrations of BCAA are associated with the risk of colorectal adenoma (CRA), a precursor lesion of colorectal cancer.Patients and methodsCRA cases and controls were identified from examinees who underwent total colonoscopy as part of a cancer screening program between 2004 and 2005 and responded to self-administered dietary and lifestyle questionnaires. We measured plasma concentrations of leucine, isoleucine and valine in 629 patients with adenoma and 584 controls. Unconditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between BCAA and CRA risk after adjustment for potential confounders.ResultsHigh plasma concentrations of leucine, valine and total BCAA were inversely associated with CRA risk after adjustment of potential confounders. The multivariate-adjusted ORs for the highest versus lowest quartiles were 0.60 (95% CI 0.42–0.87,P_trend = 0.006) for leucine, 0.68 (95% CI 0.48–0.97,P_trend = 0.09) for valine and 0.68 (95% CI 0.48–0.98,P_trend = 0.10) for total BCAA. Further analysis by gender revealed that this inverse association was clearly evident in men, but not in women: the corresponding OR for leucine, valine and total BCAA was 0.50 (95% CI 0.32–0.80,P_trend = 0.003), 0.60 (95% CI 0.38–0.95,P_trend = 0.01) and 0.58 (95% CI 0.37–0.93,P_trend = 0.04), respectively, in men and 0.78 (95% CI 0.42–1.45,P_trend = 0.44), 0.77 (95% CI 0.41–1.43,P_trend = 0.85) and 0.84 (95% CI 0.45–1.57,P_trend = 0.81), respectively, in women.ConclusionOur finding suggests that BCAAs may have a beneficial influence against the process of colorectal carcinogenesis, at least in the early stage. The mechanisms underlying this potential association between BCAA and colorectal carcinogenesis warrant further investigation.     

Serum organochlorines and breast cancer: a case–control study among African-American women

This population-based case–control study of African-American women (355 breast cancer case patients, 327 controls) examined the association between breast cancer and circulating levels of PCBs and dichlorodiphenyldichloroethene (DDE), a metabolite of DDT. Case patients were diagnosed with invasive breast carcinoma and interviewed between June 1995 and July 1998, and control subjects were identified by random digit dialing methods. Serum levels of DDE and total PCBs were adjusted for total lipid content. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable unconditional logistic regression methods. Effect modification by tumor receptor status and cancer treatment was investigated. Breast cancer risk was not associated with increasing quintiles of lipid-adjusted PCBs or DDE (highest versus lowest quintile adjusted for age, body mass index (BMI) and breastfeeding for DDE: OR = 1.02, 95% CI = (0.61, 1.72), p-trend = 0.74; for PCBs: OR = 1.01, 95% CI = (0.63, 1.63), p-trend = 0.56). Risk did not differ by strata of BMI, breastfeeding, parity, menopausal status or tumor receptor status. This study, the largest study of African-American women to date, does not support a role of DDE and total PCBs in breast cancer risk at the levels measured.     

Use of nonsteroidal anti-inflammatory drugs and reduced breast cancer risk among overweight women

Chronic inflammation is associated with increased risk of multiple cancers, including breast cancer. Adipose tissues produce proinflammatory cytokines, and obesity is a risk factor for postmenopausal breast cancer. We evaluated the association of regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk, overall and by body mass index (BMI) and tumor subtypes defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status. We conducted a population-based, case-control study involving 5,078 women aged 25-75 years who were recruited primarily from the Nashville metropolitan area of Tennessee. Multivariate unconditional logistic regression models were used to estimate odds ratios and 95 % confidence intervals for breast cancer risk after adjusting for multiple potential confounding factors. Regular use of any NSAID was associated with significantly reduced breast cancer risk (OR 0.78; 95 % CI 0.69–0.89). This association was observed for regular use of baby aspirin only (OR 0.82, 95 % CI 0.69–0.99), other NSAIDs only (OR 0.81, 95 % CI 0.69–0.95), and both baby aspirin and other NSAIDs (OR 0.52, 95 % CI 0.40–0.69). These significant inverse associations were found among overweight women (BMI ≥25 kg/m²) overall and by subtypes of breast cancer, but not among women with BMI <25 kg/m² (P for interaction = 0.023). Regular use of NSAIDs was inversely associated with breast cancer risk, particularly among overweight women. Overweight women may benefit more from the protective effects of NSAID use than normal-weight women.     

Body mass index and breast cancer risk in Japan: a pooled analysis of eight population-based cohort studies

BackgroundA positive association between body mass index (BMI) and breast cancer risk among postmenopausal women has been reported, and a weak inverse association has been suggested among premenopausal women from studies in the Western population. The effects of BMI on breast cancer have remained unclear among the Asian population, especially in premenopausal women.MethodsWe assessed the associations between BMI and breast cancer incidence by a pooled analysis from eight representative large-scale cohort studies in Japan. Cancer incidence was mainly confirmed through regional population-based cancer registries and/or through active patient notification from major local hospitals. Breast cancer was defined as code C50 according to ICD10. Pooled estimates of the hazard ratios (HRs) and 95% confidence interval (CIs) for breast cancer were calculated using random-effects models.ResultsAnalytic subjects were 183 940 women, 1783 of whom had breast cancer during 2 194 211 person-years of follow-up. A positive association between BMI and the risk of postmenopausal breast cancer was observed (trend P < 0.001). The HRs for premenopausal breast cancer were 1.05 (95% CI 0.56–1.99), 1.07 (95% CI 0.76–1.52), 0.91 (95% CI 0.64–1.30), 1.15 (95% CI 0.76–1.73), 1.45 (95% CI 0.71–2.94), and 2.25 (95% CI 1.10–4.60), respectively, in BMIs of <19, 19 to <21, 21 to <23, 25 to <27, 27 to <30, and ≥30 kg/m². These results were not substantially altered after excluding the patients who were diagnosed with breast cancer in the first 2 years of follow-up.ConclusionsThe increased risk of postmenopausal breast cancer among women with higher BMIs was confirmed in Japanese. A borderline-significant positive association between BMI and premenopausal breast cancer was observed, suggesting that body mass in Asian women might have opposite effects on breast cancer compared with Western women.     

Dairy products and colorectal cancer risk: a systematic review and meta-analysis of cohort studies

BackgroundPrevious studies of the association between intake of dairy products and colorectal cancer risk have indicated an inverse association with milk, however, the evidence for cheese or other dairy products is inconsistent.MethodsWe conducted a systematic review and meta-analysis to clarify the shape of the dose–response relationship between dairy products and colorectal cancer risk. We searched the PubMed database for prospective studies published up to May 2010. Summary relative risks (RRs) were estimated using a random effects model.ResultsNineteen cohort studies were included. The summary RR was 0.83 (95% CI [confidence interval]: 0.78–0.88, I² = 25%) per 400 g/day of total dairy products, 0.91 (95% CI: 0.85–0.94, I² = 0%) per 200 g/day of milk intake and 0.96 (95% CI: 0.83–1.12, I² = 28%) per 50 g/day of cheese. Inverse associations were observed in both men and women but were restricted to colon cancer. There was evidence of a nonlinear association between milk and total dairy products and colorectal cancer risk, P < 0.001, and the inverse associations appeared to be the strongest at the higher range of intake.ConclusionsThis meta-analysis shows that milk and total dairy products, but not cheese or other dairy products, are associated with a reduction in colorectal cancer risk.     

Associations of CYP2E1 rs2031920 and rs3813867 polymorphisms with colorectal cancer risk: a systemic review and meta-analysis

Cytochrome P450 2E1 (CYP2E1) is a natural enzyme involved in the metabolic activation of many carcinogens, and the functional polymorphisms in the CYP2E1 gene might have impacts on colorectal cancer risk. Many studies were published to assess the associations of CYP2E1 rs2031920 and rs3813867 polymorphisms with colorectal cancer risk, but no consistent findings were reported. A systemic review and meta-analysis of eligible studies was performed to comprehensively assess the associations above. Odds ratios (ORs) with 95 % confidence interval (95 % CIs) were used to assess the strength of the associations. Seventeen studies from 15 publications with 17,082 individuals were finally included into this meta-analysis. Meta-analysis of the 13 studies on CYP2E1 rs2031920 polymorphism showed that there was a significant association between CYP2E1 rs2031920 polymorphism and colorectal cancer risk under two genetic models (c2 versus c1: OR?=?1.19, 95 % CI 1.03–1.37, P?=?0.022; c2c2/c2c1 versus c1c1: OR?=?1.16, 95 % CI 1.00–1.35, P?=?0.046). Meta-analysis of those four case–control studies on CYP2E1 rs3813867 polymorphism showed that there was no significant association between CYP2E1 rs3813867 polymorphism and colorectal cancer risk under all contrast models (c2 versus c1: OR?=?0.96, 95 % CI 0.80–1.16, P?=?0.672; c2c2 versus c1c1: OR?=?1.26, 95 % CI 0.43–3.67, P?=?0.672; c2c2/c1c2 versus c1c1: OR?=?0.95, 95 % CI 0.78–1.16, P?=?0.114; and c2c2 versus c1c2/c1c1: OR?=?1.17, 95 % CI 0.41–3.36, P?=?0.775). Therefore, the findings from this meta-analysis suggest that CYP2E1 rs2031920 polymorphism is associated with colorectal cancer risk, but CYP2E1 rs3813867 polymorphism is not associated with colorectal cancer risk. In addition, more well-designed studies with large sample size are needed to provide a more precise evaluation on the associations above.     

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Introduction

Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).

Methods

To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.

Results

Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10^-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10^-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10^-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).

Conclusions

The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.     

Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies

BackgroundPositive association between obesity and survival after breast cancer was demonstrated in previous meta-analyses of published data, but only the results for the comparison of obese versus non-obese was summarised.MethodsWe systematically searched in MEDLINE and EMBASE for follow-up studies of breast cancer survivors with body mass index (BMI) before and after diagnosis, and total and cause-specific mortality until June 2013, as part of the World Cancer Research Fund Continuous Update Project. Random-effects meta-analyses were conducted to explore the magnitude and the shape of the associations.ResultsEighty-two studies, including 213 075 breast cancer survivors with 41 477 deaths (23 182 from breast cancer) were identified. For BMI before diagnosis, compared with normal weight women, the summary relative risks (RRs) of total mortality were 1.41 [95% confidence interval (CI) 1.29–1.53] for obese (BMI >30.0), 1.07 (95 CI 1.02–1.12) for overweight (BMI 25.0–<30.0) and 1.10 (95% CI 0.92–1.31) for underweight (BMI <18.5) women. For obese women, the summary RRs were 1.75 (95% CI 1.26–2.41) for pre-menopausal and 1.34 (95% CI 1.18–1.53) for post-menopausal breast cancer. For each 5 kg/m² increment of BMI before, <12 months after, and ≥12 months after diagnosis, increased risks of 17%, 11%, and 8% for total mortality, and 18%, 14%, and 29% for breast cancer mortality were observed, respectively.ConclusionsObesity is associated with poorer overall and breast cancer survival in pre- and post-menopausal breast cancer, regardless of when BMI is ascertained. Being overweight is also related to a higher risk of mortality. Randomised clinical trials are needed to test interventions for weight loss and maintenance on survival in women with breast cancer.     

Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort

BackgroundExperimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors.Patients and methodsConditional logistic regression was used to analyze the data from a case–control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects.ResultsStatistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (P_het = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)_Q4–Q1 = 1.29 (95% confidence interval, CI, 1.05–1.58), P_trend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [OR_Q4–Q1 = 1.45 (95% CI 1.08–1.95), P_trend = 0.01], whereas no statistically significant association was found for the non-users of HRT [OR_Q4–Q1 = 1.11 (95%CI 0.83–1.49), P_trend = 0.80] (P_het = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [OR_Q4–Q1 = 0.70 (95% CI 0.48–1.03), P_trend = 0.16]. There was no heterogeneity in the prolactin–breast cancer association by hormone receptor status of the tumor.ConclusionOur study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.     

Cumulative exposure to premenopausal obesity and risk of postmenopausal cancer: A population-based study in Icelandic women

Obesity, often assessed at one point in time, is an established risk factor of several types of cancer, however, associations with cumulative exposure to obesity across the life course are not well understood. We investigated the relationship between combined measures of duration and intensity of premenopausal overweight and obesity and the incidence of postmenopausal breast, endometrial, and colorectal cancers in Icelandic women. Body mass index (BMI) trajectories between ages 20 and 50 of 88,809 women from the Cancer Detection Clinic Cohort were predicted using growth curve models. Indicators of overweight and obesity duration and intensity were computed and their association with risk of postmenopausal breast, endometrial, and colorectal cancers was examined using multivariate Cox models for subjects followed-up beyond the age of 50 (n = 67,488). During a mean follow-up of 17 years, incident events of 3,016 postmenopausal breast, 410 endometrial and 987 colorectal cancers were ascertained. Each 0.1 kg/m² per year increase in BMI between ages 20 and 50 was positively associated with risks of postmenopausal breast, endometrium and colorectal cancers with hazard ratios equal to 1.09 (95% Confidence Interval (CI):1.04–1.13), 1.31 (95% CI: 1.18–1.44) and 1.10 (95% CI: 1.00–1.21), respectively. Compared to women who were never obese, cumulative BMI × years of obesity were linearly positively associated with risk of endometrial cancer, whereas the association with breast cancer was initially positive, but leveled off with increasing cumulative BMI × years. Cumulative exposure to obesity may provide additional insights into the etiology of cancer and should be considered in future studies that assess obesity–cancer relationships.     

CYP2E1 T7632A and 9-bp insertion polymorphisms and colorectal cancer risk: a meta-analysis based on 4,592 cases and 5,918 controls

Previous studies suggest that genetic factors play important roles in the development of colorectal cancer. CYP2E1 T7632A and 9-bp insertion polymorphisms may influence the risk of colorectal cancer, but published results are conflicting. We therefore conducted a meta-analysis comprising 9 case–control studies with 4,592 cases and 5,918 controls. Odds ratios (ORs) with 95 % confidence interval (95 % CI) were used to assess the strength of the associations of CYP2E1 T7632A and 9-bp insertion polymorphisms with colorectal cancer. For CYP2E1 T7632A polymorphism, meta-analysis showed that there was no significant association between the CYP2E1 T7632A polymorphism and colorectal cancer risk under all contrast models (A vs. T: OR?=?1.06, 95 % CI 0.88–1.29, P?=?0.528; AA vs. TT: OR?=?0.85, 95 % CI 0.61–1.19, P?=?0.351; AA/TA vs. TT: OR?=?1.08, 95 % CI 0.87–1.34, P?=?0.484; and AA vs. TT/TA: OR?=?0.87, 95 % CI 0.62–1.21, P?=?0.395). For CYP2E1 96-bp insertion polymorphism, meta-analysis showed that there was a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk under the allele contrast model and the dominant contrast model (for the allele contrast model: OR?=?1.20, 95 % CI 1.06–1.36, P?=?0.005; for the dominant contrast model: OR?=?1.25, 95 % CI 1.07–1.45, P?=?0.005). Subgroup analysis by race suggested that there was an obvious association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk in Asians under the codominant contrast model. In conclusion, our meta-analysis demonstrates that there is a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk, and CYP2E1 9-bp insertion polymorphism is a risk factor for developing colorectal cancer.     

Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case–Control Consortium

BackgroundThe potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations.Patients and methodsWe used data from nine case–control studies from the International Pancreatic Cancer Case–Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random-effects model. From a subset of four studies, we also calculated pooled estimates of association for supplementary and total vitamin D intake.ResultsRisk of pancreatic cancer increased with dietary intake of vitamin D [per 100 international units (IU)/day: OR = 1.13, 95% confidence interval (CI) 1.07–1.19, P = 7.4 × 10^-6, P-heterogeneity = 0.52; ≥230 versus <110 IU/day: OR = 1.31, 95% CI 1.10–1.55, P = 2.4 × 10^-3, P-heterogeneity = 0.81], with the association possibly stronger in people with low retinol/vitamin A intake.ConclusionIncreased risk of pancreatic cancer was observed with higher levels of dietary vitamin D intake. Additional studies are required to determine whether or not our finding has a causal basis.