Trajectories of body mass index in adulthood and risk of subtypes of postmenopausal breast cancer.

BACKGROUND: Body fatness is a dynamic exposure throughout life. To provide more insight into the association between body mass index (BMI) and postmenopausal breast cancer, we aimed to examine the age at onset, duration, intensity, and trajectories of body fatness in adulthood in relation to risk of breast cancer subtypes. METHODS: Based on self-reported anthropometry in the prospective Norwegian Women and Cancer Study, we calculated the age at onset, duration, and intensity of overweight and obesity using linear mixed-effects models. BMI trajectories in adulthood were modeled using group-based trajectory modeling. We used Cox proportional hazards models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the associations between BMI exposures and breast cancer subtypes in 148,866 postmenopausal women. RESULTS: A total of 7223 incident invasive postmenopausal breast cancer cases occurred during follow-up. Increased overweight duration and age at the onset of overweight or obesity were associated with luminal A-like breast cancer. Significant heterogeneity was observed in the association between age at overweight and overweight duration and the intrinsic-like subtypes (pheterogeneity 0.03). Compared with women who remained at normal weight throughout adulthood, women with a descending BMI trajectory had a reduced risk of luminal A-like breast cancer (HR 0.54, 95% CI 0.33-0.90), whereas women with ascending BMI trajectories were at increased risk (HR 1.09; 95% CI 1.01-1.17 for "Normal-overweight"; HR 1.20; 95% CI 1.07-1.33 for "Normal-obesity"). Overweight duration and weighted cumulative years of overweight and obesity were inversely associated with luminal B-like breast cancer. CONCLUSIONS: In this exploratory analysis, decreasing body fatness from obesity in adulthood was inversely associated with overall, hormone receptor-positive and luminal A-like breast cancer in postmenopausal women. This study highlights the potential health benefits of reducing weight in adulthood and the health risks associated with increasing weight throughout adult life. Moreover, our data provide evidence of intrinsic-like tumor heterogeneity with regard to age at onset and duration of overweight.

Sunscreens With High Versus Low Sun Protection Factor and Cutaneous Squamous Cell Carcinoma Risk: A Population-Based Cohort Study.

Evidence on sunscreen use and cutaneous squamous cell carcinoma (cSCC) risk is limited. Most studies have not taken sun protection factor (SPF) into consideration and used nonusers of sunscreen as the reference group. Nonusers are likely a priori at lower cSCC risk than users. No study has investigated the effect of high- versus low-SPF sunscreens on cSCC, appropriately adjusting for time-varying confounding. Using data from the Norwegian Women and Cancer Study (1991-2016), we investigated whether use of SPF ≥15 versus SPF <15 sunscreens reduces cSCC risk. We used a marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weights to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During follow-up of 148,781 women (mean follow-up, 14.3 years), 653 women were diagnosed with cSCC. The effect on cSCC risk of sunscreens with SPF ≥15 versus SPF <15 was close to the null when used at any latitudes (HR = 1.02, 95% CI: 0.82, 1.27) and when used in lower-latitude settings (HR = 1.05, 95% CI: 0.84, 1.32). In conclusion, we found no indication that sunscreens with SPF ≥15 reduced Norwegian women's cSCC risk more than sunscreens with SPF <15, suggesting that either there is no difference in their effects long-term or the difference is diluted by incorrect application.

Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking.

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients.

Seroprevalence of antibodies against SARS-CoV-2 in the adult population during the pre-vaccination period, Norway, winter 2020/21.

BackgroundSince March 2020, 440 million people worldwide have been diagnosed with COVID-19, but the true number of infections with SARS-CoV-2 is higher. SARS-CoV-2 antibody seroprevalence can add crucial epidemiological information about population infection dynamics.AimTo provide a large population-based SARS-CoV-2 seroprevalence survey from Norway; we estimated SARS-CoV-2 seroprevalence before introduction of vaccines and described its distribution across demographic groups.MethodsIn this population-based cross-sectional study, a total of 110,000 people aged 16 years or older were randomly selected during November-December 2020 and invited to complete a questionnaire and provide a dried blood spot (DBS) sample.ResultsThe response rate was 30% (31,458/104,637); compliance rate for return of DBS samples was 88% (27,700/31,458). National weighted and adjusted seroprevalence was 0.9% (95% CI (confidence interval): 0.7-1.0). Seroprevalence was highest among those aged 16-19 years (1.9%; 95% CI: 0.9-2.9), those born outside the Nordic countries 1.4% (95% CI: 1.0-1.9), and in the counties of Oslo 1.7% (95% CI: 1.2-2.2) and Vestland 1.4% (95% CI: 0.9-1.8). The ratio of SARS-CoV-2 seroprevalence (0.9%) to cumulative incidence of virologically detected cases by mid-December 2020 (0.8%) was slightly above one. SARS-CoV-2 seroprevalence was low before introduction of vaccines in Norway and was comparable to virologically detected cases, indicating that most cases in the first 10 months of the pandemic were detected.ConclusionFindings suggest that preventive measures including contact tracing have been effective, people complied with physical distancing recommendations, and local efforts to contain outbreaks have been essential.

The fraction of lung cancer attributable to smoking in the Norwegian Women and Cancer (NOWAC) Study.

BACKGROUND: We examined the association between active and passive smoking and lung cancer risk and the population attributable fraction (PAF) of lung cancer due to active smoking, in the Norwegian Women and Cancer Study, a nationally representative prospective cohort study. METHODS: We followed 142,508 women, aged 31-70 years, who completed a baseline questionnaire between 1991 and 2007, through linkages to national registries through December 2015. We used Cox proportional hazards models, to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). We calculated PAF to indicate what proportion of lung cancer cases could have been prevented in the absence of smoking. RESULTS: During the more than 2.3 million person-years of observation, we ascertained 1507 lung cancer cases. Compared with never smokers, current (HR 13.88, 95% CI 10.18-18.91) smokers had significantly increased risk of lung cancer. Female never smokers exposed to passive smoking had a 1.3-fold (HR 1.34, 95% CI 0.89-2.01) non- significantly increased risk of lung cancer, compared with never smokers. The PAF of lung cancer was 85.3% (95% CI 80.0-89.2). CONCLUSION: More than 8 in 10 lung cancer cases could have been avoided in Norway, if the women did not smoke.

Prediagnostic circulating markers of inflammation and risk of oesophageal adenocarcinoma: a study within the National Cancer Institute Cohort Consortium.

OBJECTIVE: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk. DESIGN: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy. RESULTS: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk. CONCLUSION: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma.

Challenges in assessing the sunscreen-melanoma association.

Whether sunscreen use affects melanoma risk has been widely studied with contradictory results. To answer this question we performed a systematic review of all published studies, accounting for sources of heterogeneity and bias. We searched for original articles investigating the sunscreen-melanoma association in humans to February 28, 2018. We then used random-effects meta-analysis to combine estimates of the association, stratified by study design. Stratified meta-analysis and meta-regression were used to identify sources of heterogeneity. We included 21,069 melanoma cases from 28 studies published 1979-2018: 23 case-control (11 hospital-based, 12 population-based), 1 ecological, 3 cohort and 1 randomised controlled trial (RCT). There was marked heterogeneity across study designs and among case-control studies but adjustment for confounding by sun exposure, sunburns and phenotype systematically moved estimates toward decreased melanoma risk among sunscreen users. Ever- vs. never-use of sunscreen was inversely associated with melanoma in hospital-based case-control studies (adjusted odds ratio (OR) = 0.57, 95%confidence interval (CI) 0.37-0.87, pheterogeneity < 0.001), the ecological study (rate ratio = 0.48, 95%CI 0.35-0.66), and the RCT (hazard ratio (HR) = 0.49, 95%CI 0.24-1.01). It was not associated in population-based case-control studies (OR = 1.17, 95%CI 0.90-1.51, pheterogeneity < 0.001) and was positively associated in the cohort studies (HR = 1.27, 95%CI 1.07-1.51, pheterogeneity = 0.236). The association differed by latitude (pinteraction = 0.042), region (pinteraction = 0.008), adjustment for naevi/freckling (pinteraction = 0.035), and proportion of never-sunscreen-users (pinteraction = 0·012). Evidence from observational studies on sunscreen use and melanoma risk was weak and heterogeneous, consistent with the challenges of controlling for innate confounding by indication. The only RCT showed a protective effect of sunscreen.

Reproductive Factors, Exogenous Hormone Use, and Risk of B-Cell Non-Hodgkin Lymphoma in a Cohort of Women From the European Prospective Investigation Into Cancer and Nutrition.

The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992-2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.

Differential expression of the miR-17-92 cluster and miR-17 family in breast cancer according to tumor type; results from the Norwegian Women and Cancer (NOWAC) study.

BACKGROUND: MicroRNAs (miRNAs) are promising biomarkers due to their structural stability and distinct expression profile in various cancers. We wanted to explore the miRNA expression in benign breast tissue and breast cancer subgroups in the Norwegian Women and Cancer study. METHODS: Specimens and histopathological data from study participants in Northern Norway diagnosed with breast cancer, and benign tissue from breast reduction surgery were collected. Main molecular subtypes were based on surrogate markers; luminal A (ER+ and/or PR+, HER2- and Ki67 ≤ 30%), luminal B (ER+ and/or PR+, HER2- and Ki67 > 30% or ER+ and/or PR+ and HER2+), HER2 positive (ER- and PR- and HER2+) and triple-negative (ER-, PR- and HER2-). RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue, and miRNAs were successfully analyzed in 102 cancers and 36 benign controls using the 7th generation miRCURY LNA microarray containing probes targeting all human miRNAs as annotated in miRBASE version 19.0. Validation with RT-qPCR was performed. RESULTS: On average, 450 miRNAs were detected in each sample, and 304 miRNAs were significantly different between malignant and benign tissue. Subgroup analyses of cancer cases revealed 23 miRNAs significantly different between ER+ and ER- tumors, and 47 miRNAs different between tumors stratified according to grade. Significantly higher levels were found in high grade tumors for miR-17-5p (p = 0.006), miR-20a-5p (p = 0.007), miR-106b-5p (p = 0.007), miR-93-5p (p = 0.007) and miR-25-3p (p = 0.015) from the paralogous clusters miR-17-92 and miR-106b-25. Expression of miR-17-5p (p = 0.0029), miR-20a-5p (p = 0.0021), miR-92a-3p (p = 0.011) and miR-106b-5p (p = 0.021) was significantly higher in triple-negative tumors compared to the rest, and miR-17-5p and miR-20a-5p were significantly lower in luminal A tumors. CONCLUSIONS: miRNA expression profiles were significantly different between malignant and benign tissue and between cancer subgroups according to ER- status, grade and molecular subtype. miRNAs in the miR-17-92 cluster and miR-17 family were overexpressed in high grade and triple-negative tumors associated with aggressive behavior. The expression and functional role of these miRNAs should be further studied in breast cancer to explore their potential as biomarkers in diagnostic pathology and clinical oncology.

Use of skincare products and risk of cancer of the breast and endometrium: a prospective cohort study.

BACKGROUND: Concerns have been raised that extensive use of personal care products that contain endocrine disrupting compounds increase the risk of hormone sensitive cancers. OBJECTIVE: To assess the effect of skincare product use on the risk of pre- and postmenopausal breast cancer, estrogen receptor positive (ER+) and negative (ER-) breast cancer and cancer of the endometrium. METHODS: We used data from 106,978 participants in the population-based Norwegian Women and Cancer cohort. Participants were categorized into non-, light, moderate, frequent and heavy users of skincare products based on self-reported use of hand and facial cream and body lotion. Cancer incidence information from the Cancer Registry of Norway was linked to individual data through the unique identity number of Norwegian citizens. Multivariable Cox proportional hazard regression was used to assess the effect of skincare product use on the risk of cancer of the breast and endometrium. We used multiple imputation by chained equations to evaluate the effect of missing data on observed associations. RESULTS: We found no associations between use of skincare products and incidence of premenopausal breast cancer (frequent/heavy versus non-/light use: hazard ratio [HR] =1.10, 95% confidence interval [CI]: 0.92-1.32), postmenopausal breast cancer (heavy versus light use: HR = 0.87, 95% CI: 0.65-1.18, frequent versus light use: HR = 0.97, 95% CI: 0.88, 1.07) or endometrial cancer (frequent/heavy versus non-/light use: HR = 0.97, 95% CI: 0.79-1.20). Use of skincare products did not increase the risk of ER+ or ER- breast cancer and there was no difference in effect across ER status (0.58 ≤ pheterogeneity ≤ 0.99). The magnitude and direction of the effect estimates based on complete case analyses and multiple imputation were similar. CONCLUSION: Heavy use of skincare products, i.e. creaming the body up to two times per day during mid-life, did not increase the risk of cancer of the breast or endometrium.

Progestin-only and combined oral contraceptives and receptor-defined premenopausal breast cancer risk: The Norwegian Women and Cancer Study.

Receptor-defined subtypes of breast cancer represent distinct cancer types and have differences in risk factors. Whether the two main hormonal forms of oral contraceptives (OCs); i.e. progestin-only (POC) and combined oral contraceptives (COC), are differentially associated with these subtypes are not well known. The aim of our study was to assess the effect of POC and COC use on hormone receptor-defined breast cancer risk in premenopausal women in a prospective population-based cohort - The Norwegian Women and Cancer Study (NOWAC). Information on OC use was collected from 74,862 premenopausal women at baseline. Updated information was applied when follow-up information became available. Multiple imputation was performed to handle missing data, and multivariable Cox regression models were used to calculate hazard ratios (HR) for breast cancer. 1,245 incident invasive breast cancer cases occurred. POC use ≥5 years was associated with ER+ (HR = 1.59, 95% CI 1.09- 2.32, ptrend = 0.03) and ER+/PR+ cancer (HR = 1.63, 95% CI 1.07-2.48, ptrend = 0.05), and was not associated with ER- (pheterogeneity = 0.36) or ER-/PR- (pheterogeneity = 0.49) cancer. COC use was associated with ER- and ER-/PR- cancer, but did not increase risk of ER+ and ER+/PR+ cancer. Current COC use gave different estimates for ER/PR-defined subtypes (pheterogeneity = 0.04). This is the first study to show significant associations between POC use and hormone receptor-positive breast cancer. The lack of power to distinguish effects of POC use on subtype development calls for the need of larger studies to confirm our finding.

Epigenome-wide association study of adiposity and future risk of obesity-related diseases.

BACKGROUND: Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction. METHODS: DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population. RESULTS: We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10-8 to 3.27×10-18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10-7), higher triglyceride levels (P = 5.37×10-9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10-10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10-3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25×10-3), independently of obesity and established risk factors. CONCLUSION: Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.

Physical activity patterns and the risk of colorectal cancer in the Norwegian Women and Cancer study: a population-based prospective study.

INTRODUCTION: Colorectal cancer (CRC) remains the second most common cancer in women worldwide. Physical activity (PA) has been associated with reduced risk of CRC; however, this has been demonstrated more consistently in men, while results of studies in women have been largely equivocal. We aimed to further examine the relationship between PA patterns and the risk of CRC in women, using repeated measurements. METHODS: We followed participants of the Norwegian Women and Cancer (NOWAC) Study - a nationally representative cohort. Baseline information was available for 79,184 women, and we used this information in addition to follow-up information collected 6-8 years later, for repeated measurement analysis. At enrollment, participants were cancer-free and aged 30-70 years, with a median age of 51 years. We used Cox proportional hazards regression to compute hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During an average of 14.6 years of follow-up and 1.16 million person-years, 885 cases of colon and 426 cases of rectal cancer were identified through linkage to the Norwegian Cancer Registry (median age at diagnosis: 65 years). We found no association between PA level and the risk of colon cancer in baseline or repeated measurements analyses when comparing women with PA level 1-2 to those with PA level 5-6 (reference) (baseline: HR = 0.90, 95% CI 0.66-1.23, p-trend = 0.76; repeated measurements: HR = 0.78, 95% CI 0.55-1.10, p-trend = 0.27). Results were the same when comparing PA level 9-10 to the reference level (baseline: HR = 0.80, 95% CI 0.56-1.12, p-trend = 0.76; repeated measurements: HR = 0.82, 95% CI 0.58-1.16, p-trend = 0.27). Similarly, we found no association between PA levels and the risk of rectal cancer. CONCLUSIONS: Women may need to look beyond PA in order to reduce their risk of CRC.

Levonorgestrel-releasing intrauterine system use is associated with a decreased risk of ovarian and endometrial cancer, without increased risk of breast cancer. Results from the NOWAC Study.

OBJECTIVE: Women with ovarian cancer have poor survival rates, which have proven difficult to improve; therefore primary prevention is important. The levonorgestrel-releasing intrauterine system (LNG-IUS) prevents endometrial cancer, and recent studies suggested that it may also prevent ovarian cancer, but with a concurrent increased risk of breast cancer. We compared adjusted risks of ovarian, endometrial, and breast cancer in ever users and never users of LNG-IUS. METHODS: Our study cohort consisted of 104,318 women from the Norwegian Women and Cancer Study, 9144 of whom were ever users and 95,174 of whom were never users of LNG-IUS. Exposure information was taken from self-administered questionnaires, and cancer cases were identified through linkage to the Cancer Registry of Norway. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated with Poisson regression using robust error estimates. RESULTS: Median age at inclusion was 52years and mean follow-up time was 12.5 (standard deviation 3.7) years, for a total of 1,305,435 person-years. Among ever users of LNG-IUS there were 18 cases of epithelial ovarian cancer, 15 cases of endometrial cancer, and 297 cases of breast cancer. When ever users were compared to never users of LNG-IUS, the multivariable RR of ovarian, endometrial, and breast cancer was 0.53 (95% CI: 0.32, 0.88), 0.22 (0.13, 0.40), and 1.03 (0.91, 1.17), respectively. CONCLUSION: In this population-based prospective cohort study, ever users of LNG-IUS had a strongly reduced risk of ovarian and endometrial cancer compared to never users, with no increased risk of breast cancer.

Interactions between the tumor and the blood systemic response of breast cancer patients.

Although systemic immunity is critical to the process of tumor rejection, cancer research has largely focused on immune cells in the tumor microenvironment. To understand molecular changes in the patient systemic response (SR) to the presence of BC, we profiled RNA in blood and matched tumor from 173 patients. We designed a system (MIxT, Matched Interactions Across Tissues) to systematically explore and link molecular processes expressed in each tissue. MIxT confirmed that processes active in the patient SR are especially relevant to BC immunogenicity. The nature of interactions across tissues (i.e. which biological processes are associated and their patterns of expression) varies highly with tumor subtype. For example, aspects of the immune SR are underexpressed proportionally to the level of expression of defined molecular processes specific to basal tumors. The catalog of subtype-specific interactions across tissues from BC patients provides promising new ways to tackle or monitor the disease by exploiting the patient SR.

Milk and risk of colorectal, colon and rectal cancer in the Norwegian Women and Cancer (NOWAC) Cohort Study.

According to World Cancer Research Fund International/American Institute for Cancer Research, it is 'probable' that dairy products decrease the risk of colorectal cancer (CRC). However, meta-analyses restricted to women have not shown associations between milk intake and risk of CRC. The aim of this study was to examine the association between milk intake and risk of CRC, colon cancer and rectal cancer among women. Data from 81 675 participants in the Norwegian Women and Cancer Cohort Study were included, and multivariable Cox proportional hazard regression models were used to investigate milk intake using two different analytical approaches: one that included repeated measurements and one that included baseline measurements only (872 and 1084 CRC cases, respectively). A weak inverse association between milk intake and risk of colon cancer may be indicated both in repeated measurements analyses and in baseline data analyses. Hazard ratios (HR) for colon cancer of 0·80 (95 % CI 0·62, 1·03, P trend 0·07) and 0·81 (95 % CI 0·64, 1·01, P trend 0·03) and HR for rectal cancer of 0·97 (95 % CI 0·67, 1·42, P trend 0·92) and 0·71 (95 % CI 0·50, 1·01, P trend 0·03) were found when comparing the high with the no/seldom milk intake group in energy-adjusted multivariable models. Our study indicates that there may be a weak inverse association between milk intake and risk of colon cancer among women. The two analytical approaches yielded different results for rectal cancer and hence CRC. Our study indicates that the use of single or repeated measurements in analyses may influence the results.

Potato consumption and risk of pancreatic cancer in the HELGA cohort.

Potatoes have been a staple food in many countries throughout the years. Potatoes have a high glycaemic index (GI) score, and high GI has been associated with several chronic diseases and cancers. Still, the research on potatoes and health is scarce and contradictive, and we identified no prospective studies that had investigated the association between potatoes as a single food and the risk of pancreatic cancer. The aim of this study was to prospectively investigate the association between potato consumption and pancreatic cancer among 114 240 men and women in the prospective HELGA cohort, using Cox proportional hazard models. Information on diet (validated FFQ's), lifestyle and health was collected by means of a questionnaire, and 221 pancreatic cancer cases were identified through cancer registries. The mean follow-up time was 11·4 (95 % CI 0·3, 16·9) years. High consumption of potatoes showed a non-significantly higher risk of pancreatic cancer in the adjusted model (hazard ratio (HR) 1·44; 95 % CI 0·93, 2·22, P for trend 0·030) when comparing the highest v. the lowest quartile of potato consumption. In the sex-specific analyses, significant associations were found for females (HR 2·00; 95 % CI 1·07, 3·72, P for trend 0·020), but not for males (HR 1·01; 95 % CI 0·56, 1·84, P for trend 0·34). In addition, we explored the associations by spline regression, and the absence of dose-response effects was confirmed. In this study, high potato consumption was not consistently associated with a higher risk of pancreatic cancer. Further studies with larger populations are needed to explore the possible sex difference.

Lifetime number of years of menstruation as a risk index for postmenopausal endometrial cancer in the Norwegian Women and Cancer Study.

INTRODUCTION: Lifetime number of years of menstruation (LNYM) reflects a woman's cumulative exposure to endogenous estrogen and can be used as a measure of the combined effect of reproductive factors related to endometrial cancer (EC) risk. MATERIAL AND METHODS: We aimed to study the association between LNYM and EC risk among postmenopausal women and calculate the population attributable fraction of EC for different LNYM categories. Our study sample consisted of 117 589 women from the Norwegian Women and Cancer (NOWAC) Study. All women were aged 30-70 years at enrollment and completed a baseline questionnaire between 1991 and 2006. Women were followed up for EC to December 2014 through linkages to national registries. We used Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals (95% CIs), adjusted for potential confounders. RESULTS: In all, 720 women developed EC. We found a statistically significant, positive dose-response relationship between LNYM and EC, with a 9.1% higher risk for each additional year of LNYM (P for trend < .001). Using the LNYM category ≥40 as a reference, the hazard ratios for LNYM <25, 25-29, 30-34, 35-39 were 0.17 (95% CI 0.22-0.27), 0.25 (95% CI 0.17-0.36), 0.43 (95% CI 0.32-0.58), and 0.68 (95% CI 0.51-0.92), respectively. The association between LNYM and EC was independent of incomplete pregnancies, menopausal hormone therapy, diabetes, and body mass index. When considering the population attributable fraction, 67% of EC was estimated to be attributable to LNYM ≥25 years. CONCLUSIONS: Our study supports that increasing LNYM is an important and independent predictor of EC risk.

Does an epidemiological comparison support a common cellular lineage for similar subtypes of postmenopausal uterine and ovarian carcinoma? The Norwegian Women and Cancer Study.

Uterine and ovarian carcinomas have the same major histological subtypes, but whether they originate from the same cell types is a matter of ongoing debate. Uterine and ovarian endometrioid and clear cell carcinoma (ECC) and uterine and ovarian serous carcinoma (SC) may originate in the same location, or share a common lineage of differentiation. Epidemiologically, a common cellular lineage should be reflected in similar risk associations, and we explored the similarity of uterine and ovarian ECC and uterine and ovarian SC. We included 146,316 postmenopausal participants from the Norwegian Women and Cancer Study. Exposure information was taken from self-administered questionnaires, and cancer cases were identified through linkage to the Cancer Registry of Norway. Hazard ratios with 95% confidence intervals for uterine and ovarian carcinoma and their subtypes were calculated using multivariable Cox regression models, and a Wald test was used to check for heterogeneity. During 1.6 million person-years, 1,006 uterine and 601 ovarian carcinomas were identified. Parity, total menstrual lifespan, body mass index and smoking were differentially associated with total uterine and total ovarian carcinoma (pheterogeneity  = 0.041, 0.027, <0.001 and 0.001, respectively). The corresponding associations for uterine and ovarian ECC did not differ significantly (pheterogeneity  > 0.05). Smoking was differentially associated with uterine and ovarian SC (pheterogeneity  = 0.021). Our epidemiological analyses do not contradict a common differentiation lineage for uterine and ovarian ECC. Uterine and ovarian SC are less likely to be of a common lineage of differentiation, based on their difference in risk associated with smoking.

DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk.

DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-valuepooled = 4 × 10-17 ), cg03636183 in the F2RL3 gene (p-valuepooled = 2 × 10 - 13 ), cg21566642 and cg05951221 in 2q37.1 (p-valuepooled = 7 × 10-16 and 1 × 10-11 respectively), cg06126421 in 6p21.33 (p-valuepooled = 2 × 10-15 ) and cg23387569 in 12q14.1 (p-valuepooled = 5 × 10-7 ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-valuesheterogeneity ≤ 1.8 x10 - 7 ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.