Epithelial ovarian cancer. Population-based cohort studies. The NOWAC Study and Postgenome biobank

Important gaps in population-based epidemiological research on ovarian cancer include understanding how risk factors relate to cancer subtypes and anatomical sites, identifying safe and effective preventive measures, and getting a more detailed picture of the continuum of events during ovarian carcinogenesis. This thesis used prospective exposure information from the Norwegian Women and Cancer (NOWAC) Study and blood samples from the NOWAC Postgenome biobank to explore topics within these gaps. On the topic of risk factors, subtypes and anatomical sites, previous studies have shown that serous carcinomas of the ovary and fallopian tube cancers have similar risk factors. This thesis compared risk factors between the ovary/fallopian tube and uterine corpus. One risk factor association separated serous carcinomas of these sites, while no differences in risk factor associations were found for endometrioid and clear cell carcinomas. Possible alternative explanations of this result include few observations in the analysis of endometrioid and clear cell carcinomas, and histological misclassification of high-grade endometrioid carcinomas. Among preventive measures, combined oral contraceptives reduce the risk of both ovarian and uterine carcinoma. Current trends in female contraception include an increase in use of progestin-only long-acting reversible contraceptives, such as the levonorgestrel-releasing intrauterine system (LNG-IUS). In the NOWAC cohort, ever use of LNG-IUS reduced the risk of ovarian carcinoma by 53% (95% CI: 22% – 68%) and the risk of uterine carcinoma by 78% (95% CI: 60% – 87%) compared to never use. These results extend current knowledge to include postmenopausal women in a sample of the general population. The association with breast cancer was also investigated and discussed. To investigate the continuum of events during ovarian carcinogenesis, this thesis explores gene expression in peripheral blood in the years preceding ovarian cancer diagnosis. The presented study did not find strong associations. This could be because there is little association between ovarian cancer and prediagnostic gene expression in blood, but could also be due to a small sample size, or the analytic approach that was used.  Kreft i eggstokkene er forholdsvis sjelden kreftform, som har høy dødelighet. Denne doktoravhandlingen bygger på spørreskjema fra 172000 kvinner i Kvinner og kreft-studien, og på blodprøver fra 50000 av deltakerne. Blodprøvene utgjør en unik biobank med bevart genuttrykk fra de hvite blodlegemene. Fra før vet man at kvinner som har brukt p-piller har lavere risiko for eggstokkreft. I dag har mange kvinner, også de yngre, begynt å bruke hormonspiral. Det er lite kunnskap om hvorvidt kvinner som bruker hormonspiral har lavere risiko for eggstokkreft slik som p-pillebrukerne. Blant de noe eldre deltakerne i Kvinner og kreft hadde kvinner som noen gang har brukt hormonspiral en halvert risiko for eggstokkreft. Fordi det var få tilfeller, har anslaget en usikkerhet som tilsvarer mellom 10% og 70% lavere risiko. Blodprøvene i biobanken gir mulighet til å undersøke endringer i genuttrykk i immunceller opptil sju år før diagnosen ble stilt, i håp om å forstå mer om sykdomsutviklingen. Vi gjorde en utforskende analyse av blodprøver fra kvinner som hadde fått eggstokkreft, men fant ikke entydige endringer i genuttrykket

Kvik: Interactive exploration of genomic data from the NOWAC postgenome biobank

We have developed Kvik, a system for interactive exploration of genomicdata from the Norwegian Women and Cancer (NOWAC) postgenomebiobank. The goal of the NOWAC study is to understand the dynamicsof carcinogenesis through multi-level functional analyses of transcriptomicsand epigenetics using blood and tissue samples. Kvik provides a tool forexploring gene expression data, incorporating both statistical analysis andinteractive visualizations in a single system. The tool is open-sourced atgithub.com/fjukstad/kvik

Reproductive factors and epithelial ovarian cancer survival in the EPIC cohort study

Background: Reproductive factors influence the risk of developing epithelial ovarian cancer (EOC), but little is known about their association with survival. We tested whether prediagnostic reproductive factors influenced EOC-specific survival among 1025 invasive EOC cases identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which included 521 330 total participants (approximately 370 000 women) aged 25–70 years at recruitment from 1992 to 2000. Methods: Information on reproductive characteristics was collected at recruitment. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and multivariable models were adjusted for age and year of diagnosis, body mass index, tumour stage, smoking status and stratified by study centre. Results: After a mean follow-up of 3.6 years (±3.2 s.d.) following EOC diagnosis, 511 (49.9%) of the 1025 women died from EOC. We observed a suggestive survival advantage in menopausal hormone therapy (MHT) users (ever vs never use, HR=0.80, 95% CI=0.62–1.03) and a significant survival benefit in long-term MHT users (⩾5 years use vs never use, HR=0.70, 95% CI=0.50–0.99, Ptrend=0.04). We observed similar results for MHT use when restricting to serous cases. Other reproductive factors, including parity, breastfeeding, oral contraceptive use and age at menarche or menopause, were not associated with EOC-specific mortality risk. Conclusions: Further studies are warranted to investigate the possible improvement in EOC survival in MHT users

Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models: results from the EPIC cohort.

BACKGROUND: Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening. METHODS: We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression. RESULTS: CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination. CONCLUSIONS: This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors

Coffee consumption and the risk of malignant melanoma in the Norwegian Women and Cancer (NOWAC) Study

Background: Coffee contains biologically-active substances that suppress carcinogenesis in vivo, and coffee consumption has been associated with a lower risk of malignant melanoma. We studied the impact of total coffee consumption and of different brewing methods on the incidence of malignant melanoma in a prospective cohort of Norwegian women. Methods: We had baseline information on total coffee consumption and consumption of filtered, instant, and boiled coffee from self-administered questionnaires for 104,080 women in the Norwegian Women and Cancer (NOWAC) Study. We also had follow-up information collected 6–8 years after baseline. Multiple imputation was used to deal with missing data, and multivariable Cox regression models were used to calculate hazard ratios (HR) for malignant melanoma by consumption category of total, filtered, instant, and boiled coffee. Results: During 1.7 million person-years of follow-up, 762 cases of malignant melanoma were diagnosed. Compared to light consumers of filtered coffee (≤1 cup/day), we found a statistically significant inverse association with low-moderate consumption (>1–3 cups/day, HR = 0.80; 95 % confidence interval [CI] 0.66–0.98) and high-moderate consumption of filtered coffee (>3–5 cups/day, HR = 0.77; 95 % CI 0.61–0.97) and melanoma risk (ptrend = 0.02). We did not find a statistically significant association between total, instant, or boiled coffee consumption and the risk of malignant melanoma in any of the consumption categories. Conclusions: The data from the NOWAC Study indicate that a moderate intake of filtered coffee could reduce the risk of malignant melanom

Kvik: three-tier data exploration tools for flexible analysis of genomic data in epidemiological studies

Published version. Source at https://doi.org/10.12688/f1000research.6238.1.Kvik is an open-source system that we developed for explorative analysis of functional genomics data from large epidemiological studies. Creating such studies requires a significant amount of time and resources. It is therefore usual to reuse the data from one study for several research projects. Often each project requires implementing new analysis code, integration with specific knowledge bases, and specific visualizations. Existing data exploration tools do not provide all the required functionality for such multi-study data exploration. We have therefore developed the Kvik framework which makes it easy to implement specialized data exploration tools for specific projects. Applications in Kvik follow the three-tier architecture commonly used in web applications, with REST interfaces between the tiers. This makes it easy to adapt the applications to new statistical analyses, metadata, and visualizations. Kvik uses R to perform on-demand data analyses when researchers explore the data. In this note, we describe how we used Kvik to develop the Kvik Pathways application to explore gene expression data from healthy women with high and low plasma ratios of essential fatty acids using biological pathway visualizations. Researchers interact with Kvik Pathways through a web application that uses the JavaScript libraries Cytoscape.js and D3. We use Docker containers to make deployment of Kvik Pathways simple

Kvik: three-tier data exploration tools for flexible analysis of genomic data in epidemiological studies [v2; ref status: indexed, http://f1000r.es/5hl]

Kvik is an open-source framework that we developed for explorative analysis of functional genomics data from large epidemiological studies. Creating such studies requires a significant amount of time and resources. It is therefore usual to reuse the data from one study for several research projects. Often each project requires implementing new analysis code, integration with specific knowledge bases, and specific visualizations. Although existing data exploration tools are available for single study data exploration, no tool provides all the required functionality for multistudy data exploration. We have therefore used the Kvik framework to develop Kvik Pathways, an application for exploring gene expression data in the context of biological pathways. We have used Kvik Pathways to explore data from both a cross-sectional study design and a case-control study within the Norwegian Women and Cancer (NOWAC) cohort. Kvik Pathways follows the three-tier architecture in web applications using a powerful back-end for statistical analyses and retrieval of metadata.In this note, we describe how we used the Kvik framework to develop the Kvik Pathways application. Kvik Pathways was used by our team of epidemiologists toexplore gene expression data from healthy women with high and low plasma ratios of essential fatty acids

Epithelial ovarian cancer subtypes attributable to smoking in the Norwegian Women and Cancer Study, 2012

Among European women, ovarian cancer is the fifth most common cancer. Smoking is an established risk factor for mucinous tumors. We estimated the impact of smoking in Norwegian women using population attributable fractions (PAFs) of epithelial ovarian cancer (EOC), by invasiveness and by histological subtypes in the Norwegian Women and Cancer Study with an average of 13.2 years of follow-up. During >2 million person-years, a total of 915 incident EOC cases, of which 667 (73%) invasive and 248 (27%) borderline, were identified among 154,234 women aged 34–70 years at enrolment. Compared with never smokers, current smokers had a nonstatistically significant increased risk of mucinous tumors (hazard ratio [HR] = 1.67 [95% confidence interval, (CI), 0.96–2.96]) and more than twice statistically significant risk of borderline mucinous tumors (HR = 2.17 [95% CI, 1.06–4.45]). The corresponding PAF estimates were 16.5% for mucinous and 25% for borderline mucinous. We found that among middle-aged women, one in six mucinous tumors and one in four borderline mucinous tumors could have been prevented if women did not smoke

Additional file 1: of Coffee consumption and the risk of malignant melanoma in the Norwegian Women and Cancer (NOWAC) Study

Table S1. Hazard ratios (HRs) with 95 % confidence intervals (CI) of malignant melanoma (n = 762) according to total, filtered, instant, and boiled coffee consumption in the Norwegian Women and Cancer Study, 1991–2013 (omitted adjustment for phenotypic and sun related factors, N = 104,080). Table S2. Hazard ratios (HRs) with 95 % confidence intervals (CI) of malignant melanoma (n = 762) according to, filtered, instant, and boiled coffee consumption with ≤3 cups/month as the reference cut-off in the Norwegian Women and Cancer Study, 1991–2013, N = 104,080. (DOCX 16 kb