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Background Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. Methods We conducted a genome-wide by environment interaction study (GWEIS) in 18,532 patients with depression from hospital-based settings and 20,184 population controls. All individuals were drawn from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Information on stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability, and child maltreatment was identified from the registers and operationalized as a time-varying count variable. Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. Our replication sample included 22,880 depression cases and 50,378 controls from the UK Biobank. Results The GWEIS in the iPSYCH2012 sample yielded three novel, genome-wide–significant (p < 5 × 10−8) loci located in the ABCC1 gene (rs56076205, p = 3.7 × 10−10), the AKAP6 gene (rs3784187, p = 1.2 × 10−8), and near the MFSD1 gene (rs340315, p = 4.5 × 10−8). No hits replicated in the UK Biobank (rs56076205: p = .87; rs3784187: p = .93; rs340315: p = .71). Conclusions In this large, population-based GWEIS, we did not find any replicable hits for interaction. Future gene-by-stress research in depression should focus on establishing even larger collaborative GWEISs to attain sufficient power.

Background: Colorectal cancer screening program using a fecal immunochemical test aims to reduce morbidity and mortality through early detection. Although screening participation is free-of-charge, almost 40% of the invited individuals choose not to participate. To bring new insight into how non-participation can be identified and targeted, we examined the association between marital status and screening participation; with a focus on partner concordance in participation and sex differences. Methods: This nationwide cross-sectional study included all Danish citizens aged 50-74 years, who were invited to colorectal cancer screening between 2014 and 2017. Logistic regression analysis was used to estimate odds ratio (OR) of participation while adjusting for sociodemographic variables. Results: A total of 1 909 662 individuals were included in the analysis of which 62.7% participated in the screening program. Participation was highest among women. Stratified by marital status, screening participation was markedly lower in widowed (61.5%), divorced (54.8%) and single (47.3%), while participation reached 68.4% in married individuals. This corresponded to ORs of 0.59 (95% CI 0.58-0.59) for widowed, 0.56 (95% CI 0.55-0.56) for divorced and 0.47 (95% CI 0.47-0.48) for single, compared to married individuals. Individuals married to a participating partner were five times more likely to participate than married individuals with a non-participating partner, regardless of gender. Conclusions: Marital status was strongly associated with participation in colorectal cancer screening, and participation was even higher in married individuals with a participating partner. Future efforts to increase participation in colorectal cancer screening could potentially benefit from considering the role of partner concordance.

Purpose: Unrecognised psychological distress among cancer survivors may be identified using short screening tools. We validated the accuracy of the distress thermometer (DT) to detect psychological distress on the Hospital Anxiety and Depression Scale (HADS) among early stage gynaecological cancer survivors and whether the women’s DT and HADS scores were associated with the need of an individualised supportive intervention. Methods: One hundred sixty-five gynaecological cancer survivors answered DT and HADS before randomisation in a trial testing a nurse-led, person-centred intervention using supportive conversations. The number of conversations was decided in the woman-nurse dyad based on the woman’s perceived need. Nurses were unaware of the women’s DT and HADS scores. We validated DT’s accuracy for screening using HADS as gold standard and receiver operating characteristic curves. Associations between DT and HADS scores and the number of conversations received were investigated. Results: For screening of distress (HADS ≥ 15), a DT score ≥ 2, had a sensitivity of 93% (95% CI 82–98%), a specificity of 40% (32–49%), and positive and negative predictive values of 36% (28–45%), and 94% (84–98%), respectively; area under curve was 0.73 (0.64–0.81). Higher DT and HADS scores were associated with more interventional conversations. Conclusions: In gynaecological cancer survivors, DT may perform fairly well as a first stage screening tool for distress, but a second stage is likely needed due to a high number of false positives. DT and HADS scores may predict the number of supportive conversations needed in an individualised intervention in gynaecological cancer survivors.

Background: Maternal hormonal contraception has been suspected of being linked to an increased risk of childhood cancer. The aim of this study was to assess the association between maternal use of hormonal contraception and diagnosis of leukaemia in their children. Methods: In this cohort study, we followed a nationwide cohort of 1 185 157 liveborn children between 1996 and 2014 listed in the Danish Medical Birth Registry and identified those diagnosed with leukaemia in the Danish Cancer Registry. Redeemed prescriptions from the Danish National Prescription Registry provided information about maternal hormonal contraceptive use, categorised as: no use (never used contraception before birth; reference category), previous use (>3 months before start of pregnancy), and recent use (≤3 months before and during pregnancy). We also calculated risk estimates separately for maternal hormonal contraceptive use during pregnancy. The primary outcome of interest was a diagnosis of any leukaemia in the children. Secondary outcomes were diagnoses of lymphoid leukaemia and non-lymphoid leukaemia. We used Cox proportional hazards models to estimate hazard ratios (HRs) with 95% CIs for risk of leukaemia in children. The Data Protection Agency registration number for this study is 2017-41-5221. Findings: Between Jan 1, 1996, and Dec 31, 2014, the 1 185 157 liveborn children accumulated 11 114 290 person-years of follow-up (median 9·3 years, IQR 4·6–14·2), during which 606 children were diagnosed with leukaemia (465 with lymphoid leukaemia and 141 with non-lymphoid leukaemia). Children born to women with recent use of any type of hormonal contraception were at higher risk for any leukaemia than children of women who never used contraception (HR 1·46, 95% CI 1·09–1·96; p=0·011); and for exposure during pregancy the risk was 1·78 (0·95–3·31; p=0·070). No association was found between timing of use and risk for lymphoid leukaemia (HR 1·23, 95% CI 0·97–1·57, p=0·089, for previous use

BACKGROUND: Pelvic inflammatory disease (PID) has been proposed as a risk factor for ovarian cancer. However, the existing literature on the association between PID and ovarian cancer risk is inconclusive, and only few cohort studies have been conducted.METHODS: Using nationwide Danish registries, we conducted a population-based cohort study including all women from the birth cohorts 1940 to 1970 in Denmark during 1978-2012 (n = 1,318,929) to investigate the association between PID and subsequent risk of epithelial ovarian cancer. Among women in the cohort, 81,281 women were diagnosed with PID and 5,356 women developed ovarian cancer during follow-up through 2012. Cox regression models were used to estimate HRs and 95% confidence intervals (CI) for the association between PID and ovarian cancer, both overall and according to histotype.RESULTS: For ovarian cancer overall, we observed no association with PID (HR, 1.05; 95% CI, 0.92-1.20). However, in histotype-specific analyses, we found a statistically significantly increased risk of serous ovarian cancer among women with PID (HR, 1.19; 1.00-1.41; P = 0.047). Conversely, PID was not convincingly associated with risk of any of the other histotypes of ovarian cancer.CONCLUSIONS: PID was associated with a modestly increased risk of serous ovarian cancer, but not other histotypes.IMPACT: Our results indicate that PID is not a strong risk factor for ovarian cancer. Whether PID is slightly associated with risk of serous ovarian cancer has to be confirmed in other studies. Cancer Epidemiol Biomarkers Prev; 26(1); 104-9. ©2016 AACR.

BACKGROUND: First-line treatment for patients with disseminated germ cell cancer (GCC) is bleomycin, etoposide, and cisplatin (BEP). A prognostic classification of patients receiving chemotherapy was published by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997, but only a small proportion of the patients received BEP.OBJECTIVE: To estimate survival probabilities after BEP, evaluate the IGCCCG prognostic classification, and propose new prognostic factors for outcome.DESIGN, SETTING, AND PARTICIPANTS: Of a Danish population-based cohort of GCC patients (1984-2007), 1889 received first-line BEP, with median follow-up of 15 yr. Covariates evaluated as prognostic factors were age, year of treatment, primary site, non-pulmonary visceral metastases, pulmonary metastases, and tumor markers.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes measured were 5-yr progression-free survival (PFS), 5-yr disease-specific survival (DSS), and 5-yr overall survival (OS) as calculated using the Kaplan-Meier method and the Cox proportional hazards model.RESULTS AND LIMITATIONS: The 5-yr PFS, DSS, and OS were 87%, 95%, and 93%, respectively, for patients with seminomatous GCC (SGCC) and good prognosis. For nonseminomatous GCC (NSGCC) with good, intermediate, and poor prognosis, the 5-yr probabilities were 90%, 76%, and 55% for PFS; 97%, 87%, and 66% for DSS; and 95%, 85%, and 64% for OS, respectively. For SGCC patients, new adverse prognostic factors not included in the IGCCCG classification were higher age and lactate dehydrogenase ≥1.5 times the upper limit of normal. For NSGCC patients, higher age and pulmonary metastases were additional adverse prognostic factors. Treatment in earlier years was associated with higher mortality. Limitations include the small number of patients in the prognostic groups, and the inability to adjust for performance status and comorbidity.CONCLUSIONS: Our study reveals improved survival for

Familial aggregation and the role of genetic and environmental factors can be investigated through family studies analysed using the liability-threshold model. The liability-threshold model ignores the timing of events including the age of disease onset and right censoring, which can lead to estimates that are difficult to interpret and are potentially biased. We incorporate the time aspect into the liability-threshold model for case-control-family data following the same approach that has been applied in the twin setting. Thus, the data are considered as arising from a competing risks setting and inverse probability of censoring weights are used to adjust for right censoring. In the case-control-family setting, recognising the existence of competing events is highly relevant to the sampling of control probands. Because of the presence of multiple family members who may be censored at different ages, the estimation of inverse probability of censoring weights is not as straightforward as in the twin setting but requires consideration. We propose to employ a composite likelihood conditioning on proband status that markedly simplifies adjustment for right censoring. We assess the proposed approach using simulation studies and apply it in the analysis of two Danish register-based case-control-family studies: one on cancer diagnosed in childhood and adolescence, and one on early-onset breast cancer.

Importance: Patients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options.Objective: To evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens.Design, Setting, and Participants: This study examined a Danish nationwide cohort of 5190 men with GCC who entered the Danish Testicular Cancer database between January 1, 1984, and December 31, 2007. Treatment results were compared with a randomly sampled, age-stratified, population-based control group. Cases of gonadal and extragonadal primary were included in the nationwide cohort. The treatments were surveillance only; retroperitoneal radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL).Main Outcomes and Measures: Cumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls.Results: The study population comprised 2804 patients with seminoma and 2386 with nonseminoma. The median follow-up was 14.4 years (interquartile range, 8.6-20.5 years). The 20-year cumulative incidence of SMN with death as a competing risk was 7.8% (surveillance), 7.6% (BEP), 13.5% (RT), 9.2% (MTOL), and 7.0% (controls). We found no increased risk for SMN after surveillance, while the HRs were 1.7 (95% CI, 1.4-2.0), 1.8 (95% CI, 1.5-2.3), and 3.7 (95% CI, 2.5-5.5), respectively, after BEP, RT, and MTOL. Mortality owing to non-GCC causes was decreased after surveillance, but increased by 1.3 times after BEP and RT and by 2.6 times after MTOL. Excess mortality due to SMN was found after BEP (HR, 1.6; 95% CI, 1.2-2.2), RT (HR, 2.1; 95% CI, 1.5-2.9), and MTO

Objective Some studies suggest that pelvic inflammatory disease (PID) is a potential risk factor for ovarian cancer. However, only few studies have investigated the association between PID and risk of borderline ovarian tumors. We conducted a population-based cohort study to investigate the association between PID and risk of borderline ovarian tumors. Methods Using various nationwide Danish registries we identified all women in Denmark during 1978–2012, who were born during 1940–1970 (n = 1,318,925). Of these, 81,263 women were diagnosed with PID in the study period, and 2736 women had a borderline ovarian tumor (1290 serous and 1344 mucinous). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PID and risk of borderline tumors were estimated using Cox regression models with adjustment for potential confounders. Results A history of PID was associated with an increased risk of borderline ovarian tumors (HR = 1.39; 95% CI: 1.19–1.61). However, histotype-specific analyses revealed significant variation in risk as PID was only associated with an increased risk of serous borderline tumors (HR = 1.85; 95% CI: 1.52–2.24), but not with mucinous borderline tumors (HR = 1.06; 95% CI: 0.83–1.35). Conclusions PID is associated with an increased risk of serous borderline tumors. Further research on the potential underlying biological mechanisms and on the identification of the subset of women with PID who are at increased risk of serous borderline tumors is warranted.