European Journal of Epidemiology

Cancer risk after in utero exposure to diethylstilbestrol

In utero exposure to diethylstilbestrol (DES) is associated with increased risk of clear cell adenocarcinoma (CCAC) of the vagina or cervix. It is not clear whether these risks remain increased at older ages, and if the risks of other cancer sites, including breast cancer, are increased. This nationwide cohort study included 12,249 DES-exposed women and 2,070 unexposed sisters. Hormone-related risk factors and medical history were assessed through questionnaires, and cancer incidence through linkages with nationwide registries. Comparison with general population rates showed no difference in overall cancer risk (SIR = 0.98, 95%CI 0.93-1.04) or breast cancer risk (SIR = 1.03, 95%CI 0.96-1.11) for DES-exposed women. The rate of vaginal cancer was strongly increased for DES-exposed women (SIR = 10.5, 95%CI 5.72-17.6) and was increased in all age categories, including age 60-69 years (SIR = 8.3, 95%CI 1.00-29.9). Risks of both CCAC (SIR = 49.1, 95%CI 21.2-96.8) and squamous cell carcinoma (SCC; SIR = 5.86, 95%CI 2.15-12.8) of the vagina were significantly elevated. When comparing DES-exposed women with DES-unexposed sisters, overall cancer risk and risk of breast cancer were similar (HR = 0.93, 95%CI 0.78-1.11 and HR = 0.97, 95%CI 0.76-1.23, respectively). Apart from the established increased risk of vaginal cancer, women exposed to DES in utero do not seem to be at increased risk of cancer, including breast cancer. The risk of vaginal cancer remains increased also for women in their fifties/sixties. Moreover, the increased risk of vaginal cancer was seen for both subtypes CCAC and SCC. Screening for vaginal cancer up to higher ages than currently recommended (< 60 years) should be considered.

A prospective study of smoking-related white blood cell DNA methylation markers and risk of bladder cancer

AbstractBladder cancer, a common neoplasm, is primarily caused by tobacco smoking. Epigenetic alterations including DNA methylation have the potential to be used as prospective markers of increased risk, particularly in at-risk populations such as smokers. We aimed to investigate the potential of smoking-related white blood cell (WBC) methylation markers to contribute to an increase in bladder cancer risk prediction over classical questionnaire-based smoking metrics (i.e., duration, intensity, packyears) in a nested case–control study within the prospective prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial and the alpha-tocopherol, beta-carotene cancer (ATBC) Prevention Study (789 cases; 849 controls). We identified 200 differentially methylated sites associated with smoking status and 28 significantly associated (after correction for multiple testing) with bladder cancer risk among 2670 previously reported smoking-related cytosine–phosphate–guanines sites (CpGs). Similar patterns were observed across cohorts. Receiver operating characteristic (ROC) analyses indicated that cg05575921 (AHHR), the strongest smoking-related association we identified for bladder cancer risk, alone yielded similar predictive performance (AUC: 0.60) than classical smoking metrics (AUC: 0.59–0.62). Best prediction was achieved by including the first principal component (PC1) from the 200 smoking-related CpGs alongside smoking metrics (AUC: 0.63–0.65). Further, PC1 remained significantly associated with elevated bladder cancer risk after adjusting for smoking metrics. These findings suggest DNA methylation profiles reflect aspects of tobacco smoke exposure in addition to those captured by smoking duration, intensity and packyears, and/or individual susceptibility relevant to bladder cancer etiology, warranting further investigation.

Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947–1964: The Nurses’ Health Study II, a prospective cohort study

AbstractOral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses’ Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65–0.91]; &gt;10 years of use, 0.43 [0.32–0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (&gt; 5 years) of ethinyl estradiol (0.52 [0.41–0.67]) and second-generation progestins (0.43 [0.30–0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50–0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49–0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (&lt; vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.

Offspring sex and risk of epithelial ovarian cancer: a multinational pooled analysis of 12 case–control studies

While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. We performed a pooled analysis among parous participants from 12 case-controls studies comprising 6872 EOC patients and 9101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case-control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR = 1.45; 95% CI = 1.01-2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR = 1.71 vs 0.99; P-interaction = 0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR = 1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR = 0.49, 95% CI = 0.28-0.83) but with higher risk among women without any of those conditions (OR = 1.64 95% CI = 1.14-2.34; P-interaction = 0.003). Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk.