Susanna C Larsson

Serum Estradiol and 20 Site-Specific Cancers in Women: Mendelian Randomization Study

AbstractContextThe causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear.ObjectiveThis Mendelian randomization study assessed the causal associations of endogenous 17β-estradiol (E2), the most potent estrogen, with cancer risk in women.MethodsAs primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio.ResultsGenetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor (ER)-positive breast cancer (OR 1.02; 95% CI, 1.01-1.03; P = 2.5 × 10−3), endometrial cancer overall (OR 1.09; 95% CI, 1.06-1.11; P = 7.3 × 10−13), and endometrial cancer of the endometrioid histology subtype (OR 1.10; 95% CI, 1.07-1.13; P = 2.1 × 10−11). There were suggestive associations with breast cancer overall (OR 1.01; 95% CI, 1.00-1.02; P = 0.02), ovarian cancer of the endometrioid subtype (OR 1.05; 95% CI, 1.01-1.10; P = 0.02), and stomach cancer (OR 1.12; 95% CI, 1.00-1.26; P = 0.05), but no significant association with other cancers.ConclusionThis study supports a role of E2 in the development of ER-positive breast cancer and endometrioid endometrial cancer but found no strong association with other cancers in women.

Association of the Age at Menarche with Site-Specific Cancer Risks in Pooled Data from Nine Cohorts

Abstract The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31–39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89–0.94), liver cancer (HR = 0.92; 95% CI, 0.85–0.99), melanoma (HR = 0.95; 95% CI, 0.93–0.98), bladder cancer (HR = 0.96; 95% CI, 0.93–0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96–0.99), lung (HR = 0.98; 95% CI, 0.96–0.99), and breast (HR = 0.98; 95% CI, 0.93–0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. Significance: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

Cohort Profile: The Ovarian Cancer Cohort Consortium (OC3)