Laure Dossus

Metabolically Defined Body Size Phenotypes and Risk of Endometrial Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Abstract Background: Obesity is a risk factor for endometrial cancer but whether metabolic dysfunction is associated with endometrial cancer independent of body size is not known. Methods: The association of metabolically defined body size phenotypes with endometrial cancer risk was investigated in a nested case–control study (817 cases/ 817 controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC). Concentrations of C-peptide were used to define metabolically healthy (MH; <1st tertile) and metabolically unhealthy (MU; ≥1st tertile) status among the control participants. These metabolic health definitions were combined with normal weight (NW); body mass index (BMI)<25 kg/m2 or waist circumference (WC)<80 cm or waist-to-hip ratio (WHR)<0.8) and overweight (OW; BMI≥25 kg/m2 or WC≥80 cm or WHR≥0.8) status, generating four phenotype groups for each anthropometric measure: (i) MH/NW, (ii) MH/OW, (iii) MU/NW, and (iv) MU/OW. Results: In a multivariable-adjusted conditional logistic regression model, compared with MH/NW individuals, endometrial cancer risk was higher among those classified as MU/NW [ORWC, 1.48; 95% confidence interval (CI), 1.05–2.10 and ORWHR, 1.68; 95% CI, 1.21–2.35] and MU/OW (ORBMI, 2.38; 95% CI, 1.73–3.27; ORWC, 2.69; 95% CI, 1.92–3.77 and ORWHR, 1.83; 95% CI, 1.32–2.54). MH/OW individuals were also at increased endometrial cancer risk compared with MH/NW individuals (ORWC, 1.94; 95% CI, 1.24–3.04). Conclusions: Women with metabolic dysfunction appear to have higher risk of endometrial cancer regardless of their body size. However, OW status raises endometrial cancer risk even among women with lower insulin levels, suggesting that obesity-related pathways are relevant for the development of this cancer beyond insulin. Impact: Classifying women by metabolic health may be of greater utility in identifying those at higher risk for endometrial cancer than anthropometry per se.

Use of menopausal hormone therapy and ovarian cancer risk in a French cohort study

Abstract Background Epidemiological studies have found that menopausal hormone therapy (MHT) use is associated with an increased ovarian cancer risk. However, whether different MHT types confer the same level of risk is unclear. We estimated the associations between different MHT types and the risk of ovarian cancer in a prospective cohort. Methods The study population included 75 606 postmenopausal women from the E3N cohort. Exposure to MHT was identified from self-reports in biennial questionnaires between 1992 and 2004 and from drug claim data matched to the cohort between 2004 and 2014. Hazard ratios and 95% confidence intervals (CIs) of ovarian cancer were estimated using multivariable Cox proportional hazards models with MHT as a time-varying exposure. Tests of statistical significance were 2-sided. Results Over an average 15.3 years follow-up, 416 ovarian cancers were diagnosed. Hazard ratios of ovarian cancer associated with ever use of estrogens combined with progesterone or dydrogesterone and ever use of estrogens combined with other progestagen were equal to 1.28 (95% CI = 1.04 to 1.57) and 0.81 (95% CI = 0.65 to 1.00), respectively (Phomogeneity = .003), compared with never use. The hazard ratio for unopposed estrogen use was 1.09 (95% CI = 0.82 to 1.46). We found no trend according to duration of use or time since last use except for estrogens combined with progesterone or dydrogesterone, which showed decreasing risk with increasing time since last use. Conclusion Different MHT types may impact ovarian cancer risk differentially. The possibility that MHT containing progestagens other than progesterone or dydrogesterone may confer some protection should be evaluated in other epidemiological studies.

Thyroid hormones and epithelial ovarian cancer risk and survival: results from the European Prospective Investigation into Cancer and Nutrition study

Abstract Background Thyroid-stimulating hormone (TSH) and thyroid hormones (free triiodothyronine [fT3] and free thyroxine [fT4]) may influence cancer outcomes, but evidence for ovarian cancer is limited. Methods We conducted a nested case–control study comparing 578 epithelial ovarian cancer (EOC) cases with matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC). To examine associations between circulating TSH, fT3, and fT4 levels and EOC risk, we estimated risk ratios (RRs) and 95% confidence intervals (CIs) per SD using conditional logistic regression. Among cases, we evaluated all-cause and EOC-specific survival by prediagnostic hormone levels. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable Cox regression. We also estimated covariate-adjusted restricted mean survival time (RMST) and survival probabilities at 5 and 10 years. Results Thyroid hormones were not associated with EOC risk (RR [95% CI] per SD increase: TSH = 0.99 [0.87 to 1.12], fT3 = 1.12 [0.70 to 1.79], and fT4 = 1.08 [0.56 to 2.07]) levels. However, higher TSH levels were associated with better survival (HR [95% CI] per SD: all-cause death = 0.90 [0.82 to 0.99], EOC-specific = 0.88 [0.79 to 0.97]), whereas higher fT4 levels were associated with worse survival (all-cause = 1.10 [1.00 to 1.22], EOC-specific = 1.17 [1.05 to 1.30]), but no association for fT3. RMST and survival probabilities showed similar patterns: for TSH, 10-year RMST and survival increased from 5.3 years and 42.2% in Quartile 1 (Q1) to 6.4 years and 50.7% in Q4. Conversely, for fT4, 10-year RMST declined from 5.6 years (Q1) to 5.1 years Q4, and survival from 46.3% to 37.8%. Conclusion TSH and thyroid hormones might not affect ovarian cancer risk. However, high fT4 and low TSH concentrations may be associated with poorer survival. Further evaluation is suggested in other populations.

The Effect of Circulating Proteins and Their Role in Mediating Adiposity’s Effect on Endometrial Cancer Risk: Mendelian Randomization and Colocalization Analyses

Abstract Background: Proteomics could enhance our understanding of endometrial carcinogenesis. However, addressing confounding in traditional observational studies remains challenging, especially given the strong impact of adiposity on the plasma proteome and endometrial cancer risk. Methods: Using Mendelian randomization (MR) and colocalization analyses, we examined the causal association between 2,751 unique proteins from the UK Biobank (N proteins = 2,031; N = 52,363) and deCODE (N proteins = 1,667; N = 35,559) with endometrial cancer risk [overall (N cases = 12,270; N controls = 46,126), endometrioid (N cases = 8,758), and nonendometrioid (N cases = 1,230)]. We performed enrichment analyses to explore pathways overrepresented among plasma proteins in endometrioid and nonendometrioid cancer subtypes. We assessed whether circulating proteins mediated the effect of body mass index on endometrial cancer risk using uni- and multivariable MR. Results: Twenty proteins were associated with endometrial cancer risk in MR and colocalization analyses. GSTO1-1 and SKAP1 were positively and MMP10 was negatively associated with overall and endometrioid endometrial cancer; DTYMK and ABO were positively and TSSC4 was negatively associated with overall endometrial cancer; IGF2R was positively associated with endometrioid cancer; and MAPK9 was positively and DNAJB14, IFI16, LCN2, and SCT were negatively associated with nonendometrioid endometrial cancer. Distinct pathways were overrepresented in endometrioid (e.g., platelet-derived growth factor signaling and PTEN gene regulation) and nonendometrioid (e.g., noncanonical NF-κB signaling) cancer subtypes. There was weak evidence of associated proteins mediating the relationship between body mass index and endometrial cancer risk. Conclusions: We identified distinct plasma proteins and pathways associated with endometrioid and nonendometrioid endometrial cancer risk. Impact: Prioritized proteins may support noninvasive methods to differentiate endometrial cancer subtypes.