Elio Riboli

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.

Copy Number Variants Are Ovarian Cancer Risk Alleles at Known and Novel Risk Loci

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.