Allan Jensen

Fertility treatment and risk of ovarian cancer in a large nationwide cohort of infertile Danish women

AbstractWhether fertility treatment increases the risk of ovarian cancer has been a concern for many decades, but previous research has yielded conflicting findings. We therefore investigated this association within a large population‐based cohort study of infertile women aged 20–45 years and living in Denmark between 1995 and 2017, as identified in the Danish Infertility Cohort (n = 146,110). The study cohort was linked to nationwide registers to obtain information on fertility drug use, cancer diagnoses, covariates, emigration, and vital status was. Hazard ratios (HR) and 95% confidence intervals (CI) with adjustment for potential confounders for ovarian cancer overall and for serous ovarian cancer were estimated using Cox proportional hazard models. During a median 10.3 years of follow‐up, 114 women were diagnosed with ovarian cancer of which 65 had serous ovarian cancer. Our results showed that the rate of serous ovarian cancer (HR 1.92; 95% CI 1.16–3.17) was increased after every use of progesterone but the association was not affected by increased follow‐up time since first use or with increased cumulative dose. We performed a secondary analysis adding less extensive data from 1971 through 1994 from the Danish Infertility Cohort. In this study cohort, 332 women developed ovarian cancer of which 192 had serous ovarian cancer. The overall results were similar, including the association between every use of progesterone and serous ovarian cancer (HR 2.05: 95% CI: 1.31–3.21). In conclusion, the novel finding that use of progesterone is associated with an increased rate of serous ovarian cancer warrants further investigation.

A framework for assessing interactions for risk stratification models: the example of ovarian cancer

Abstract Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

Risk of endometrial cancer among women with benign ovarian tumors — A Danish nationwide cohort study

The few studies on the association between benign ovarian tumors and endometrial cancer have been inconclusive. Using data from a large Danish register-based cohort study, we assessed the overall and type-specific risk of endometrial cancer among women with a benign ovarian tumor. We identified all Danish women diagnosed with a benign ovarian tumor during 1978-2016 in the Danish National Patient Register (n = 149,807). The study population was followed for subsequent development of endometrial cancer by linkage to the Danish Cancer Register and standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) were calculated after correction for hysterectomy. After a one-year delayed study entry, women with benign ovarian tumors had a decreased incidence of endometrial cancer (SIR = 0.74, 95% CI: 0.68-0.81) compared with women in the general Danish population. Both solid benign ovarian tumors (SIR = 0.79, 95% CI 0.70-0.88) and cystic benign ovarian tumors (SIR = 0.68, 95% CI 0.58-0.78) were associated with decreased incidences of endometrial cancer. Likewise, women with benign ovarian tumors had decreased incidences of both type I and type II endometrial cancer. The incidence of endometrial cancer was decreased to virtually the same magnitude irrespective of the age at diagnosis of a benign ovarian tumor and the reduction persisted throughout the follow-up period. The risk of endometrial cancer was decreased beyond the first year after a benign ovarian tumor and the decrease persisted for 20 or more years. The possible underlying mechanisms are not known and should be investigated further.

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.

Frandsen et al. respond to “A note on variable adjustments”

Abstract In response to M. Naylor’s valuable critique of our study “Polycystic Ovary Syndrome and Endometrial Cancer Risk: Results from a Nationwide Cohort Study,” we recognize the merit in the suggested areas. We recognize that including information on hormone therapy may have added to the understanding of the relationship between polycystic ovary syndrome (PCOS) and endometrial cancer risk. We further acknowledge the importance of the frequency of gynecological visits, which we have treated as a mediator rather than a confounder, given its role in reflecting PCOS severity and management. This approach, however, may introduce surveillance bias by influencing early cancer detection rates. Although the Danish health care system is fully subsidized, our exclusive use of hospital records may miss some PCOS cases managed in primary or specialized care settings outside the hospital, potentially leading to underestimation of the true association. Incorporating these variables in future studies could enhance analytical scope, though it would involve complex methodologies. We appreciate the comprehensive feedback, which underscores the necessity for further studies to elucidate the links between PCOS and endometrial cancer. These insights will inform future research and advance understanding in this area.

Polycystic ovary syndrome and endometrial cancer risk: results from a nationwide cohort study

Abstract Most previous studies found an elevated risk of endometrial cancer among women with polycystic ovary syndrome (PCOS). However, these had highly varying methods for ascertainment of PCOS diagnoses and limitations such as few exposed women and short follow-up. In this cohort study, we investigated the association between PCOS and endometrial cancer among women born in Denmark between January 1, 1940, and December 31, 1993 (n = 1 719 121). Data in this study, including PCOS and endometrial cancer diagnoses and covariates, were derived from nationwide registers. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% CIs. A total of 7862 endometrial cancer cases were identified during 23.7 years of follow-up (IQR, 37.7-61.9). We found an increased risk of endometrial cancer among women with PCOS compared with women without PCOS (HR = 3.02; 95% CI, 2.03-4.49). The risk was increased for premenopausal women (HR = 5.82; 95% CI, 3.64-9.30), whereas no marked association was seen for postmenopausal women. However, for postmenopausal women, results were limited by few cases and young age at the end of follow-up. Mounting evidence of an increased risk for endometrial cancer among women with PCOS reinforces the need for prevention and early detection. This article is part of a Special Collection on Gynecological Cancers.

Risk of Epithelial Ovarian Tumors among Women Diagnosed with Hypothyroidism and Hyperthyroidism: Findings from a Large Nationwide Cohort Study

Abstract Background: Prior research on the association between thyroid disease, ovarian cancer, and borderline ovarian tumors has been inconsistent. This nationwide cohort study investigated the risk of epithelial ovarian cancer and borderline ovarian tumors among 1,058,745 Danish women born between January 1, 1960, and December 31, 1997, and were followed until December 31, 2022, in relation to hypothyroidism and hyperthyroidism. Methods: Data on thyroid diagnoses, ovarian tumors, covariates, migration, and vital status were retrieved from Danish national registers. Hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer and borderline ovarian tumors overall and for histologic subtypes were estimated using adjusted Cox proportional hazard models. A landmark analysis assessed ovarian tumor risk at age 60 years by thyroid disease status before age 40 years. Results: Over a median of 18.4 years of follow-up, 49,015 women developed hypothyroidism, 26,950 hyperthyroidism, 905 ovarian cancer, and 1,111 borderline ovarian tumors. No association was found between hypothyroidism and ovarian cancer (HR, 1.10; CI, 0.78–1.55) or borderline tumors (HR, 0.88; CI, 0.60–1.29). Hyperthyroidism was associated with increased rates of serous ovarian cancer (HR, 1.62; CI, 1–2.63) and borderline ovarian tumors (HR, 1.78; CI, 1.26–2.52), especially in postmenopausal and premenopausal women, respectively. However, absolute risk differences at age 60 years were small and not statistically significant. Conclusions: Hyperthyroidism may increase the rate of epithelial ovarian tumors, though clinical significance remains unclear, warranting further research. Impact: These findings indicate that hyperthyroidism may modestly influence epithelial ovarian tumor risk, underscoring the need to clarify shared biological mechanisms between thyroid and ovarian function.