Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis.

BACKGROUND: Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours. METHODS AND FINDINGS: Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk. CONCLUSIONS: Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.

The acceptability of vaginal self-sampling for human papillomavirus (HPV) testing among a multi-ethnic Asian female population / 부인종양

Objective@#In Malaysia, a cytology based program for cervical screening was implemented in 1969. Unfortunately, pap smear uptake has been low. The most common barriers to screening were embarrassment, time constraint and poor awareness to screening. As Malaysia is transitioning from a cytology-based screening to self-sampling human papillomavirus (HPV) testing as the primary screening method, it is therefore important to assess the acceptability of this screening approach in this multiethnic setting. @*Methods@#This was a cross-sectional study which recruited women aged 30–65 from several community-based cervical screening programs using self-sampling HPV testing across urban and suburban areas in all over Malaysia from April 2018 to May 2022. All women were instructed to self-collect vaginal samples for HPV testing using a dry flocked swab. All samples were genotyped on a clinically validated platform which allowed the detection of any high-risk HPV DNA. Approximately 2,000 women were randomly selected and interviewed to document their screening experience after the self-sampling procedure. @*Results@#A total of 19,835 women participated in the community-based cervical screening program using self-sampling HPV testing. The major ethnic group was Malay (68.4%) followed by Chinese (16.4%) and Indians (9.9%). Of these, 1,113 (5.7%) were positive for any high-risk HPV infection whereas 371 (1.9%) did not yield valid HPV results due to insufficient human DNA. A total of 2,012 participants responded to an interview regarding their screening experience using self-sampling HPV testing. Among these women, 1,179 (58.5%) did not attend regular Pap smear screening. Out of those who had ever performed Pap smear, 83.2% of them indicated a preference towards self-sampling HPV testing over Pap smear. Furthermore, 99% of them were willing to repeat this screening test as a routine screening method in the future. More than 95% of women perceived self-sampling HPV testing as easy, convenient and not embarrassing. Additionally, more than 80% of women felt comfortable and confident collecting their vaginal samples. This implies that self-sampling HPV testing is highly acceptable in our setting. @*Conclusion@#HPV testing via self-collection method is highly acceptable and preferred over Pap smear in the Malaysian multiethnic population. It is a promising approach to increase screening coverage which is an essential key target to be achieved in order to eliminate cervical cancer in Malaysia.

Non-bacterial thrombotic endocarditis: A rare manifestation of cervical adenocarcinoma

@#Non-bacterial thrombotic endocarditis (NBTE) denotes the presence of sterile non-infective vegetation on structurally normal, or subtly degenerate cardiac valves and is often associated with advanced malignancies. In gynaecological cancer in particular, NBTE has been most commonly associated with ovarian cancer.1,2 Here we report a rare but interesting case of NBTE in a patient with locally advanced cervical adenocarcinoma.