Pathogens as Instruments of Murder: The Forensic and Cultural Legacy of Karl Hopf.

Estimates of lifetime risks of tubo-ovarian cancer approach 40% among carriers of germline pathogenic variants (PVs) and range from 10%–17% among BRCA carriers, compared with 1.3% in the general population [,]. Genetic counseling, based on abundant evidence, provides carriers with information needed to consider family planning and risk reduction approaches for tubo-ovarian cancers []. Specifically, the American College of Obstetricians and Gynecologists (ACOG), and the National Comprehensive Cancer Network (NCCN) recommend that carriers ages 35–40 years and carriers ages 40–45 years undergo risk-reducing salpingo-oophorectomy. In contrast, evidence linking and PVs to increased endometrial cancer (EC) risk is less abundant and not entirely consistent. A review of six international guidelines found that only three addressed the issue of hysterectomy at risk-reducing surgery, all of which recommended individualized decision making []. As carriers pursue risk-reducing gynecologic surgery (RRS), guidance about risks and benefits of concurrent hysterectomy is needed to inform patient decisions. Thus, establishing carriers’ perceptions about EC risks and preferences for receiving information is important for providing optimal education. Counseling carriers about hysterectomy is challenging. Carriers are at increased relative risk for developing EC, but absolute risks remain modest at early ages. An analysis of 5980 carriers in the Netherlands found that PVs in increased EC risk 3.5-fold and that PVs in increased risk 1.7-fold [], confirming associations found in some other studies [,]. Notably, a small percentage of carriers [–] develop aggressive forms of ECs with serous histology and/or somatic mutations, sometimes at uncharacteristically early ages []. Although relative risks of EC are elevated among carriers, a meta-analysis estimated that absolute risks of any EC were 0.54% (about twice population expected value) and 0.29% for uterine serous carcinoma (more than ten times population expected value) []. Carriers with an intact uterus face difficult choices about management. Women who use tamoxifen for adjuvant therapy or chemoprevention for breast cancer have increased risk of uterine cancer, including for aggressive subtypes, and also develop benign endometrial polyps that may produce abnormal uterine bleeding []. In addition, premenopausal women who undergo oophorectomy experience early menopause, potentially resulting in neurologic, cardiovascular, urologic, sexual and cognitive side effects, osteoporosis, and shortened lifespan []. Recent epidemiological studies suggest that risks of cardiovascular disease and mental health conditions may be increased with hysterectomy, even with ovarian conservation [,]. Hormone replacement mitigates many of these effects, although not all especially among the youngest women [,]. However, use of estrogen-only regimens is contraindicated among women with a uterus because of increased EC risk, and while combined estrogen and progesterone limits EC risk, data related to breast cancer risks are inconsistent; nonetheless, many clinicians consider short-term use acceptable [].