Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Physical Activity During Adolescence and Early-adulthood and Ovarian Cancer Among Women with a BRCA1 or BRCA2 Mutation.

In the general population, physical activity has been associated with a lower risk of several cancers; however, the evidence for ovarian cancer is not clear. It is suggested that early-life physical activity may differentially impact risk. Whether this is true among women at high risk due to a pathogenic variant (mutation) in the BRCA1 or BRCA2 genes has not been evaluated. Thus, we performed a matched case-control study to evaluate the association between adolescent and early-adulthood physical activity and ovarian cancer. BRCA mutation carriers who completed a research questionnaire on various exposures and incident disease and with data available on physical activity were eligible for inclusion. Self-reported activity at ages 12-13, 14-17, 18-22, 23-29, and 30-34 was used to calculate the average metabolic equivalent of task (MET)-hours/week for moderate, vigorous, and total physical activity during adolescence (ages 12-17) and early-adulthood (ages 18-34). Conditional logistic regression was used to estimate the OR and 95% confidence intervals (CI) of invasive ovarian cancer associated with physical activity. This study included 215 matched pairs (mean age = 57.3). There was no association between total physical activity during adolescence (ORhigh vs. low = 0.91; 95% CI: 0.61-1.36; Ptrend = 0.85), early-adulthood (ORhigh vs. low = 0.78; 95% CI: 0.51-1.20; Ptrend = 0.38) and overall (ORhigh vs. low = 0.81; 95% CI: 0.54-1.23; Ptrend = 0.56) and ovarian cancer. Findings were similar for moderate (Ptrend ≥ 0.25) and vigorous (Ptrend ≥ 0.57) activity. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, physical activity should continue to be encouraged to promote overall health. SIGNIFICANCE: In this matched case-control study, we observed no association between physical activity during adolescence or early-adulthood and subsequent risk of ovarian cancer. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, being active remains important to promote overall health and well-being.

BRCAShare-Assessment of an animated digital message for intrafamilial communication of pathogenic variant positive test results: A feasibility study.

While genetic testing for hereditary breast and ovarian cancer syndrome (HBOC) is well-established in the field of medicine, family members' uptake of cascade genetic testing for known familial pathogenic variants remains low. Probands often become responsible for initiating familial communication about their testing results, and barriers to communication may include difficulty in conveying information to relatives and a lack of communication resources for probands' use. In this study, we tested a two-minute animated digital message (ADM) intervention guided by the Health Belief Model (HBM) in an unselected sample to determine hypothetical individual perceptions of susceptibility and severity and behavioral intention to act on the information provided in the ADM. We recruited genetic testing naïve adults from the United States with no personal history of cancer through Amazon Mechanical Turk to participate in this study. Participants were presented a hypothetical scenario describing a relative's recent HBOC diagnosis, viewed the ADM, and answered a questionnaire assessing participants' perception of the HBM constructs in relation to the hypothetical scenario and participants' intentions to pursue cascade genetic testing, talk to a healthcare professional, or talk to family members after ADM viewing. Participants (n = 373) largely perceived HBOC as serious and believed that they could benefit from the information provided by genetic testing; 76% hypothetically intended to pursue genetic testing at a cost of $100 or less, and 90% intended to either pursue testing or talk to a healthcare provider or family members. This feasibility study in an unaffected population could mimic the experience of distant/less-engaged relatives in HBOC families after receiving unexpected information about cascade genetic testing. Most participants demonstrated behavioral intention toward cascade testing, at a rate higher than literature would suggest is typical in high-risk families, indicating that a theory-supported, simple to use intervention may be useful in clinical practice.

The impact of a cascade testing video on recipients' knowledge, cognitive message processing, and affective reactions: A formative evaluation.

Cascade genetic testing is essential to clarify cancer risk in families with hereditary breast and ovarian cancer syndrome (HBOC) due to pathogenic variants (PVs) in BRCA1 or BRCA2. To date, data suggest that family communication of genetic testing results, with or without the aid of clinical resources such as a provider-written family letter, is impacted by multiple barriers. These barriers eventually lead to sub-optimal uptake of cascade genetic testing. We designed a 2-min animated video that a proband can share with relatives to notify them that the proband has tested positive for a pathogenic variant in BRCA1 or BRCA2. We studied the video via hypothetical scenario in an unselected population to simulate the process by which a relative receives unsolicited genetics information about their family member. We assessed the impact of the video on three specific domains: knowledge, cognitive message processing, and affective reactions. A total of 399 participants recruited through Amazon Mechanical Turk completed the study, and 373 were analyzed. The video significantly improved content knowledge/recall (p < .0001) from pre- to post-video viewing, indicating effective message communication. Items used to measure cognitive processing showed preliminary tendencies toward systematic message processing, which could be desired in familial communication aimed at initiating a specific action-in this case, cascade genetic testing. A majority of participants (66%) reported positive affective reaction as they indicated that they would feel gratitude if they received the video message from a relative, and did not evidence a negative affective reaction to receiving the information. Our data suggest that a video message can effectively communicate information about cascade genetic testing to potential relatives with as little as two minutes of content. Our data suggest that video messaging to assist family communication is a reasonable approach that increases understanding and is unlikely to cause harm.