Association between a 46-SNP Polygenic Risk Score and melanoma risk in Dutch patients with familial melanoma

Background Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%–40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma. Methods Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma. Results The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40–60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204). Conclusion Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families

Predicting the development of stress urinary incontinence 3 years after hysterectomy

We aimed to develop a prediction rule to predict the individual risk to develop stress urinary incontinence (SUI) after hysterectomy. Prospective observational study with 3-year follow-up among women who underwent abdominal or vaginal hysterectomy for benign conditions, excluding vaginal prolapse, and who did not report SUI before surgery (n = 183). The presence of SUI was assessed using a validated questionnaire. Significant prognostic factors for de novo SUI were BMI (OR 1.1 per kg/m(2), 95% CI 1.0-1.2), younger age at time of hysterectomy (OR 0.9 per year, 95% CI 0.8-1.0) and vaginal hysterectomy (OR 2.3, 95% CI 1.0-5.2). Using these variables, we developed the following rule to predict the risk of developing SUI: 32 + BMI-age + (7.5 × route of surgery). We defined a prediction rule that can be used to counsel patients about their individual risk on developing SUI following hysterectom

Addition of a 161-SNP polygenic risk score to family history-based risk prediction: impact on clinical management in non-BRCA1/2 breast cancer families.

BACKGROUND: The currently known breast cancer-associated single nucleotide polymorphisms (SNPs) are presently not used to guide clinical management. We explored whether a genetic test that incorporates a SNP-based polygenic risk score (PRS) is clinically meaningful in non-BRCA1/2 high-risk breast cancer families. METHODS: 101 non-BRCA1/2 high-risk breast cancer families were included; 323 cases and 262 unaffected female relatives were genotyped. The 161-SNP PRS was calculated and standardised to 327 population controls (sPRS). Association analysis was performed using a Cox-type random effect regression model adjusted by family history. Updated individualised breast cancer lifetime risk scores were derived by combining the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm breast cancer lifetime risk with the effect of the sPRS. RESULTS: The mean sPRS for cases and their unaffected relatives was 0.70 (SD=0.9) and 0.53 (SD=0.9), respectively. A significant association was found between sPRS and breast cancer, HR=1.16, 95% CI 1.03 to 1.28, p=0.026. Addition of the sPRS to risk prediction based on family history alone changed screening recommendations in 11.5%, 14.7% and 19.8 % of the women according to breast screening guidelines from the USA (National Comprehensive Cancer Network), UK (National Institute for Health and Care Excellence and the Netherlands (Netherlands Comprehensive Cancer Organisation), respectively. CONCLUSION: Our results support the application of the PRS in risk prediction and clinical management of women from genetically unexplained breast cancer families.This work was supported by the Dutch Cancer Society (KWF), grants UL2009-4388 and UL2014-7473

Advantages of expanded universal carrier screening: what is at stake?

Expanded universal carrier screening (EUCS) entails a twofold expansion of long-standing (preconception) carrier screening programmes: it not only allows the simultaneous screening of a large list of diseases ('expanded'), but also refers to a pan-ethnic screening offer ('universal'). Advocates mention three main moral advantages of EUCS as compared with traditional (targeted and/or ancestry-based) forms of carrier screening: EUCS will (1) maximise opportunities for autonomous reproductive choice by informing prospective parents about a much wider array of reproductive risks; (2) provide equity of access to carrier testing services; (3) reduce the risk of stigmatisation. This empirical ethics study aims to widen this account and provide a balanced picture of the potential pros and cons of EUCS. Semi-structured interviews were conducted with 17 health (policy) professionals and representatives of patient organisations about their views on carrier screening including a possible EUCS scenario. Stakeholders acknowledged the potential benefits of EUCS, but also expressed five main moral concerns: (1) Does EUCS respond to an urgent problem or population need? (2) Is it possible to offer couples both understandable and sufficient information about EUCS? (3) How will societal views on 'reproductive responsibility' change as a result of EUCS? (4) Will EUCS lead to a lower level of care for high-risk populations? (5) Will EUCS reinforce disability-based stigmatisation? While having the potential to overcome some moral limits inherent in traditional carrier screening, EUCS comes with moral challenges of its own. More research is needed to (further) anticipate the ethical and practical consequences of EUCS

Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases.

Peer reviewed: TrueAcknowledgements: We would like to thank Mary Velthuizen (University Medical Center Utrecht), J Margriet Collée (Erasmus Medical Center Rotterdam), Wendy Prager-van den Smissen (Erasmus Medical Center Rotterdam), Daoud Ait Moha (The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital), Jan C Oosterwijk (University Medical Center Groningen), Janet R Vos (Radboud University Medical Center), Jeroen FJ Laros (Leiden University Medical Center) and Adri JM Krol (Leiden University Medical Center) for collecting and converting the pedigree files of the included families.BACKGROUND: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families. METHODS: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known. RESULTS: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM. CONCLUSIONS: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes