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

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.

Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays.

PURPOSE: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway. EXPERIMENTAL DESIGN: Two hundred thirty-eight BRCA1 VUS-comprising most BRCA1 VUS known in the Netherlands and Belgium-were tested for their ability to complement Brca1-deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families. RESULTS: All three assays showed 100% sensitivity and specificity (95% confidence interval, 83%-100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 13 of these 26 variants, we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of 7 (likely) pathogenic variants. CONCLUSIONS: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.

Dissociating spatial and spatiotemporal aspects of navigation ability in chronic stroke patients.

OBJECTIVE: The notion of distinguishable processing mechanisms for spatial and spatiotemporal information has largely been neglected in the context of navigation. Only a recent neuropsychological case study has provided initial evidence for the idea that these elements can be differentiated at a functional level. The aim of the current study was therefore to critically verify this double dissociation by adopting a systematic, large-scale approach. METHOD: Sixty-five chronic stroke patients and 60 matched healthy controls watched a route through a realistic virtual environment. They were assessed on their knowledge of this route in 4 different tasks after the learning phase. Performance on the scene recognition and route continuation tasks was taken as an indication of knowledge of the spatial route aspects. By contrast, spatiotemporal knowledge of the route was assessed in the route order and route progression tasks. RESULTS: Based on single case statistics, 6 patients showed an exceptionally large difference in their performance on the spatial and spatiotemporal tasks. Moreover, 2 patients satisfied formal criteria for a classical dissociation. CONCLUSIONS: Our findings showed that spatial and spatiotemporal performance was closely associated in most patients. Nonetheless, the study also provided partial support for the notion of separate space- and time-based processing mechanisms in the context of navigation. This distinction is of particular relevance to the investigation into the cognitive structure underlying navigation behavior. (PsycINFO Database Record

Distance comparisons in virtual reality: effects of path, context, and age.

In this large scale, individual differences study (N = 521), the effects of cardinal axes of an environment and the path taken between locations on distance comparisons were assessed. The main goal was to identify if and to what extent previous findings in simple 2D tasks can be generalized to a more dynamic, three-dimensional virtual reality environment. Moreover, effects of age and gender were assessed. After memorizing the locations of six objects in a circular environment, participants were asked to judge the distance between objects they encountered. Results indicate that categorization (based on the cardinal axes) was present, as distances within one quadrant were judged as being closer together, even when no visual indication of the cardinal axes was given. Moreover, strong effects of the path taken between object locations were found; objects that were near on the path taken were perceived as being closer together than objects that were further apart on this path, regardless of the metric distance between the objects. Males outperformed females in distance comparison, but did not differ in the extent of the categorization and path effects. Age also affected performance; the categorization and path effects were highly similar across the age range tested, but the general ability to estimate distances does show a clear pattern increase during development and decrease with aging.