J. Margriet Collée's research while affiliated with Erasmus MC and other places

Background No validation has been conducted for the BOADICEA multifactorial breast cancer risk prediction model specifically in BRCA1/2 pathogenic variant (PV) carriers to date. Here, we evaluated the performance of BOADICEA in predicting five-year breast cancer risks in a prospective cohort of BRCA1/2 PV carriers ascertained through clinical genetic centres. Methods We evaluated the model calibration and discriminatory ability in the prospective TRANsIBCCS cohort study comprising 1,614 BRCA1 and 1,365 BRCA2 PV carriers (209 incident cases). Study participants had lifestyle, reproductive, hormonal, anthropometric risk factor information, a polygenic risk score based on 313 single nucleotide polymorphisms, and family history information. Results The full multifactorial model considering family history together with all other risk factors was well calibrated overall (E/O=1.07, 95%CI:0.92-1.24) and in quintiles of predicted risk. Discrimination was maximized when all risk factors were considered (Harrell's C-index=0.70, 95%CI:0.67-0.74; AUC=0.79, 95%CI:0.76-0.82). The model performance was similar when evaluated separately in BRCA1 or BRCA2 PV carriers. The full model identified 5.8%, 12.9% and 24.0% of BRCA1/2 PV carriers with five-year breast cancer risks of <1.65%, <3% and <5% respectively, risk thresholds commonly used for different management and risk-reduction options. Conclusion BOADICEA may be used to aid personalised cancer risk management and decision making for BRCA1 and BRCA2 PV carriers. It is implemented in the free-access CanRisk tool (www.canrisk.org).

To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families. In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups. The surveillance advice was reclassified in 37.9 % of heterozygotes and 32.2 % of non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 20.0 % of heterozygotes and 13.2 % of non-carriers; and a subanalysis showed that adding breast density on top shifted another 17.9 % of heterozygotes and 33.3 % of non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance. The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.

Objective To study the impact of premenopausal risk‐reducing salpingo‐oophorectomy (RRSO), compared with postmenopausal RRSO, on urinary incontinence (UI) ≥10 years later. Design Cross‐sectional study, nested in a nationwide cohort. Setting Multicentre in the Netherlands. Population 750 women (68% BRCA1/2 pathogenic variant carriers) who underwent either premenopausal RRSO (≤45 years, n = 496) or postmenopausal RRSO (≥54 years, n = 254). All participants were ≥55 years at the time of the study. Methods Urinary incontinence was assessed by the urinary distress inventory‐6 (UDI‐6); a score ≥33.3 indicated symptomatic UI. The incontinence impact questionnaire short form (IIQ‐SF) was used to assess the impact on women's health‐related quality of life (HR‐QoL). Differences between groups were analysed using regression analyses adjusting for current age and other confounders. Main outcome measures Differences in UDI‐6 scores and IIQ‐SF scores between women with a premenopausal and a postmenopausal RRSO. Results Women in the premenopausal RRSO group had slightly higher UDI‐6 scores compared with women in the postmenopausal RRSO group (P = 0.053), and their risk of symptomatic UI was non‐significantly increased (odds ratio [OR] 2.1, 95% confidence interval [95% CI] 0.93–4.78). A premenopausal RRSO was associated with a higher risk of stress UI (OR 3.5, 95% CI 1.2–10.0) but not with urge UI. The proportions of women with a significant impact of UI on HR‐QoL were similar in the premenopausal and postmenopausal RRSO groups (10.4% and 13.0%, respectively; P = 0.46). Conclusions More than 15 years after premenopausal RRSO, there were no significant differences in overall symptomatic UI between women with a premenopausal and those with a postmenopausal RRSO.

Background CHEK2 c.1100delC was the first moderate-risk breast cancer (BC) susceptibility allele discovered. Despite several genomic, transcriptomic and functional studies, however, it is still unclear how exactly CHEK2 c.1100delC promotes tumorigenesis. Since the mutational landscape of a tumor reflects the processes that have operated on its development, the aim of this study was to uncover the somatic genomic landscape of CHEK2-associated BC. Methods We sequenced primary BC (pBC) and normal genomes of 20 CHEK2 c.1100delC mutation carriers as well as their pBC transcriptomes. Including pre-existing cohorts, we exhaustively compared CHEK2 pBC genomes to those from BRCA1/2 mutation carriers, those that displayed homologous recombination deficiency (HRD) and ER− and ER+ pBCs, totaling to 574 pBC genomes. Findings were validated in 517 metastatic BC genomes subdivided into the same subgroups. Transcriptome data from 168 ER+ pBCs were used to derive a TP53-mutant gene expression signature and perform cluster analysis with CHEK2 BC transcriptomes. Finally, clinical outcome of CHEK2 c.1100delC carriers was compared with BC patients displaying somatic TP53 mutations in two well-described retrospective cohorts totaling to 942 independent pBC cases. Results BC genomes from CHEK2 mutation carriers were most similar to ER+ BC genomes and least similar to those of BRCA1/2 mutation carriers in terms of tumor mutational burden as well as mutational signatures. Moreover, CHEK2 BC genomes did not show any evidence of HRD. Somatic TP53 mutation frequency and the size distribution of structural variants (SVs), however, were different compared to ER+ BC. Interestingly, BC genomes with bi-allelic CHEK2 inactivation lacked somatic TP53 mutations and transcriptomic analysis indicated a shared biology with TP53 mutant BC. Moreover, CHEK2 BC genomes had an increased frequency of > 1 Mb deletions, inversions and tandem duplications with peaks at specific sizes. The high chromothripsis frequency among CHEK2 BC genomes appeared, however, not associated with this unique SV size distribution profile. Conclusions CHEK2 BC genomes are most similar to ER+ BC genomes, but display unique features that may further unravel CHEK2-driven tumorigenesis. Increased insight into this mechanism could explain the shorter survival of CHEK2 mutation carriers that is likely driven by intrinsic tumor aggressiveness rather than endocrine resistance.

Objective: To examine the effect of a premenopausal risk-reducing salpingo-oophorectomy (RRSO) in women at increased risk of ovarian cancer on objective and subjective cognition at least 10 years after RRSO. Design: A cross-sectional study with prospective follow-up, nested in a nationwide cohort SETTING: Multicenter in the Netherlands POPULATION OR SAMPLE: 641 women (66% BRCA1/2 pathogenic variant carriers) who underwent either a premenopausal RRSO ≤ age 45 (n=436) or a postmenopausal RRSO ≥ age 54 (n=205). All participants were older than 55 years at recruitment. Methods: Participants completed an online cognitive test battery and a questionnaire on subjective cognition. We used multivariable regression analyses, adjusting for age, education, breast cancer, hormone replacement therapy, cardiovascular risk factors and depression. Main outcome measures: The influence of RRSO on objective and subjective cognition of women with a premenopausal RRSO compared with women with a postmenopausal RRSO RESULTS: After adjustment, women with a premenopausal RRSO (mean time since RRSO 18.2 years) performed similarly on objective cognitive tests as women with a postmenopausal RRSO (mean time since RRSO 11.9 years). However, they more frequently reported problems with reasoning (odds ratio (OR) 1.8 (95% confidence interval (95%CI) 1.1-3.1)) and multitasking (OR 1.9 (95%CI 1.1-3.4)) than women with a postmenopausal RRSO. This difference between groups disappeared in an analysis restricted to women of comparable ages (60-70 years). Conclusions: Reassuringly, approximately 18 years after RRSO, we found no association between premenopausal RRSO and objective cognition.

Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.