Background: Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation... Show moreBackground: Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines.Methods: For 425 cancer-free women with cancer FH (mean age 40.6 years, range 21-74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS306) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. >= 20 % and >= 30 % eLTR, or >= 5 % e10YR were determined.Findings: Of the women with non-informative PV status, including PRS306 and NGRFs changed clinical recommendations for 31.0 %, (57/184, 20 % eLTR), 15.8 % (29/184, 30 % eLTR) and 22.4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16.7 % (25/150), 1.3 % (2/150) and 9.5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2 , PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS <30 years, and women tested non-informative/negative for whom IBS may be postponed. Interpretation: For women who tested non-informative/negative, PRS and NGRFs have a considerable impact on IBS recommendations. Combined consideration of eLTRs and e10YRs allows personalizing IBS starting age.Funding: Horizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Koln Fortune. Show less
AimsDuring the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias.... Show moreAimsDuring the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients.Methods and resultsWe investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27–51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P < 0.001).ConclusionAlmost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed. Show less
Background: The Oncotype DX assay is a clinically validated 17-gene genomic assay that provides a genomic prostate score (GPS; scale 0-100) measuring the heterogeneous nature of prostate tumors.... Show moreBackground: The Oncotype DX assay is a clinically validated 17-gene genomic assay that provides a genomic prostate score (GPS; scale 0-100) measuring the heterogeneous nature of prostate tumors. The test is performed on prostate tissue collected during biopsy. There is a lack of data on the association between the GPS and tumor pathology after radical prostatectomy (RP). Objective: To investigate the association between GPS and final pathology, including extra prostatic extension (EPE), positive surgical margin (PSM), and seminal vesicle invasion (SVI). Design, setting, and participants: Data for the 749 patients who underwent Oncotype DX assay and RP at a referral prostate cancer center between 2015 and 2019 were retrospectively assessed to evaluate the association between GPS and unfavorable pathology parameters. Intervention: After a GPS genetic test, patients underwent robotic RP performed by the same surgeon. Outcome measurement and statistical analysis: Multivariable logistic regression analyses were performed to assess the association between GPS and EPE, PSM, and SVI. The models were adjusted for age, clinical stage, prostate-specific antigen (PSA) level, Gleason score, and time between the genomic assay and surgery. The median time between Oncotype DX assay and surgery was 176 d (interquartile range [IQR] 141-226). The median age was 63 yr (IQR 58-68), median GPS was 29 (IQR 21-39), and median PSA was 5.7 ng/ml (IQR 4.6-7.7). In multivariable analyses assessing the odds ratio (OR) per 20-point change in GPS, GPS was an independent predictor of EPE (OR 1.8, 95% confidence interval [CI] 1.4-2.3) and SVI (OR 2.1, 95% CI 1.3-3.4). In addition, when patients were grouped by GPS quartile, the percentage of cases with EPE and SVI increased with the GPS quartile. Conclusions: We provide evidence that the Oncotype DX GPS is significantly associated with adverse pathology after RP. Specifically, the risk of EPE and SVI increases with the GPS. Therefore, use of the Oncotype DX GPS may help clinicians to improve preoperative patient counseling and develop surgical strategies for patients with a higher chance of EPE or unfavorable pathological features. Patient summary: We studied whether the score for a prostate genetic test was associated with prostate cancer pathology findings for patients who had their prostate removed. We found that the risk of prostate cancer spread outside the gland and to the seminal vesicle increases with higher test scores. These findings may help surgeons in counseling patients on surgical options for prostate cancer. (C) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less
Background: In recent years, germline testing of women with a risk of developing breast and ovarian cancer has increased rapidly. This is due to lower costs for new high-throughput sequencing... Show moreBackground: In recent years, germline testing of women with a risk of developing breast and ovarian cancer has increased rapidly. This is due to lower costs for new high-throughput sequencing technologies and the manifold preventive and therapeutic options for germline mutation carriers. The growing demand for genetic counseling meets a shortfall of counselors and illustrates the need to involve the treating clinicians in the genetic testing process. This survey was undertaken to assess their state of knowledge and training needs in the field of genetic counseling and testing. Methods: A cross-sectional survey within the European Bridges Study (Breast Cancer Risk after Diagnostic Gene Sequencing) was conducted among physician members (n = 111) of the German Cancer Society who were primarily gynecologists. It was designed to examine their experience in genetic counseling and testing. Results: Overall, the study revealed a need for training in risk communication and clinical recommendations for persons at risk. One-third of respondents communicated only relative disease risks (31.5%) instead of absolute disease risks in manageable time spans. Moreover, almost one-third of the respondents (31.2%) communicated bilateral and contralateral risk-reducing mastectomy as an option for healthy women and unilateral-diseased breast cancer patients without mutations in high-risk genes (e.g. BRCA1 or BRCA2). Most respondents expressed training needs in the field of risk assessment models, the clinical interpretation of genetic test results, and the decision-making process. Conclusion: The survey demonstrates a gap of genetic and risk literacy in a relevant proportion of physicians and the need for appropriate training concepts. Show less
Eggermann, T.; Elbracht, M.; Kurth, I.; Juul, A.; Johannsen, T.H.; Netchine, I.; ... ; European Reference Network Rare 2020
Background With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of... Show moreBackground With the development of molecular high-throughput assays (i.e. next generation sequencing), the knowledge on the contribution of genetic and epigenetic alterations to the etiology of inherited endocrine disorders has massively expanded. However, the rapid implementation of these new molecular tools in the diagnostic settings makes the interpretation of diagnostic data increasingly complex. Main body This joint paper of the ENDO-ERN members aims to overview chances, challenges, limitations and relevance of comprehensive genetic diagnostic testing in rare endocrine conditions in order to achieve an early molecular diagnosis. This early diagnosis of a genetically based endocrine disorder contributes to a precise management and helps the patients and their families in their self-determined planning of life. Furthermore, the identification of a causative (epi)genetic alteration allows an accurate prognosis of recurrence risks for family planning as the basis of genetic counselling. Asymptomatic carriers of pathogenic variants can be identified, and prenatal testing might be offered, where appropriate. Conclusions The decision on genetic testing in the diagnostic workup of endocrine disorders should be based on their appropriateness to reliably detect the disease-causing and -modifying mutation, their informational value, and cost-effectiveness. The future assessment of data from differentomicapproaches should be embedded in interdisciplinary discussions using all available clinical and molecular data. Show less
Pre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about... Show morePre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about panel testing. It is presently unknown whether and how uncertainty is discussed during initial cancer genetic counseling. We therefore investigated whether and how counselors discuss and address uncertainty, and the extent of shared decision-making (SDM), and explored associations between counselors' communication and their characteristics in consultations on panel testing for cancer. For this purpose, consultations of counselors discussing a multigene panel with a simulated patient were videotaped. Simulated patients represented a counselee who had had multiple cancer types, according to a script. Before and afterwards, counselors completed a survey. Counselors' uncertainty expressions, initiating and the framing of expressions, and their verbal responses to scripted uncertainties of the simulated patient were coded by two researchers independently. Coding was done according to a pre-developed coding scheme using The Observer XT software for observational analysis. Additionally, the degree of SDM was assessed by two observers. Correlation and regression analyses were performed to assess associations of communicated uncertainties, responses and the extent of SDM, with counselors' background characteristics. In total, twenty-nine counselors, including clinical geneticists, genetic counselors, physician assistants-in-training, residents and interns, participated of whom working experience varied between 0 and 25 years. Counselors expressed uncertainties mainly regarding scientific topics (94%) and on their own initiative (95%). Most expressions were framed directly (77%), e.g. We don't know, and were emotionally neutral (59%; without a positive/negative value). Counselors mainly responded to uncertainties of the simulated patient by explicitly referring to the uncertainty (69%), without providing space for further disclosure (66%). More experienced counselors provided less space to further disclose uncertainty (p < 0.02), and clinical geneticists scored lower on SDM compared with other types of counselors (p < 0.03). Our findings that counselors mainly communicate scientific uncertainties and use space-reducing responses imply that the way counselors address counselees' personal uncertainties and concerns during initial cancer genetic counseling is suboptimal. Show less
Early-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast... Show moreEarly-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31years. However, large studies investigating TP53 mutation prevalence in this population are scarce. We collected nationwide laboratory records for all young breast cancer patients tested for TP53 mutations in the Netherlands. Between 2005 and 2016, 370 women diagnosed with breast cancer younger than 30years of age were tested for TP53 germline mutations, and eight (2.2%) were found to carry a (likely) pathogenic TP53 sequence variant. Among BRCA1/BRCA2 mutation negative women without a family history suggestive of LFS or a personal history of multiple LFS-related tumours, the TP53 mutation frequency was <1% (2/233). Taking into consideration that TP53 mutation prevalence was comparable or even higher in some studies selecting patients with breast cancer onset at older ages or HER2-positive breast cancers, raises the question of whether a very early age of onset is an appropriate single TP53 genetic testing criterion. Show less
Hemoglobinopathies (HbP) are recessive hereditary disorders of hemoglobin, characterized by microcytic hypochromic anemia. HbP diagnostics encompasses three specialties: hematological, biochemical... Show moreHemoglobinopathies (HbP) are recessive hereditary disorders of hemoglobin, characterized by microcytic hypochromic anemia. HbP diagnostics encompasses three specialties: hematological, biochemical and molecular testing. Results of all tests together form the complete diagnosis. The main objective of this thesis was to improve post- and prenatal diagnostics of the hemoglobinopathies. Several molecular assays have been designed, tested and validated. In addition, a number of informative hemoglobinopathy cases have been studied in detail. Diagnostics for hemoglobinopathies is strongly improved over the recent years. In particular the implementation of the MLPA technique made it possible to detect deletions and duplications in the globin gene clusters in patients who remain undiagnosed by applying the conventional techniques. The aCGH technology was developed in order to characterize the breakpoints of novel deletions detected by MLPA more precisely. This has led to the design of several relatively simple gap-PCR assays, which are useful in laboratories where MLPA and aCGH is not available. In addition, gap-PCR can be used for quick screening for the more locally occurring deletions or in family studies. A non-invasive prenatal diagnosis assay for hemoglobinopathies was developed by combining the PAP and MCA techniques. This method will be implemented in the current flow for prenatal diagnosis and will eventually make 50% of the invasive procedures redundant. Show less
Molecular confirmation of a clinical diagnosis of an inherited disease or of congenital malformations is of paramount importance for patients and their families. It is the conclusion of the... Show moreMolecular confirmation of a clinical diagnosis of an inherited disease or of congenital malformations is of paramount importance for patients and their families. It is the conclusion of the differential diagnostic process, and provides information on the prognosis, in some cases on the therapeutic options, and on the recurrence risk. Currently, targeted sequencing of gene (s) of interest is the preferred approach for searching for small pathogenic mutations. The work presented in this thesis describes the application of new techniques for detecting small variations (mutations) in genomic DNA that underlie various disorders. These techniques include High Resolution Melting Curve Analysis (HR-MCA) followed by Sanger sequencing, targeted, X-exome and whole exome capture followed by Next Generation Sequencing (NGS). We have optimized, tested and applied the different new molecular techniques mentioned above to 1) faci litate the detection of disease causing mutations in several disorders with suspected Mendelian inheritance, 2) to speed up the identification of disease genes, 3) to provide a systematic tool for classifying previously intractable genetic diseases Show less
The studies described in this thesis had two main aims: 1) To study the quality of life of patients with venous thrombosis and to examine the role of illness perceptions in explaining the quality... Show moreThe studies described in this thesis had two main aims: 1) To study the quality of life of patients with venous thrombosis and to examine the role of illness perceptions in explaining the quality of life of these patients. 2) To assess the psychological consequences of genetic testing for thrombophilia, using the Common-Sense Model (Leventhal et al.., 1984) as a theoretical framework.The studies performed to assess aim 1 form the first part of the thesis and show that the effect of venous thrombosis on quality of life should not be underestimated, even some years after the venous thrombosis. Furthermore, results give an indication that besides the presence of the postthrombotic syndrome, illness perceptions may help to explain quality of life in patients with venous thrombosis.In the second part of the thesis aim 2 is addressed. Genetic testing for thrombophilia does not have many adverse psychological consequences. However, certain vulnerable individuals may still experience considerable worry about getting venous thrombosis. Furthermore, results indicate that the Common-Sense Model can act as a useful framework to enhance understanding of how factors contribute to influence psychological response to risk of disease. Show less
