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Each year approximately 15,000 patients are diagnosed with colorectal cancer (CRC) in the Netherlands, of whom 5-10% are associated with a hereditary syndrome. To enable future research into hereditary CRC, we established a collaborative biobank for hereditary CRC in all eight University Medical Centers (UMCs) in the Netherlands in 2009. This Biobank Hereditary CRC is part of the Parelsnoer Institute (PSI), which is funded by the Dutch Federation of UMCs and the Dutch Government. Besides the multicenter collaboration, the multidisciplinary nature of this biobank - involving Gastroenterology, Genetics and Surgery - is essential for its functionality and value. Patients at increased risk of hereditary CRC and/or Polyposis, or with a proven germline mutation causing CRC and/or Polyposis are included. Both clinical data (demographic data, details on medical and family history, information on surveillance, endoscopy and surgery, results of microsatellite instability and molecular genetic tests) and biomaterial (DNA, plasma, serum and tissue) are collected in a standardized manner. [ABSTRACT FROM AUTHOR]

Objectives: To assess quality and reusability of coded cancer diagnoses in routine primary care data. To identify factors that influence data quality and areas for improvement.Methods: A dynamic cohort study in a Dutch network database containing 250,000 anonymized electronic medical records (EMRs) from 52 general practices was performed. Coded data from 2000 to 2011 for the three most common cancer types (breast, colon and prostate cancer) was compared to the Netherlands Cancer Registry.Measurements: Data quality is expressed in Standard Incidence Ratios (SIRs): the ratio between the number of coded cases observed in the primary care network database and the expected number of cases based on the Netherlands Cancer Registry. Ratios were multiplied by 100% for readability.Results: The overall SIR was 91.5% (95%CI 88.5-94.5) and showed improvement over the years. SIRs differ between cancer types: from 71.5% for colon cancer in males to 103.9% for breast cancer. There are differences in data quality (SIRs 76.2% - 99.7%) depending on the EMR system used, with SIRs up to 232.9% for breast cancer. Frequently observed errors in routine healthcare data can be classified as: lack of integrity checks, inaccurate use and/or lack of codes, and lack of EMR system functionality.Conclusions: Re-users of coded routine primary care Electronic Medical Record data should be aware that 30% of cancer cases can be missed. Up to 130% of cancer cases found in the EMR data can be false-positive. The type of EMR system and the type of cancer influence the quality of coded diagnosis registry. While data quality can be improved (e.g. through improving system design and by training EMR system users), re-use should only be taken care of by appropriately trained experts. [ABSTRACT FROM AUTHOR]

Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327). BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi. Because of this increased risk, it is important to identify patients with BAP1-TPDS. The associated tumors are treated by different medical disciplines, emphasizing the need for generally applicable guidelines for initiating genetic analysis. In this study, we describe the path to identification of BAP1-TPDS in 21 probands found in the Netherlands and the family history at the time of presentation. We report two cases of de novo BAP1 germline mutations (2/21, 9.5%). Findings of this study combined with previously published literature, led to a proposal of guidelines for genetic referral. We recommend genetic analysis in patients with ≥2 BAP1-TPDS-associated tumors in their medical history and/or family history. We also propose to test germline BAP1 in patients diagnosed with UM <40 years, CM <18 years, MMe <50 years, or RCC <46 years. Furthermore, other candidate susceptibility genes for tumor types associated with BAP1-TPDS are discussed, which can be included in gene panels when testing patients. [ABSTRACT FROM AUTHOR]

Objective: Conventional genetic tests (quantitative fluorescent-PCR [QF-PCR] and single nucleotide polymorphism-array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield., Methods: We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first-degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes., Results: We established a genetic rES-based diagnosis in 8 out of 23 fetuses (35%) without QF-PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker-Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8-20) days., Conclusion: Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance., (© 2020 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Purpose: Li-Fraumeni syndrome (LFS) is a hereditary cancer syndrome, characterized by a high risk of developing cancer at various sites and ages. To date, limited clinical benefits of genetic testing for LFS have been demonstrated, and there are concerns about the potential adverse psychosocial impact of genetic testing for LFS. In this study, we evaluated the uptake of genetic testing and the psychosocial impact of undergoing or not undergoing a genetic test for LFS., Patients and Methods: In total, 18 families with a p53 germline mutation in the Netherlands were identified. Eligible family members were invited to complete a self-report questionnaire assessing motives for undergoing or not undergoing genetic testing, LFS-related distress and worries, and health-related quality of life., Results: Uptake of presymptomatic testing was 55% (65 of 119). Of the total group, 23% reported clinically relevant levels of LFS-related distress. Carriers were not significantly more distressed than noncarriers or than those with a 50% risk who did not undergo genetic testing. Those with a lack of social support were more prone to report clinically relevant levels of distress (odds ratio, 1.3; 95% CI, 1.0 to 1.5)., Conclusion: Although preventive and treatment options for LFS are limited, more than half of the family members from known LFS families choose to undergo presymptomatic testing. An unfavorable genetic test result, in general, does not cause adverse psychological effects. Nonetheless, it is important to note that a substantial proportion of individuals, irrespective of their carrier status, exhibit clinically relevant levels of distress which warrant psychological support.

This prospective study explored the contribution of illness representations and coping to cancer-related distress in unaffected individuals undergoing predictive genetic testing for an identified mutation in BRCA1/2 (BReast CAncer) or an HNPCC (Hereditary Nonpolyposis Colorectal Cancer)-related gene, based on the common sense model of self-regulation. Coping with hereditary cancer (UCL), illness representations (IPQ-R) and risk perception were assessed in 235 unaffected applicants for genetic testing before test result disclosure. Hereditary cancer distress (IES) and cancer worry (CWS) were assessed before, 2 weeks after and 6 months after result disclosure. Timeline (r = 0.30), consequences (r = 0.25), illness coherence (r = 0.21) and risk perception (r = 0.20) were significantly correlated to passive coping. Passive coping predicted hereditary cancer distress and cancer worry from pre-test (beta = 0.46 and 0.42, respectively) up to 6 months after result disclosure (beta = 0.32 and 0.19, respectively). Illness coherence predicted hereditary cancer distress up to 6 months after result disclosure (beta = 0.24), too. The self-regulatory model may be useful to predict the cognitive and emotional reactions to genetic cancer susceptibility testing. Identifying unhelpful representations and cognitive restructuring may be appropriate interventions to help distressed individuals undergoing genetic susceptibility testing for a BRCA1/2 or a HNPCC-related mutation.

Objective: To study differences between individuals opting for genetic cancer susceptibility testing of a known familial BRCA1/2 and HNPCC related germline mutation., Methods: Coping, illness perceptions, experiences with cancer in relatives and family system characteristics were assessed in 271 applicants for genetic testing before test result disclosure. Hereditary cancer distress, worry and cancer risk perception were assessed before, 1 week after, and 6 months after disclosure., Results: Individuals from BRCA1/2 and HNPCC mutation families did not differ with regard to the number of experiences with cancer in relatives, grief symptoms, the course of cancer distress, worry and risk perception through time and most illness perceptions, coping responses and family characteristics. Individuals from BRCA1/2 families perceived hereditary cancer as more serious. They reported more frequently a passive coping style, cancer worry and a less open communication with their partner and children., Conclusion: Besides subtle differences, psychological mechanisms may be mainly identical in individuals opting for BRCA1/2 and HNPCC susceptibility testing., Practice Implications: Based on our findings, using a similar counseling approach for individuals opting for BRCA1/2 or HNPCC genetic susceptibility testing is justified. In this approach, attention should be directed more to individual aspects than to the type of disorder.

Purpose: Recently, we found a certain haplotype in the human leukocyte antigen Class III subregion to be associated with breast cancer. Epidemiologic studies have shown that breast cancer and colorectal cancer have several risk factors in common. In view of these studies and because polymorphisms located in the human leukocyte antigen III region have been found to be associated with colorectal cancer, we wondered whether the same region also is involved in colorectal cancer susceptibility., Methods: The human leukocyte antigen region was genotyped with 14 microsatellite markers in germline DNA from 643 colorectal cancer patients and 841 family-based controls. Association analyses and the Haplotype Sharing Statistic were used to search for differences between patients and controls. Subgroup analyses were performed for gender, age at diagnosis, and localization of the tumor., Results: The Haplotype Sharing Statistic analysis revealed neither a difference in mean haplotype sharing between all patients and controls, nor in any of the subgroups. The single allele, genotype, and two-locus association analyses for all patients and for the different subgroups did not show an association with colorectal cancer for the 14 microsatellite markers. Also, no association was observed between the tumor necrosis factor-beta polymorphism and colorectal cancer., Conclusions: No association was observed between commonly occurring haplotypes and alleles in the human leukocyte antigen region and colorectal cancer risk.