Von Hippel-Lindau Disease

A germline mutation in the Von-Hippel Lindau (VHL) gene predisposes carriers to development of abundantly vascularised tumours in the retina, cerebellum, spine, kidney, adrenal gland and pancreas. Most VHL patients die from the consequences of cerebellar haemangioblastoma or renal cell carcinoma. The VHL gene is a tumour suppressor gene and is involved in angiogenesis by regulation of the activity of hypoxia-inducible factor 1-α (HIF1-α). Clinical diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene, which is informative in virtually all VHL families. A patient with (suspicion for) VHL is an indication for genetic counselling and periodical examination

Uptake of prenatal diagnostic testing for retinoblastoma compared to other hereditary cancer syndromes in the Netherlands

Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands. Uptake for retinoblastoma (Rb) was compared with uptake for Von Hippel–Lindau disease (VHL), Li–Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and hereditary breast ovarian cancer (HBOC). A questionnaire was completed by all nine DNA-diagnostic laboratories assessing the number of independent mutation-positive families identified from the start of diagnostic testing until May 2013, and the number of PNDs performed for these syndromes within these families. Of 187 families with a known Rb-gene mutation, 22 had performed PND (11.8%), this was significantly higher than uptake for FAP (1.6%) and HBOC (<0.2%). For VHL (6.5%) and LFS (4.9%) the difference was not statistically significant. PND for Rb started 3 years after introduction of diagnostic DNA testing and remained stable over the years. For the other cancer syndromes PND started 10–15 years after the introduction and uptake for PND showed an increase after 2009. We conclude that uptake of PND for Rb was significantly higher than for FAP and HBOC, but not different from VHL and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences

MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients

Contains fulltext : 170909.pdf (publisher's version ) (Open Access)BACKGROUND: Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10-30 % of those patients have no mutation in the MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up. METHODS: This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population. RESULTS: A total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5-76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001). CONCLUSIONS: Mutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors

A simple method for co-segregation analysis to evaluate the pathogenicity of unclassified variants; BRCA1 and BRCA2 as an example

BACKGROUND: Assessment of the clinical significance of unclassified variants (UVs) identified in BRCA1 and BRCA2 is very important for genetic counselling. The analysis of co-segregation of the variant with the disease in families is a powerful tool for the classification of these variants. Statistical methods have been described in literature but these methods are not always easy to apply in a diagnostic setting. METHODS: We have developed an easy to use method which calculates the likelihood ratio (LR) of an UV being deleterious, with penetrance as a function of age of onset, thereby avoiding the use of liability classes. The application of this algorithm is publicly available http://www.msbi.nl/cosegregation. It can easily be used in a diagnostic setting since it requires only information on gender, genotype, present age and/or age of onset for breast and/or ovarian cancer. RESULTS: We have used the algorithm to calculate the likelihood ratio in favour of causality for 3 UVs in BRCA1 (p.M18T, p.S1655F and p.R1699Q) and 5 in BRCA2 (p.E462G p.Y2660D, p.R2784Q, p.R3052W and p.R3052Q). Likelihood ratios varied from 0.097 (BRCA2, p.E462G) to 230.69 (BRCA2, p.Y2660D). Typing distantly related individuals with extreme phenotypes (i.e. very early onset cancer or old healthy individuals) are most informative and give the strongest likelihood ratios for or against causality. CONCLUSION: Although co-segregation analysis on itself is in most cases insufficient to prove pathogenicity of an UV, this method simplifies the use of co-segregation as one of the key features in a multifactorial approach considerably

Attitude towards pre-implantation genetic diagnosis for hereditary cancer

The use of pre-implantation genetic diagnosis (PGD) for hereditary cancer is subject to on-going debate, particularly among professionals. This study evaluates the attitude towards PGD and attitude-associated characteristics of those concerned: family members with a hereditary cancer predisposition. Forty-eight Von Hippel-Lindau and 18 Li–Fraumeni Syndrome families were identified via the 9 family cancer clinics in the Netherlands. In total, 216 high risk family members and partners were approached, of whom 179 (83%) completed a self-report questionnaire. Of the high risk family members, 35% expressed a positive attitude towards PGD. Those with a current desire to have children were significantly more likely to have a positive attitude: 48% would consider the use of PGD. No other sociodemographic, medical or psychosocial variables were associated significantly with a positive attitude. The most frequently reported advantage of PGD is the avoidance of a possible pregnancy termination. Uncertainty about late effects was the most frequently reported disadvantage. These results indicate that approximately half of those contemplating a future pregnancy would consider the use of PGD. The actual uptake, however, is expected to be lower. There is no indication that psychosocial factors affect interest in PGD

A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history

Introduction Unclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs. Methods We developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families). Results The models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/ or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p. S1655F, p. R1699W, and p. R1699Q variants in BRCA1 and the p. Y2660D, p. R2784Q, and p. R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p. L246V variant in BRCA1 and of the p. Y42C, p. E462G, p. R2888C, and p. R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p. R2784W variant in BRCA2 remains uncertain. Conclusions The present study shows that these developed models are useful to classify UVs in clinical genetic practic

Behavioral and psychosocial effects of rapid genetic counseling and testing in newly diagnosed breast cancer patients: Design of a multicenter randomized clinical trial

<p>Abstract</p> <p>Background</p> <p>It has been estimated that between 5% and 10% of women diagnosed with breast cancer have a hereditary form of the disease, primarily caused by a <it>BRCA1 </it>or <it>BRCA2 </it>gene mutation. Such women have an increased risk of developing a new primary breast and/or ovarian tumor, and may therefore opt for preventive surgery (e.g., bilateral mastectomy, oophorectomy). It is common practice to offer high-risk patients genetic counseling and DNA testing after their primary treatment, with genetic test results being available within 4-6 months. However, some non-commercial laboratories can currently generate test results within 3 to 6 weeks, and thus make it possible to provide <it>rapid </it>genetic counseling and testing (RGCT) prior to primary treatment. The aim of this study is to determine the effect of RGCT on treatment decisions and on psychosocial health.</p> <p>Methods/Design</p> <p>In this randomized controlled trial, 255 newly diagnosed breast cancer patients with at least a 10% risk of carrying a <it>BRCA </it>gene mutation are being recruited from 12 hospitals in the Netherlands. Participants are randomized in a 2:1 ratio to either a RGCT intervention group (the offer of RGCT directly following diagnosis with tests results available before surgical treatment) or to a usual care control group. The primary behavioral outcome is the uptake of direct bilateral mastectomy or delayed prophylactic contralateral mastectomy. Psychosocial outcomes include cancer risk perception, cancer-related worry and distress, health-related quality of life, decisional satisfaction and the perceived need for and use of additional decisional counseling and psychosocial support. Data are collected via medical chart audits and self-report questionnaires administered prior to randomization, and at 6 month and at 12 month follow-up.</p> <p>Discussion</p> <p>This trial will provide essential information on the impact of RGCT on the choice of primary surgical treatment among women with breast cancer with an increased risk of hereditary cancer. This study will also provide data on the psychosocial consequences of RGCT and of risk-reducing behavior.</p> <p>Trial registration</p> <p>The study is registered at the Netherlands Trial Register (NTR1493) and ClinicalTrials.gov (NCT00783822).</p

Ассоциативно-семантическая группа как языковая основа концепта

Статья посвящена описанию особой лексико-семантической парадигмы ассоциативно-семантической группы, которая является частью ассоциативно- семантического комплекса и рассматривается как языковая основа концепта. Исследование проведено с применением описательного, структурного и функционального методов.Статтю присвячено опису особливої лексико-семантичної парадигми асоціативно-семантичної групи, яка є частиною асоціативно-семантичного комплексу і являє собою мовну основу концепту. Дослідження проведено із застосуванням описового, структурного та функціонального методів.The particular lexico-semantic paradigm – associative-semantic group (ASG) which is the part of associative-semantic complex (ASC) – is investigated in the article as a linguistic base of concept. Descriptive, structural, and functional methods were used

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive as