N. Hoogerbrugge
Radboudumc Nijmegen - The Netherlands, Human Genetics, Faculty Member
Introduction/Background Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is recommended for BRCA1/2 germline mutation carriers. As recent data indicate the Fallopian tube as origin of high grade serous ovarian carcinoma... more
Introduction/Background Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is recommended for BRCA1/2 germline mutation carriers. As recent data indicate the Fallopian tube as origin of high grade serous ovarian carcinoma (HGSC), risk-reducing salpingectomy (RRS) with delayed oophorectomy (RRO) is studied as an innovative strategy to delay premature menopause. The TUBA-study (NCT02321228) compares menopause-related quality of life (QOL) between standard RRSO and the innovative RRS with delayed RRO. Methodology A multicentre preference trial in 13 Dutch centres started in January 2015. BRCA1/2 mutation carriers choose between the standard strategy (RRSO at age 35–40 (BRCA1) or 40–45 (BRCA2)) and the innovative strategy (RRS with delayed RRO until the age of 40–45 (BRCA1) or 45–50 years (BRCA2)). Results August first 2019, 493 participants were included with a mean age of 37 years: 51% carried a BRCA1 and 49% carried a BRCA2 mutation. In total, 72% of women chose RRS with delayed RRO. At three months and one year after surgery, data showed a better menopause-related QOL in women after RRS when compared to women after RRSO (P<0.001), also after adjustment for age, hospital and baseline score. Additionally, a decline in cancer worry was found at three months and one year after surgery in both groups. Conclusion The menopause-related QOL is significantly better in BRCA mutation carriers after RRS (with delayed RRO) when compared to RRSO. Furthermore, a favourable effect on cancer worry is found among participating women in both arms. At the time of the conference we will have finished recruitment and have one year of follow up in more than 300 women. Based on our results, the Dutch TUBA and American WISP study (NCT02760849) are initializing a combined international TUBA-WISP-II study to assess the safety of RRS with delayed RRO in BRCA germline mutation carriers. Disclosure Nothing to disclose.
Research Interests:
Research Interests:
Research Interests:
Ataxia‐telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia‐telangiectasia mutated (ATM) gene. Logically, blood... more
Ataxia‐telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia‐telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence‐based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2–2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9–2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1–4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacki...
Research Interests:
Research Interests:
Research Interests: Genetics, Algorithms, Family, Biology, Immunohistochemistry, and 15 moreMedicine, Humans, genetic Counselling, DNA methylation, Microsatellite, Aged, Lynch syndrome, Carcinoma, Adult, Indexation, Low Risk, DNA binding proteins, Cancer Risk, Colorectal Neoplasms, and Genetic predisposition to disease
Endometrial cancer diagnosed at a relatively young age or in a patient with a medical history of colorectal cancer may be indicative of Lynch syndrome. Four women, aged 43, 60, 41 and 54 respectively, with a family history of endometrial... more
Endometrial cancer diagnosed at a relatively young age or in a patient with a medical history of colorectal cancer may be indicative of Lynch syndrome. Four women, aged 43, 60, 41 and 54 respectively, with a family history of endometrial or colorectal neoplasm were examined for microsatellite instability (MSI) in tumour tissue with positive results. Subsequently, a mutation was found in one of the DNA mismatch repair genes. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is caused by a germline mutation in a mismatch repair gene and is an autosomal dominant disorder that is characterized by the development of carcinoma of the endometrium and colorectum at a relatively young age. Until recently, recognition of Lynch syndrome was mainly based on an, often incomplete, family history, but today the presence of MSI in tumour tissue can be used to identify patients at risk for Lynch syndrome. A pathologist can contribute to identifying a patient at risk f...
Research Interests: Cancer, Medicine, Family history, Colorectal cancer, Endometrial Cancer, and 15 moreMedical History, Humans, Female, Pubmed, Pedigree, Middle Aged, Lynch syndrome, Carcinoma, Adult, Endometrial carcinoma, Age Factors, Autosomal Dominant, Microsatellite instability, Endometrial neoplasms, and Germ-line mutation
Due to high cancer risks, women carrying a BRCA 1/2 mutation face a complex choice between breast and ovarian cancer surveillance and prophylactic surgery. The aim of this study is to evaluate educational-support groups, which are offered... more
Due to high cancer risks, women carrying a BRCA 1/2 mutation face a complex choice between breast and ovarian cancer surveillance and prophylactic surgery. The aim of this study is to evaluate educational-support groups, which are offered to facilitate mutual support between BRCA mutation carriers and to provide adequate information. Female BRCA mutation carriers were approached by a social worker after genetic test disclosure and offered participation in educational-support groups. Data regarding emotional well-being, breast cancer risk knowledge and perception, cancer risk management behaviour and family communication were collected both before (T1) and after group participation (T2). Of the 34 participants, mean levels of negative mood states at T1 were significantly higher compared to those of a norm group (depression p < 0.001, anger p < 0.001, fatigue p = 0.04, tension p = 0.03) and remained high at T2. Self-perceived breast cancer risk and frequency of cancer thoughts w...
Research Interests:
A deficient mismatch repair system (dMMR) is present in 10-20% of patients with sporadic colorectal cancer (CRC) and is associated with a favourable prognosis in early stage disease. Data on patients with advanced disease are scarce. Our... more
A deficient mismatch repair system (dMMR) is present in 10-20% of patients with sporadic colorectal cancer (CRC) and is associated with a favourable prognosis in early stage disease. Data on patients with advanced disease are scarce. Our aim was to investigate the incidence and outcome of sporadic dMMR in advanced CRC. Data were collected from a phase III study in 820 advanced CRC patients. Expression of mismatch repair proteins was examined by immunohistochemistry. In addition microsatellite instability analysis was performed and the methylation status of the MLH1 promoter was assessed. We then correlated MMR status to clinical outcome. Deficient mismatch repair was found in only 18 (3.5%) out of 515 evaluable patients, of which 13 were caused by hypermethylation of the MLH1 promoter. The median overall survival in proficient MMR (pMMR), dMMR caused by hypermethylation of the MLH1 promoter and total dMMR was 17.9 months (95% confidence interval 16.2-18.8), 7.4 months (95% CI 3.7-16...
Research Interests: British, Immunohistochemistry, Medicine, Colorectal cancer, Humans, and 15 moreInternal Medicine, Female, Male, DNA methylation, Disease Control, Incidence, Aged, Middle Aged, Adult, Camptothecin, Confidence Interval, Adenocarcinoma, Colorectal Neoplasms, Microsatellite instability, and fluorouracil
To determine whether an investigation of microsatellite instability (MSI) in patients with colorectal carcinoma that have been selected by the pathologist could increase the number of detected families with hereditary non-polyposis... more
To determine whether an investigation of microsatellite instability (MSI) in patients with colorectal carcinoma that have been selected by the pathologist could increase the number of detected families with hereditary non-polyposis colorectal carcinoma (HNPCC). Prospective inventory. Pathologists selected patients with a newly diagnosed colorectal carcinoma for MSI analysis of their tumour tissue if they met one of the following four criteria: (a) colorectal carcinoma diagnosed below 50 years of age; (b) a second colorectal carcinoma; (c) a combination of colorectal carcinoma and another HNPCC-related cancer; (d) colorectal adenoma with high-grade dysplasia diagnosed below 40 years of age. Patients with a positive MSI-test were referred to a clinical geneticist. The new strategy was introduced and explored in 5 hospitals for a period of to months. The new strategy was adopted and implemented successfully by pathologists and surgeons and accepted with satisfaction by the patients. Of...
Research Interests: Medicine, Family history, Colorectal cancer, Prospective studies, Humans, and 15 moreInternal Medicine, Genetic Testing, Female, Male, Netherlands, Differential Diagnosis, Pedigree, Middle Aged, Carcinoma, Adult, Genomic instability, Predictive value of tests, Msh, Colorectal Neoplasms, and Microsatellite instability
Observational studies suggest a synergistic effect of hypertension and hyperlipidaemia on the progression of atherosclerosis. The alpha-blocker doxazosin has favourable effects on plasma lipids, insulin resistance and blood pressure,... more
Observational studies suggest a synergistic effect of hypertension and hyperlipidaemia on the progression of atherosclerosis. The alpha-blocker doxazosin has favourable effects on plasma lipids, insulin resistance and blood pressure, while the diuretic hydrochlorothiazide (HCTZ) principally affects blood pressure and increases insulin resistance. A randomised double-blind study over 36 months was performed to compare the effects of doxazosin and HCTZ on fasting lipids and on progression of peripheral atherosclerosis. Eighty males (45 to 70 years) with peripheral atherosclerotic disease and increased cholesterol levels (5.2-8.0 mmol/l) were treated for essential hypertension with either doxazosin (n = 41) or HCTZ (n = 39). Main outcome measures were arterial intima-media thickness (IMT) of the carotid and femoral arteries and fasting lipid parameters. In the doxazosin-treated group, significant changes were observed in the concentration of triglycerides (-13.7%, p < 0.01), HDLc (+...
Research Interests: Endocrinology, Medicine, Humans, Internal Medicine, Hypertension, and 15 moreBlood Pressure, Diuretics, Male, Hypercholesterolemia, Hydrochlorothiazide, Aged, Blood Pressure Control, Disease Progression, Drug Effects, Carotid Artery, Femoral Artery, Essential Hypertension, Carotid Arteries, Antihypertensive agents, and Doxazosin
Research Interests:
The effects of growth hormone (GH) administration on hepatic lipase (HL) activity and mRNA levels were studied in pair-fed hypothyroid rats. In the hypothyroid state, liver HL mRNA levels and liver and postheparin plasma HL activities... more
The effects of growth hormone (GH) administration on hepatic lipase (HL) activity and mRNA levels were studied in pair-fed hypothyroid rats. In the hypothyroid state, liver HL mRNA levels and liver and postheparin plasma HL activities were decreased. In hypothyroid rats, GH normalized HL mRNA levels and HL activity in postheparin plasma; GH also increased the activity of HL in the liver, which remained lower than that in controls. These data indicate that at least part of the decrease of HL activity during hypothyroidism is due to the concomitant GH deficiency, and that GH rather than thyroid hormone may regulate HL mRNA levels.
Research Interests:
One of the primary risk factors for atherosclerosis is hypercholesterolemia. Patients with isolated hypercholesterolemia or combined hypercholesterolemia-hypertriglyceridemia are at risk to develop premature atherosclerosis. Diet-induced... more
One of the primary risk factors for atherosclerosis is hypercholesterolemia. Patients with isolated hypercholesterolemia or combined hypercholesterolemia-hypertriglyceridemia are at risk to develop premature atherosclerosis. Diet-induced hypercholesterolemia in animals leads to an increased adhesion of monocytes to and transmigration through the intact endothelium of the vessel wall. In the present study, we investigated in vitro binding of freshly isolated monocytes from patients and healthy controls to a monolayer of endothelial cells obtained from human umbilical vein. All four diagnosed patient groups with isolated or combined hypercholesterolemia showed a significant increase in monocyte binding as compared with the control group (familial hypercholesterolemia [FH], +41%; polygenic hypercholesterolemia [PH] +35%; familial combined hypercholesterolemia [FCH], +47%; nonfamilial combined hypercholesterolemia-hypertriglyceridemia [CHH], +67%). In a longitudinal study it was observed that diet or medication induced a decrease in cholesterol and triglycerides; however, these therapeutic conditions did not diminish in vitro monocyte binding in the patient groups. There was no correlation between monocyte binding and plasma cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, or lipoprotein(a) within hyperlipidemic patient groups. The presence of heart and vessel disease in hyperlipidemic patients was not associated with a change in monocyte binding. The adhesion to endothelial cells of monocytes from smoking patients with combined hypercholesterolemia (27%) was significantly higher (+23%) than that of monocytes from nonsmoking patients. Cytofluorimetric analysis of monocytes from FCH and CHH patients for specific monocyte differentiation markers and integrins did not show differences as compared with monocytes from healthy controls.
Research Interests:
Research Interests: Endocrinology, Biology, Growth Hormone, Humans, Child, and 15 moreInternal Medicine, Female, Lipid metabolism, Dose, Clinical Sciences, Carbohydrate metabolism, High Density Lipoprotein, Indexation, Lipid Profile, Glucose Tolerance Test, Area Under the Curve, Healthy Subjects, Frequency Response, Child preschool, and Impaired Glucose Tolerance
Research Interests: Psychology, Medicine, Stroke, Humans, Internal Medicine, and 15 moreHyperglycemia, Blood Glucose, Epinephrine, Diabetes mellitus, Female, Male, Two Stroke Engine, Norepinephrine, Clinical Sciences, Aged, Middle Aged, Cerebrovascular Disorders, Neurosciences, Stress Physiological, and Cardiovascular medicine and haematology
Hoogerbrugge N, Kerkhofs LGN, Jansen H (University Hospital Dijkzigt, Rotterdam, The Netherlands). Gemfibrozil decreases autoantibodies against oxidized low‐density lipoprotein in men with combined hyperlipidaemia. J Intern Med 1998; 243:... more
Hoogerbrugge N, Kerkhofs LGN, Jansen H (University Hospital Dijkzigt, Rotterdam, The Netherlands). Gemfibrozil decreases autoantibodies against oxidized low‐density lipoprotein in men with combined hyperlipidaemia. J Intern Med 1998; 243: 355–59.ObjectivesGemfibrozil is the most widely used fibric acid for the management of combined hyperlipidaemia. It has beneficial effects in the prevention of coronary heart disease (CHD). The mechanisms by which it exerts this effect are not completely resolved. We studied whether gemfibrozil affects low‐density lipoprotein (LDL) size and LDL oxidation parameters in males with a moderate combined hyperlipidaemia at high risk for progressive atherosclerosis.DesignOpen treatment with 2 × 600 mg gemfibrozil daily for 12 weeks.SettingOutpatient lipid clinic of a tertiary referral centre.SubjectsTwenty‐three patients with combined hyperlipidaemia and CHD or a positive family history for both CHD and hyperlipidaemia.Main outcome measuresEffects on trig...
Research Interests: Endocrinology, Risk, Treatment Outcome, Medicine, Lipids, and 15 moreHumans, Internal Medicine, Hyperlipidemia, Male, Lipid peroxidation, Clinical Sciences, Aged, Middle Aged, Adult, Disease Progression, Low Density Lipoprotein (LDL), Autoantibodies, Triglyceride, Severity of Illness Index, and Hyperlipidemias
Research Interests: Cancer, Flow Cytometry, Biology, DNA repair, Family history, and 15 moreColorectal cancer, Humans, Female, Aged, DNA content, Lynch syndrome, Adult, Genetic Instability, Chromosomal Instability, Genetic Susceptibility, DNA binding proteins, Age of Onset, Colorectal Neoplasms, chromosome instability, and Genetic predisposition to disease
Research Interests: Family history, Colorectal cancer, General Surgery, Genetic Testing, Female, and 15 moreFeasibility Studies, Cost effectiveness, Clinical Sciences, Adult, Analytical Model, Cost Benefit Analysis, Genomic instability, Gut, Abdominal Surgery, Cholecystectomy, Health Care Costs, Abdominal Pain, Gallstones, Colorectal Neoplasms, and Decision Support Techniques
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests: Decision Making, Cancer, Breast Cancer, Biology, Gene expression, and 15 moreHumans, Breast Cancer Early Detecion and Treatment, Genetic Testing, genetic Counselling, Female, Classification, DNA methylation, Aged, Adult, Breast carcinoma, Array, Comparative Genomic Hybridization, Breast Neoplasms, Chromosome aberrations, and Genetic predisposition to disease
Research Interests:
Research Interests:
Research Interests:
Research Interests:
In 3 patients, 2 men aged 46 and 51 years and a woman aged 54 years, with colorectal cancer there was insufficient information on the basis of the family history to diagnose &#39;hereditary non-polyposis colorectal cancer&#39;... more
In 3 patients, 2 men aged 46 and 51 years and a woman aged 54 years, with colorectal cancer there was insufficient information on the basis of the family history to diagnose &#39;hereditary non-polyposis colorectal cancer&#39; (HNPCC). Further investigation showed microsatellite instability in the tumour material, an indicator for a mutation in DNA-&#39;mismatch repair&#39; (MMR-) genes. Immunohistochemical study of lymphocytes showed an absence of the gene products MSH2 and MSH6. Study of the MMR genes revealed a pathogenic germ-line mutation in MSH2. All three patients were satisfied with genetic testing of the MMR-genes as this gave their children and their family members the opportunity to clarify genetic status. HNPCC is a clinical diagnosis, based on family history. As family history taking is often incomplete, the diagnosis is regularly not considered. The following individual criteria can help to recognize a patient at risk for HNPCC: (a) colorectal cancer diagnosed below 50 years of age, (b) second colorectal cancer, (c) a combination of colorectal and endometrial cancer.
Research Interests:
For the Mutation Pathogenicity Special Issue It is important to identify a germline mutation in a patient with an inherited cancer syndrome to allow mutation carriers to be included in cancer surveillance programs, which have been proven... more
For the Mutation Pathogenicity Special Issue It is important to identify a germline mutation in a patient with an inherited cancer syndrome to allow mutation carriers to be included in cancer surveillance programs, which have been proven to save lives. Many of the mutations identified result in premature termination of translation, and thus in loss-of-function of the encoded mutated protein. However, the significance of a large proportion of the sequence changes reported is unknown. Some of these variants will be associated with a high risk of cancer and have direct clinical consequence. Many criteria can be used to classify variants with unknown significance; most criteria are based on the characteristics of the amino acid change, on segregation data and appearance of the variant, on the presence of the variant in controls, or on functional assays. In inherited cancers, tumor characteristics can also be used to classify variants. It is worthwhile to examine the clinical, morphological and molecular features of a patient, and his or her family, when assessing whether the role of a variant is likely to be neutral or pathogenic. Here we describe the advantages and disadvantages of using the tumor characteristics of patients carrying germline variants of uncertain significance (VUS) in BRCA1, BRCA2, or in one of the mismatch repair (MMR) genes, MLH1, MSH2, or MSH6, to infer pathogenicity.
Research Interests: Decision Making, Breast Cancer, Ovarian Cancer, Humans, Breast Cancer Early Detecion and Treatment, and 12 moreGenetic Testing, genetic Counselling, Female, Classification, DNA methylation, Aged, Middle Aged, Adult, Breast carcinoma, Method Validation, Predictive value of tests, and Comparative Genomic Hybridization
Only about 25% of familial breast cancer is explained by mutations in brca1 and brca2 , fewer by moderate penetrance genes like p53, pten, chek2, atm and palb2
Research Interests:
Research Interests:
... Bilateral prophylactic mas-tectomy in healthy women with a BRCA mutation is associated with a 90% reduc-tion in breast cancer incidence (Meijers-Heijboer et al., 2001; Rebbeck et al., 2004). ... of Prevalent High-Risk Epithelial... more
... Bilateral prophylactic mas-tectomy in healthy women with a BRCA mutation is associated with a 90% reduc-tion in breast cancer incidence (Meijers-Heijboer et al., 2001; Rebbeck et al., 2004). ... of Prevalent High-Risk Epithelial Lesions Peter Bult and Nicoline Hoogerbrugge ...
Research Interests:
Research Interests:
Genetic testing offered directly after the diagnosis of colorectal cancer: a pilot study on the reactions of patients: When colorectal cancer is diagnosed before the age of 50 years, then consideration should be given to a hereditary... more
Genetic testing offered directly after the diagnosis of colorectal cancer: a pilot study on the reactions of patients: When colorectal cancer is diagnosed before the age of 50 years, then consideration should be given to a hereditary cause. Indications of heredity can be found in tumour tissue with the aid of microsatellite instability (MSI) testing. A positive MSI test means an increased risk of hereditary colorectal cancer, the so-called Lynch syndrome. Until recently, the usual approach was to postpone genetic testing for colorectal cancer until the family history had been studied extensively and information had been made available by a clinical geneticist about the possible consequences. However, it is now possible for MSI testing to be performed on the initiative of the pathologist when the newly diagnosed patient with colorectal cancer is younger than 50 years. This speeds up the procedure considerably. The psychological effects of discussing genetic testing and referring pati...
Research Interests:
Renal cell carcinomas (RCC) occur in both sporadic and familial forms. The best known example of a familial RCC syndrome is the Von Hippel Lindau cancer syndrome. In addition, RCC families segregating constitutional chromosome 3... more
Renal cell carcinomas (RCC) occur in both sporadic and familial forms. The best known example of a familial RCC syndrome is the Von Hippel Lindau cancer syndrome. In addition, RCC families segregating constitutional chromosome 3 translocations have been reported. The list of these latter families is rapidly expanding. We have initiated a survey of all Dutch families known to segregate chromosome 3 translocations for (i) the ocurrence of RCCs and (ii) the establishment of refined risk estimates. This information will be critical for genetic counseling and clinical patient management. Within the families 'at risk' that we have identified so far, this approach has already led to early RCC detection and surgical intervention.
Research Interests: Philosophy, Humans, Female, Renal cell Carcinoma, Male, and 3 moreRisk factors, Middle Aged, and Risk Factors
Twenty hyperlipidaemic patients on a cholesterol-poor diet were selected on the basis of a raised lipoprotein (a) (Lp(a); apo (a) > 300 U/litre) and treated with 1000 mg MgO per day during 6 weeks. Serum magnesium slightly increased... more
Twenty hyperlipidaemic patients on a cholesterol-poor diet were selected on the basis of a raised lipoprotein (a) (Lp(a); apo (a) > 300 U/litre) and treated with 1000 mg MgO per day during 6 weeks. Serum magnesium slightly increased compared to pretreatment levels (P < 0.001). Serum apo(a) concentrations (mean +/- S.D.) were not affected: pretreatment level 963 +/- 552 U/litre; during treatment 999 +/- 536 U/litre; and after washout 995 +/- 524 U/litre. Serum cholesterol increased slightly during MgO treatment because of an increase in LDL-cholesterol (10 per cent) and returned to pretreatment levels after a washout period.