A H Bröcker-Vriends

Erasmus MC, Rotterdam, South Holland, Netherlands

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Publications (45)367.7 Total impact

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    ABSTRACT: 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.
    Psycho-Oncology 01/2008; 16(12):1121-9. · 3.51 Impact Factor
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    ABSTRACT: This study assessed the impact of genetic testing for cancer susceptibility on family relationships and determinants of adverse consequences for family relationships. Applicants for genetic testing of a known familial pathogenic mutation in BRCA1/2 or a HNPCC related gene (N=271) rated the prevalence and nature of changes in family relationships, familial difficulties and conflicts due to genetic testing 6 months after receiving the test result. The level of family functioning, differentiation from parents, support and familial communication style regarding hereditary cancer were assessed before receiving the test result. Genetic testing affected some family relationships in a positive way (37%), i.e. by feeling closer, improved communication and support, more appreciation of the relative and relief of negative test result. A minority reported unwanted changes in relationships (19%), problematic situations (13%) or conflicts (4%). Adverse effects comprised feelings of guilt towards children and carrier siblings, imposed secrecy and communication problems. Predictors of adverse consequences on family relationships were reluctance to communicate about hereditary cancer with relatives and disengaged-rigid or enmeshed-chaotic family functioning. Open communication between relatives should be stimulated because a lack of open communication may be an important determinant of familial adverse effects.
    Psycho-Oncology 05/2007; 16(4):320-8. · 3.51 Impact Factor
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    ABSTRACT: This study explored predictors for hereditary cancer distress six months after genetic susceptibility testing for a known familial BRCA1/2 or HNPCC related mutation, in order to gain insight into aspects relevant for the identification of individuals needing additional psychosocial support. Coping, illness representations, experiences with cancer in relatives and family system characteristics were assessed in 271 applicants for genetic testing before result disclosure. Hereditary cancer distress was assessed prospectively up to six months after disclosure. Regression analysis revealed that the pretest level of distress, complicated grief, the number of affected first-degree relatives and strong emotional illness representations were factors that best explained hereditary cancer distress. Other significant predictors were illness coherence, passive coping, distraction seeking, being aged <13 years when a parent was affected by cancer and family communication. Individuals who may benefit from additional support may be identified before result disclosure using a short instrument assessing the relevant aspects.
    European Journal of Cancer 02/2007; 43(1):71-7. · 5.06 Impact Factor
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    ABSTRACT: To study differences between individuals opting for genetic cancer susceptibility testing of a known familial BRCA1/2 and HNPCC related germline mutation. 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. 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. Besides subtle differences, psychological mechanisms may be mainly identical in individuals opting for BRCA1/2 and HNPCC susceptibility testing. 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.
    Patient Education and Counseling 02/2007; 65(1):58-68. · 2.60 Impact Factor
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    ABSTRACT: This study explores the effect of age at the time of parental cancer diagnosis or death on psychological distress and cancer risk perception in individuals undergoing genetic testing for a specific cancer susceptibility. Cancer-related distress, worry and risk perception were assessed in 271 applicants for genetic testing of an identified mutation in BRCA1/2 (BReast CAncer) or a HNPCC (Hereditary Nonpolyposis Colorectal Cancer) related gene before, one week after, and six months after genetic test disclosure. The course of distress and risk perception were compared between individuals having witnessed parental cancer or loss due to cancer in childhood, adolescence, adulthood and having unaffected parents. Individuals with parental cancer in childhood (under age 13) reported the highest level of cancer related distress, worry and risk perception. Women having their mother affected by breast cancer in puberty (aged 10-13 years) perceived higher breast cancer risks than women with an affected mother in adulthood or without an affected mother. Individuals with an affected parent perceived cancer risks as higher than individuals without an affected parent, but were not more distressed. Experience of parental cancer in childhood is a risk factor for psychological distress during the genetic testing process.
    Annals of Oncology 08/2006; 17(7):1090-5. · 7.38 Impact Factor
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    ABSTRACT: A wide range of factor VIII and IX levels is observed in heterozygous carriers of hemophilia as well as in noncarriers. In female carriers, extreme lyonization may lead to low clotting factor levels. We studied the effect of heterozygous hemophilia carriership on the occurrence of bleeding symptoms. A postal survey was performed among most of the women who were tested for carriership of hemophilia in the Netherlands before 2001. The questionnaire included items on personal characteristics, characteristics of hemophilia in the affected family members, and carrier testing and history of bleeding problems such as bleeding after tooth extraction, bleeding after tonsillectomy, and other operations. Information on clotting factor levels was obtained from the hospital charts. Logistic regression was used to assess the relation of carrier status and clotting factor levels with the occurrence of hemorrhagic events. In 2004, 766 questionnaires were sent, and 546 women responded (80%). Of these, 274 were carriers of hemophilia A or B. The median clotting factor level of carriers was 0.60 IU/mL (range, 0.05-2.19 IU/mL) compared with 1.02 IU/mL (range, 0.45-3.28 IU/mL) in noncarriers. Clotting factor levels from 0.60 to 0.05 IU/mL were increasingly associated with prolonged bleeding from small wounds and prolonged bleeding after tooth extraction, tonsillectomy, and operations. Carriers of hemophilia bleed more than other women, especially after medical interventions. Our findings suggest that not only clotting factor levels at the extreme of the distribution, resembling mild hemophilia, but also mildly reduced clotting factor levels between 0.41 and 0.60 IU/mL are associated with bleeding.
    Blood 08/2006; 108(1):52-6. · 9.78 Impact Factor
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    ABSTRACT: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. We performed Southern blot analysis in 112 patients from MLH1-, MSH2-, and MSH6-negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer, we performed immunohistochemistry using antibodies against MLH1, MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. We show that heterozygous truncating mutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with absent staining for the PMS2 protein.
    Gastroenterology 02/2006; 130(2):312-22. · 12.82 Impact Factor
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    ABSTRACT: ABSTRACT diagnostic workup of familial colorectal cancer is an elaborate and time consuming process in which the family and several medical specialists closely collaborate. However, establishing a diagnosis can be very rewarding. If a mutation is detected in the family, a satisfactory explanation can be provided for an accumulation of tumors at young age, and often of untimely death. Appropriate presymptomatic testing can be offered to reduce mortality among at-risk family members, and relatives not at risk can avoid uncertainty and needlessly intensive surveillance. We show the differential diagnostic considerations when an individual with a family history of colorectal carcinoma is encountered, with emphasis on Lynch syndrome (Hereditary Nonpolyposis Colorectal Carcinoma [HNPCC]). Practical recommendations for laboratory workup of suspected Lynch syndrome, including analysis of tumor tissue by microsatellite instability analysis and immunohistochemistry, and germline DNA analysis are given. Furthermore, the clinical management after a molecular diagnosis has been made is described. The diagnostic scheme presented here allows efficient and effective analysis of colorectal carcinoma cases with (suspected) Lynch syndrome, making optimal use of currently available technology.
    CA A Cancer Journal for Clinicians 01/2006; 56(4):213-25. · 153.46 Impact Factor
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    ABSTRACT: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10-99 polyps or 100-1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25-30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated.
    Journal of Medical Genetics 10/2005; 42(9):e54. · 5.70 Impact Factor
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    ABSTRACT: The aim of this study was to identify the prevalence of catecholamine excess and phaeochromocytomas in a well-defined population of people with hereditary head and neck paragangliomas. We studied in a prospective follow-up protocol all consecutive patients referred to the Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands with documented head and neck paragangliomas and either a positive family history for paragangliomas or a proven SDHD gene mutation. Initial analysis included medical history, physical examination and the measurement of excretion of catecholamines in two 24-h urine collections. In the case of documented catecholamine excess iodinated meta-iodobenzylguanidine (123I-MIBG) scintigraphy and magnetic resonance imaging were done. Between 1988 and 2003, 40 consecutive patients (20 male and 20 female) with documented head and neck paragangliomas were screened. Biochemical screening revealed urinary catecholamine excess in 15 patients (37.5%). In nine of these 15 patients a lesion was found by 123I-MIBG scintigraphy. Exact localization by magnetic resonance imaging revealed phaeochromocytomas in seven of the 15 patients. One of the nine patients had an extra-adrenal paraganglioma. Histopathological examination in a subset of tumors displayed loss of heterozygosity of the wild-type SDHD allele in all cases. The prevalence of catecholamine excess (37.5%) and phaeochromocytomas (20.0%) is high in patients with familial head and neck paragangliomas. Therefore, patients with hereditary head and neck paragangliomas require lifelong follow up by biochemical testing for catecholamine excess.
    European Journal of Endocrinology 02/2005; 152(1):87-94. · 3.14 Impact Factor
  • Statistics in Medicine - STAT MED. 01/2005; 42(9).
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    ABSTRACT: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is caused by a mutated mismatch repair (MMR) gene. The aim of our study was to determine the cumulative risk of developing cancer in a large series of MSH6 mutation carriers. Mutation analysis was performed in 20 families with a germline mutation in MSH6. We compared the cancer risks between MSH6 and MLH1/MSH2 mutation carriers. Microsatellite instability (MSI) analysis and immunohistochemistry (IHC) were performed in the available tumors. A total of 146 MSH6 mutation carriers were identified. In these carriers, the cumulative risk for colorectal carcinoma was 69% for men, 30% for women, and 71% for endometrial carcinoma at 70 years of age. The risk for all HNPCC-related tumors was significantly lower in MSH6 than in MLH1 or MSH2 mutation carriers (P = 0.002). In female MSH6 mutation carriers, the risk for colorectal cancer was significantly lower (P = 0.0049) and the risk for endometrial cancer significantly higher (P = 0.02) than in MLH1 and MSH2 mutation carriers. In male carriers, the risk for colorectal cancer was lower in MSH6 mutation carriers, but the difference was not significant (P = 0.0854). MSI analysis in colorectal tumors had a sensitivity of 86% in predicting a MMR defect. IHC in all tumors had a sensitivity of 90% in predicting a mutation in MSH6. We recommend starting colonoscopic surveillance in female MSH6 mutation carriers from age 30 years. Prophylactic hysterectomy might be considered in carriers older than 50 years. MSI and IHC analysis are sensitive tools to identify families eligible for MSH6 mutation analysis.
    Gastroenterology 07/2004; 127(1):17-25. · 12.82 Impact Factor
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    ABSTRACT: Immunohistochemistry (IHC) and microsatellite instability (MSI) analysis can be used to identify patients with a possible DNA mismatch repair defect [hereditary nonpolyposis colorectal carcinoma (HNPCC)]. The Bethesda criteria have been proposed to select families for determination of MSI. The aims of this study were to assess the yield of MSI analysis in families suspected for HNPCC, to compare the results of immunohistochemical staining and MSI analysis, and to assess the additional value of PMS2 staining. Clinical data and tumors were collected from 725 individuals from 631 families with suspected HNPCC. MSI analysis was performed using eight markers including the 5 National Cancer Institute markers. Four immunohistochemical staining antibodies were used (MLH1, MSH2, MSH6 and PMS2). A MSI-H (tumors with instability for >30% of the markers) phenotype in colorectal cancers (CRCs) was observed in 21-49% of families that met the various Bethesda criteria. In families with three cases of CRC diagnosed at age > 50 years, families with a solitary case of CRC diagnosed between ages 45 and 50 years, and families with one CRC case and a first-degree relative with a HNPCC-related cancer, one diagnosed between ages 45 and 50 years (all Bethesda-negative families), the yield of MSI-H was 10-26%. Immunohistochemical staining confirmed the MSI results in 93% of the cases. With IHC, adding PMS2 staining led to the identification of an additional 23% of subjects with an hMLH1 germ-line mutation (35 carriers were tested). The Bethesda guidelines for MSI analysis should include families with three or more cases of CRC diagnosed at age > 50 years. The age at diagnosis of CRC in the original guidelines should be raised to 50 years. Routine IHC diagnostics for HNPCC should include PMS2 staining.
    Clinical Cancer Research 03/2004; 10(3):972-80. · 7.84 Impact Factor
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    ABSTRACT: Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) is a dominantly inherited syndrome characterized by the development of colorectal cancer, endometrial cancer and other cancers and the presence of microsatellite instability (MSI) in tumors. The Bethesda guidelines have been proposed for the identification of families suspected of HNPCC that require further molecular analysis. We have evaluated the yield of MSI-analysis in a large series of Dutch families suspected of HNPCC. We also analysed whether the loss of mismatch repair (MMR) protein detected by immunohistochemistry (IHC) of colorectal cancer (CRC) and endometrial cancer correlated with the presence of MSI and/or a MMR gene mutation. The results showed that the Bethesda criteria with a few modifications are appropriate to identify families eligible for genetic testing. In addition, we found that MSI and IHC-analysis of CRC using antibodies against MLH1, MSH2, MSH6 and PMS2 proteins are equally effective for identifying carriers of the known MMR gene defects. However, as long as the role of other putative MMR genes in hereditary CRC has not been elucidated, IHC-analysis cannot completely replace MSI. For this reason, we prefer MSI-analysis as first step in families suspected of HNPCC. On the other hand, in families fulfilling the revised Amsterdam criteria in which the probability of detecting a mutation is relatively high, we would recommend IHC as first diagnostic step because the result might predict the specific underlying MMR gene mutation. MSI or IHC-analysis of endometrial cancer alone was found to be less sensitive compared with these tests performed in colorectal cancer. Therefore, probably the best approach in the analysis of this cancer is to perform both techniques. The identification of HNPCC is important as it makes it possible to target effective preventative measures. Our studies showed that MSI and IHC analysis of colorectal and endometrial cancer, are reliable cost-effective tools that can be used to identify patients with HNPCC.
    Disease markers 02/2004; 20(4-5):207-13. · 2.14 Impact Factor
  • N. J. Leschot, J. M. Cobben, A. H. J. T. Bröcker-Vriends
    Proceedings of The National Academy of Sciences - PNAS. 01/2004;
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    ABSTRACT: Immunohistochemistry (IHC) of mismatch repair (MMR) proteins in colorectal tumors together with microsatellite analysis (MSI) can be helpful in identifying families eligible for mutation analysis. The aims were to determine sensitivity of IHC for MLH1, MSH2, and MSH6 and MSI analysis in tumors from known MMR gene mutation carriers; and to evaluate the use of tissue microarrays for IHC (IHC-TMA) of colon tumors in its ability to identify potential carriers of MMR gene mutations, and compare it with IHC on whole slides. IHC on whole slides was performed in colorectal tumors from 45 carriers of a germline mutation in one of the MMR genes. The TMA cohort consisted of 129 colon tumors from (suspected) hereditary nonpolyposis colorectal cancer (HNPCC) patients. Whole slide IHC analysis had a sensitivity of 89% in detecting MMR deficiency in carriers of a pathogenic MMR mutation. Sensitivity by MSI analysis was 93%. IHC can also be used to predict which gene is expected to harbor the mutation: for MLH1, MSH2, and MSH6, IHC on whole slides would have correctly predicted the mutation in 48%, 92%, and 75% of the cases, respectively. We propose a scheme for the diagnostic approach of families with (suspected) HNPCC. Comparison of the IHC results based on whole slides versus TMA, showed a concordance of 85%, 95%, and 75% for MLH, MSH2, and MSH6, respectively. This study therefore shows that IHC-TMA can be reliably used to simultaneously screen a large number of tumors from (suspected) HNPCC patients, at first in a research setting.
    American Journal Of Pathology 03/2003; 162(2):469-77. · 4.60 Impact Factor
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    ABSTRACT: Bannayan-Riley-Ruvalcaba syndrome (BRRS) is characterised by macrocephaly, intestinal hamartomatous polyps, lipomas, pigmented maculae of the glans penis, developmental delay and mental retardation. The syndrome follows an autosomal dominant pattern of inheritance. In 1997 reports on two BRRS patients with a deletion at 10q23.2-q24.1 were published. In the same year, the first two families with BRRS and a mutation of the PTEN gene were reported. Mutations in the PTEN gene have also been demonstrated in patients with Cowden syndrome (CS), which shows partial clinical overlap with BRRS, and in families with cases both of BRRS and CS. PTEN mutation positive BRRS and CS are likely to be different phenotypic presentations of the same syndrome. If BRRS and CS are one single condition, the question arises whether patients with BRRS should be screened for malignant tumours, since patients with Cowden syndrome have an increased risk of breast, endometrial, thyroid and renal cancer. We present two isolated cases and one family and confirm that BRRS and CS are allelic. Furthermore, we review the PTEN mutation positive BRRS cases, to further delineate the phenotype and to compare the cases with a genomic deletion with the cases with a point mutation. We recommend offering BRRS cases with a mutation in PTEN the same surveillance protocol for (malignant) tumours as is currently recommended for CS. In addition, we propose a yearly haemoglobin test from early infancy for the early detection of intestinal hamartomas, which are likely to give severe complications, especially in BRRS cases.
    Familial Cancer 02/2003; 2(2):79-85. · 1.94 Impact Factor
  • P E M Taschner, A H J T Bröcker-Vriends, A G L van der Mey
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    ABSTRACT: Hereditary paragangliomas are rare benign tumours arising from neuroectodermal tissue in the head and neck region. In families with paraganglioma, occasionally adrenal and extra-adrenal pheochromocytomas are found. Paragangliomas, adrenal and extra-adrenal pheochromocytomas may be caused by mutations in the SDHB, SDHC and SDHD genes encoding different subunits of mitochondrial respiratory chain complex II. Most paraganglioma cases in the Netherlands are caused by SDHD mutations. Presymptomatic DNA diagnosis is available for families with paragangliomas caused by SDHD mutations.
    Nederlands tijdschrift voor geneeskunde 12/2002; 146(46):2188-90.
  • J M Cobben, A H J T Bröcker-Vriends, N J Leschot
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    ABSTRACT: Prenatal testing for a BRCA mutation, the hereditary trait for mammary and ovarian carcinoma, with the intention of selective termination of pregnancy in case of a female carrier is a controversial ethical issue. Based on a review of the (limited) medical literature as well as of Dutch policy statements relating to this subject, the following conclusions and recommendations are proposed: (a) the decision to opt for prenatal BRCA testing and selective termination of pregnancy in case of a BRCA mutation in the foetus cannot immediately be judged unacceptable from an ethical point of view; (b) prenatal BRCA testing is morally defensible only in case of a female foetus and if the parents at least have the intention to terminate the pregnancy if the foetus is a carrier, although the final decision is in any case up to the parents only; (c) prental testing for a BRCA mutation should only be done after extensive counselling of the parents, during which not only the medical genetic aspects but also the ethical aspects of prenatal BRCA testing are discussed.
    Nederlands tijdschrift voor geneeskunde 09/2002; 146(31):1461-5.
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    ABSTRACT: Recently, we and others reported instability in the (C)8 repeat in exon 5 of MSH6 as a preferential target for somatic mutations in tumours from MSH6 germline mutation carriers. Here, we report that in 45% of tumours from MLH1, MSH2 and MSH6 germline mutation carriers no sequence change in the (C)8 repeat of MSH6 was found upon DNA sequencing analysis of PCR products with a shift in electrophoresis mobility. Using "standard" PCR primers a high frequency of instability (50-86%) of the (C)8 repeat was found, but using a modified PCR reverse primer, accomplishing modulation of non-templated addition of adenine during in vitro PCR amplification by the Taq polymerase, a markedly lower frequency of instability was found in tumours from MLH1, MSH2 and MSH6 mutation carriers (6, 13 and 40%, respectively). Furthermore, a significant difference of the frequency of instability of the (C)8 repeat in tumours from MSH6 mutation carriers was found compared to MLH1, MSH2 mutation carriers. These results might have important implications for the detection of instability of other short mononucleotide repeats, e.g. TGFbetaRII, BAX, IGFRII, PTEN, BRCA2.
    Oncogene 10/2001; 20(43):6241-4. · 8.56 Impact Factor

Publication Stats

2k Citations
367.70 Total Impact Points

Institutions

  • 2007–2008
    • Erasmus MC
      • Department of Clinical Genetics
      Rotterdam, South Holland, Netherlands
    • Erasmus Universiteit Rotterdam
      • Department of Clinical Genetics
      Rotterdam, South Holland, Netherlands
  • 1988–2008
    • Leiden University Medical Centre
      • • Department of Pathology
      • • Department of Clinical Genetics
      • • Department of Clinical Epidemiology
      Leyden, South Holland, Netherlands
  • 1993
    • University of Amsterdam
      • Department of Medical Psychology
      Amsterdam, North Holland, Netherlands
  • 1990
    • University of Groningen
      • Department of Health Sciences
      Groningen, Province of Groningen, Netherlands