81 results on '"Menko, F H"'
Search Results
2. Colorectal cancer risk variants at 8q23.3 and 11q23.1 are associated with disease phenotype in APC mutation carriers.
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Ghorbanoghli Z, Nieuwenhuis MH, Houwing-Duistermaat JJ, Jagmohan-Changur S, Hes FJ, Tops CM, Wagner A, Aalfs CM, Verhoef S, Gómez García EB, Sijmons RH, Menko FH, Letteboer TG, Hoogerbrugge N, van Wezel T, Vasen HF, and Wijnen JT
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- Adenoma genetics, Adenomatous Polyposis Coli genetics, Adult, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Mutation, Polymorphism, Single Nucleotide, Adenomatous Polyposis Coli Protein genetics, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 8, Colorectal Neoplasms genetics
- Abstract
Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome caused by germline mutations in the APC gene and characterized by the development of multiple colorectal adenomas and a high risk of developing colorectal cancer (CRC). The severity of polyposis is correlated with the site of the APC mutation. However, there is also phenotypic variability within families with the same underlying APC mutation, suggesting that additional factors influence the severity of polyposis. Genome-wide association studies identified several single nucleotide polymorphisms (SNPs) that are associated with CRC. We assessed whether these SNPs are associated with polyp multiplicity in proven APC mutation carriers. Sixteen CRC-associated SNPs were analysed in a cohort of 419 APC germline mutation carriers from 182 families. Clinical data were retrieved from the Dutch Polyposis Registry. Allele frequencies of the SNPs were compared for patients with <100 colorectal adenomas versus patients with ≥100 adenomas, using generalized estimating equations with the APC genotype as a covariate. We found a trend of association of two of the tested SNPs with the ≥100 adenoma phenotype: the C alleles of rs16892766 at 8q23.3 (OR 1.71, 95 % CI 1.05-2.76, p = 0.03, dominant model) and rs3802842 at 11q23.1 (OR 1.51, 95 % CI 1.03-2.22, p = 0.04, dominant model). We identified two risk variants that are associated with a more severe phenotype in APC mutation carriers. These risk variants may partly explain the phenotypic variability in families with the same APC gene defect. Further studies with a larger sample size are recommended to evaluate and confirm the phenotypic effect of these SNPs in FAP.
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- 2016
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3. Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt-Hogg-Dubé syndrome.
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Johannesma PC, van de Beek I, van der Wel JW, Paul MA, Houweling AC, Jonker MA, van Waesberghe JH, Reinhard R, Starink TM, van Moorselaar RJ, Menko FH, and Postmus PE
- Abstract
Background and Objectives: Birt-Hogg-Dubé syndrome is an autosomal dominant disorder characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cell cancer due to germline folliculin (FLCN) mutations (Menko et al. in Lancet Oncol 10(12):1199-1206, 2009). The aim of this study was to evaluate the incidence of spontaneous pneumothorax in patients with BHD during or shortly after air travel and diving., Methods: A questionnaire was sent to a cohort of 190 BHD patients and the medical files of these patients were evaluated. The diagnosis of BHD was confirmed by FLCN mutations analysis in all patients. We assessed how many spontaneous pneumothoraces (SP) occurred within 1 month after air travel or diving., Results: In total 158 (83.2 %) patients returned the completed questionnaire. A total of 145 patients had a history of air travel. Sixty-one of them had a history of SP (42.1 %), with a mean of 2.48 episodes (range 1-10). Twenty-four (35.8 %) patients had a history of pneumothorax on both sides. Thirteen patients developed SP < 1 month after air travel (9.0 %) and two patients developed a SP < 1 month after diving (3.7 %). We found in this population of BHD patients a pneumothorax risk of 0.63 % per flight and a risk of 0.33 % per episode of diving. Symptoms possible related to SP were perceived in 30 patients (20.7 %) after air travel, respectively in ten patients (18.5 %) after diving., Conclusion: Based on the results presented in this retrospective study, exposure of BHD patients to considerable changes in atmospheric pressure associated with flying and diving may be related to an increased risk for developing a symptomatic pneumothorax. Symptoms reported during or shortly after flying and diving might be related to the early phase of pneumothorax. An individualized advice should be given, taking also into account patients' preferences and needs.
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- 2016
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4. Low penetrance of paraganglioma and pheochromocytoma in an extended kindred with a germline SDHB exon 3 deletion.
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Rijken JA, Niemeijer ND, Corssmit EP, Jonker MA, Leemans CR, Menko FH, and Hensen EF
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- Adolescent, Adult, Aged, Aged, 80 and over, Child, Female, Genotype, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Paraganglioma diagnosis, Paraganglioma mortality, Pedigree, Phenotype, Pheochromocytoma diagnosis, Pheochromocytoma mortality, Young Adult, Exons, Germ-Line Mutation, Paraganglioma genetics, Penetrance, Pheochromocytoma genetics, Sequence Deletion, Succinate Dehydrogenase genetics
- Abstract
In the Netherlands, the majority of hereditary paragangliomas (PGL) is caused by SDHD, SDHB and SDHAF2 mutations. Founder mutations in SDHD are particularly prevalent, but several SDHB founder mutations have also been described. Here, we describe an extended PGL family with a Dutch founder mutation in SDHB, c.201-4429_287-933del. The proband presented with apparently sporadic head and neck paraganglioma at advanced age. Subsequently, evaluation of the family identified several unaffected mutation carriers, asymptomatic and symptomatic PGL patients, and patients presenting with early-onset malignant pheochromocytoma. The calculated penetrance of the SDHB mutation in this kindred is lower than the risk suggested for SDHB mutations in the literature. This may represent a characteristic of this particular SDHB mutation, but may also be a reflection of the inclusion of relatively large numbers of asymptomatic mutation carriers in this family and adequate statistical correction for ascertainment bias. The low penetrance of SDHB mutations may obscure the hereditary nature of SDHB-linked disease and is important in the counseling of SDHB-linked patients. Risk estimates should preferably be based on the specific mutation involved., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2016
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5. Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium "Care for CMMR-D" (C4CMMR-D).
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Vasen HF, Ghorbanoghli Z, Bourdeaut F, Cabaret O, Caron O, Duval A, Entz-Werle N, Goldberg Y, Ilencikova D, Kratz CP, Lavoine N, Loeffen J, Menko FH, Muleris M, Sebille G, Colas C, Burkhardt B, Brugieres L, and Wimmer K
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- Brain Neoplasms etiology, Colorectal Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis drug therapy, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA Repair-Deficiency Disorders complications, Humans, Leukemia diagnosis, Mutation, Neoplasms etiology, Population Surveillance, Brain Neoplasms diagnosis, DNA Repair-Deficiency Disorders genetics, Digestive System Neoplasms diagnosis, Neoplasms diagnosis
- Abstract
Lynch syndrome (LS) is an autosomal dominant disorder caused by a defect in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. In the last 15 years, an increasing number of patients have been described with biallelic mismatch repair gene mutations causing a syndrome referred to as 'constitutional mismatch repair-deficiency' (CMMR-D). The spectrum of cancers observed in this syndrome differs from that found in LS, as about half develop brain tumours, around half develop digestive tract cancers and a third develop haematological malignancies. Brain tumours and haematological malignancies are mainly diagnosed in the first decade of life, and colorectal cancer (CRC) and small bowel cancer in the second and third decades of life. Surveillance for CRC in patients with LS is very effective. Therefore, an important question is whether surveillance for the most common CMMR-D-associated cancers will also be effective. Recently, a new European consortium was established with the aim of improving care for patients with CMMR-D. At a workshop of this group held in Paris in June 2013, one of the issues addressed was the development of surveillance guidelines. In 1968, criteria were proposed by WHO that should be met prior to the implementation of screening programmes. These criteria were used to assess surveillance in CMMR-D. The evaluation showed that surveillance for CRC is the only part of the programme that largely complies with the WHO criteria. The values of all other suggested screening protocols are unknown. In particular, it is questionable whether surveillance for haematological malignancies improves the already favourable outcome for patients with these tumours. Based on the available knowledge and the discussions at the workshop, the European consortium proposed a surveillance protocol. Prospective collection of all results of the surveillance is needed to evaluate the effectiveness of the programme.
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- 2014
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6. Bilateral renal tumour as indicator for birt-hogg-dubé syndrome.
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Johannesma PC, van Moorselaar RJ, Horenblas S, van der Kolk LE, Thunnissen E, van Waesberghe JH, Menko FH, and Postmus PE
- Abstract
Birt-Hogg-Dubé (BHD) syndrome is a cancer disorder caused by a pathogenic FLCN mutation characterized by fibrofolliculomas, lung cysts, pneumothorax, benign renal cyst, and renal cell carcinoma (RCC). In this case we describe a patient with bilateral renal tumour and a positive familial history for pneumothorax and renal cancer. Based on this clinical presentation, the patient was suspected for BHD syndrome, which was confirmed after molecular testing. We discuss the importance of recognizing this autosomal dominant cancer disorder when a patient is presented at the urologist with a positive family history of chromophobe renal cell cancer or a positive familial history for renal cell cancer and pneumothorax.
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- 2014
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7. Highly variable clinical manifestations in a large family with a novel GATA2 mutation.
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Mutsaers PG, van de Loosdrecht AA, Tawana K, Bödör C, Fitzgibbon J, and Menko FH
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- Adult, Aged, Female, Humans, Male, Prognosis, GATA2 Transcription Factor genetics, Mutation genetics, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology
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- 2013
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8. Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.
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Houweling AC, Gijezen LM, Jonker MA, van Doorn MB, Oldenburg RA, van Spaendonck-Zwarts KY, Leter EM, van Os TA, van Grieken NC, Jaspars EH, de Jong MM, Bongers EM, Johannesma PC, Postmus PE, van Moorselaar RJ, van Waesberghe JH, Starink TM, van Steensel MA, Gille JJ, and Menko FH
- Subjects
- Adult, Aged, Birt-Hogg-Dube Syndrome complications, Female, Humans, Kidney Neoplasms complications, Male, Middle Aged, Pneumothorax complications, Birt-Hogg-Dube Syndrome genetics, Genetic Predisposition to Disease, Kidney Neoplasms genetics, Mutation, Pneumothorax genetics, Proto-Oncogene Proteins genetics, Tumor Suppressor Proteins genetics
- Abstract
Background: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD., Methods: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families., Results: Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas., Conclusion: We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.
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- 2011
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9. Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations.
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Johannesma PC, van der Klift HM, van Grieken NC, Troost D, Te Riele H, Jacobs MA, Postma TJ, Heideman DA, Tops CM, Wijnen JT, and Menko FH
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- Adenoma diagnosis, Adenoma pathology, Age of Onset, Brain Neoplasms diagnosis, Brain Neoplasms pathology, Child, Colorectal Neoplasms diagnosis, Colorectal Neoplasms pathology, DNA Mismatch Repair, DNA Mutational Analysis, Female, Glioma diagnosis, Glioma pathology, Heterozygote, Humans, Male, Microsatellite Repeats, Mismatch Repair Endonuclease PMS2, Pedigree, Siblings, Syndrome, Young Adult, Adenoma genetics, Adenosine Triphosphatases genetics, Brain Neoplasms genetics, Colorectal Neoplasms genetics, DNA Repair Enzymes genetics, DNA-Binding Proteins genetics, Germ-Line Mutation, Glioma genetics
- Abstract
Childhood brain tumours may be due to germline bi-allelic mismatch repair (MMR) gene mutations in MLH1, MSH2, MSH6 or PMS2. These mutations can also lead to colorectal neoplasia and haematological malignancies. Here, we review this syndrome and present siblings with early-onset rectal adenoma and papillary glioneural brain tumour, respectively, due to novel germline bi-allelic PMS2 mutations. Identification of MMR protein defects can lead to early diagnosis of this condition. In addition, assays for these defects may help to classify brain tumours for research protocols aimed at targeted therapies., (2011 John Wiley & Sons A/S.)
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- 2011
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10. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility.
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Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, and Tee AR
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- Basic Helix-Loop-Helix Transcription Factors genetics, Birt-Hogg-Dube Syndrome genetics, Birt-Hogg-Dube Syndrome metabolism, Blotting, Western, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell metabolism, Cell Line, Tumor, Gene Expression, Gene Expression Profiling, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Immunohistochemistry, Kidney Neoplasms genetics, Kidney Neoplasms metabolism, Proto-Oncogene Proteins genetics, RNA, Messenger analysis, Reverse Transcriptase Polymerase Chain Reaction, Transcription, Genetic, Tumor Suppressor Proteins genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Gene Expression Regulation genetics, Glycolysis physiology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Proto-Oncogene Proteins metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Under conditions of reduced tissue oxygenation, hypoxia-inducible factor (HIF) controls many processes, including angiogenesis and cellular metabolism, and also influences cell proliferation and survival decisions. HIF is centrally involved in tumour growth in inherited diseases that give rise to renal cell carcinoma (RCC), such as Von Hippel-Lindau syndrome and tuberous sclerosis complex. In this study, we examined whether HIF is involved in tumour formation of RCC in Birt-Hogg-Dubé syndrome. For this, we analysed a Birt-Hogg-Dubé patient-derived renal tumour cell line (UOK257) that is devoid of the Birt-Hogg-Dubé protein (BHD) and observed high levels of HIF activity. Knockdown of BHD expression also caused a threefold activation of HIF, which was not as a consequence of more HIF1α or HIF2α protein. Transcription of HIF target genes VEGF, BNIP3 and CCND1 was also increased. We found nuclear localization of HIF1α and increased expression of VEGF, BNIP3 and GLUT1 in a chromophobe carcinoma from a Birt-Hogg-Dubé patient. Our data also reveal that UOK257 cells have high lactate dehydrogenase, pyruvate kinase and 3-hydroxyacyl-CoA dehydrogenase activity. We observed increased expression of pyruvate dehydrogenase kinase 1 (a HIF gene target), which in turn leads to increased phosphorylation and inhibition of pyruvate dehydrogenase. Together with increased protein levels of GLUT1, our data reveal that UOK257 cells favour glycolytic rather than lipid metabolism (a cancer phenomenon termed the 'Warburg effect'). UOK257 cells also possessed a higher expression level of the L-lactate influx monocarboxylate transporter 1 and consequently utilized L-lactate as a metabolic fuel. As a result of their higher dependency on glycolysis, we were able to selectively inhibit the growth of these UOK257 cells by treatment with 2-deoxyglucose. This work suggests that targeting glycolytic metabolism may be used therapeutically to treat Birt-Hogg-Dubé-associated renal lesions., (© 2011 Macmillan Publishers Limited)
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- 2011
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11. Perceiving cancer-risks and heredity-likelihood in genetic-counseling: how counselees recall and interpret BRCA 1/2-test results.
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Vos J, Oosterwijk JC, Gómez-García E, Menko FH, Jansen AM, Stoel RD, van Asperen CJ, Tibben A, and Stiggelbout AM
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- Female, Genes, BRCA1, Genes, BRCA2, Humans, Middle Aged, Models, Theoretical, Retrospective Studies, Surveys and Questionnaires, Breast Neoplasms genetics, Breast Neoplasms psychology, Genetic Counseling, Genetic Testing statistics & numerical data, Mental Recall, Ovarian Neoplasms genetics, Ovarian Neoplasms psychology, Perception, Risk
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Previous studies on the counsellees' perception of DNA test results did not clarify whether counsellees were asked about their recollections or interpretations, and focused only on patients' own risks and not on the likelihood that cancer is heritable in the family. We tested differences and correlations of four perception aspects: recollections and interpretations of both cancer risks and heredity likelihood. In a retrospective study, women tested for BRCA1/2 on average, 5 years ago, completed questionnaires about their perception. Participants had received an unclassified variant (n = 76), uninformative (n = 76) or pathogenic mutation (n = 51) result in BRCA1/2. Analyses included t-tests, correlations and structural equation modelling. The counsellees' perception showed to consist of four distinctive phenomena: recollections and interpretations of cancer risks and of heredity likelihood. This distinctiveness was suggested by significant differences between these perception variables. Moderate to strong correlations were found between these variables, suggesting that these differences between variables were consistent. The relationships between these variables were not influenced by actually communicated DNA test results, sociodemographics, medical and pedigree information, or framing of cancer risk questions. The largest differences between recollections and interpretations were found in the unclassified variant group and the smallest in uninformatives. Cancer risks and heredity likelihood correlated least in the pathogenic mutation group. Communication of ambiguous genetic information enlarged the differences. To understand the counsellees' perception of genetic counselling, researchers should study recollections and interpretations of cancer risks and heredity likelihood. Genetic counsellors should explicitly address the counsellees' recollections and interpretations, and be aware of possible inaccuracies., (© 2010 John Wiley & Sons A/S.)
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- 2011
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12. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.
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Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon ME, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IP, Hoefsloot LH, van Moorselaar RJ, Starink TM, Bayley JP, Frank J, van Steensel MA, and Menko FH
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- Adolescent, Adult, Carcinoma, Renal Cell diagnosis, Carcinoma, Renal Cell enzymology, Child, Child, Preschool, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Humans, Kidney Neoplasms diagnosis, Kidney Neoplasms enzymology, Netherlands, Pedigree, Skin Neoplasms diagnosis, Skin Neoplasms enzymology, Syndrome, Uterine Neoplasms diagnosis, Uterine Neoplasms enzymology, Young Adult, Carcinoma, Renal Cell genetics, Fumarate Hydratase genetics, Germ-Line Mutation, Kidney Neoplasms genetics, Leiomyomatosis enzymology, Leiomyomatosis genetics, Skin Neoplasms genetics, Uterine Neoplasms genetics
- Abstract
Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation-dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole-gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management., (© 2010 John Wiley & Sons A/S.)
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- 2011
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13. Molecular profile of ductal carcinoma in situ of the breast in BRCA1 and BRCA2 germline mutation carriers.
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van der Groep P, van Diest PJ, Menko FH, Bart J, de Vries EG, and van der Wall E
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- Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast pathology, Carcinoma, Intraductal, Noninfiltrating metabolism, Carcinoma, Intraductal, Noninfiltrating pathology, Female, Humans, Immunophenotyping, Neoplasm Proteins metabolism, Breast Neoplasms genetics, Carcinoma, Intraductal, Noninfiltrating genetics, Genes, BRCA1, Genes, BRCA2, Germ-Line Mutation
- Abstract
Aims: Ductal carcinoma in situ (DCIS) is an established late precursor of sporadic invasive breast cancer and to a large extent parallels its invasive counterpart with respect to molecular changes and immunophenotype. Invasive breast cancers in germline BRCA1 and BRCA2 mutation carriers have a distinct "basal" and "luminal" immunophenotype, respectively, but the immunophenotype of their precursor lesions has hardly been studied, and this was the aim of this study., Methods: DCIS lesions of 25 proven BRCA1 and 9 proven BRCA2 germline mutation carriers and their 22 and 6, respectively, accompanying invasive lesions were stained by immunohistochemistry for oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER)2/neu, cytokeratin (CK)5/6, CK14, epidermal growth factor receptor (EGFR) and Ki67., Results: DCIS lesions in BRCA1 mutation carriers were mostly of the basal molecular type with low ER/PR/HER2 expression, while they frequently expressed CK5/6, CK14 and EGFR, and were mostly grade 3 and highly proliferative. DCIS lesions in BRCA2 mutation carriers were mostly of luminal molecular type with frequent expression of ER/PR, and infrequent expression of CK5/6, CK14 and EGFR, and they were mostly grade 3 and showed low proliferation. In BRCA1 and BRCA2 mutation carriers there was a high concordance between DCIS lesions and their concomitant invasive counterpart with regard to expression of individual markers as well as "molecular" subtype., Conclusions: Although the number of cases studied was low, DCIS lesions in BRCA1 and BRCA2 mutations carriers are usually of the basal and luminal molecular type, respectively, similar to their accompanying invasive cancers, thereby providing evidence that DCIS is a direct precursor lesion in these hereditary predisposed patients. This also suggests that crucial carcinogenetic events leading to these phenotypes in hereditary predisposed patients occur before the stage of invasion.
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- 2009
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14. Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes.
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Menko FH, Kneepkens CM, de Leeuw N, Peeters EA, Van Maldergem L, Kamsteeg EJ, Davidson R, Rozendaal L, Lasham CA, Peeters-Scholte CM, Jansweijer MC, Hilhorst-Hofstee Y, Gille JJ, Heins YM, Nieuwint AW, and Sistermans EA
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- Abnormalities, Multiple genetics, Age of Onset, Child, Preschool, Colorectal Neoplasms etiology, Female, Gastrointestinal Diseases complications, Gastrointestinal Diseases pathology, Humans, Infant, Infant, Newborn, Intellectual Disability genetics, Intestinal Polyposis complications, Intestinal Polyposis pathology, Male, Oligonucleotide Array Sequence Analysis, Phenotype, Bone Morphogenetic Protein Receptors, Type I genetics, Chromosomes, Human, Pair 10, Gastrointestinal Diseases genetics, Intestinal Polyposis genetics, PTEN Phosphohydrolase genetics, Sequence Deletion
- Abstract
Infantile juvenile polyposis is a rare disease with severe gastrointestinal symptoms and a grave clinical course. Recently, 10q23 microdeletions involving the PTEN and BMPR1A genes were found in four patients with infantile juvenile polyposis. It was hypothesized that a combined and synergistic effect of the deletion of both genes would explain the condition. Subsequently, however, a patient with a larger 10q23 deletion including the same genes but with a mild clinical phenotype was identified. Here, we present four additional patients with 10q23 microdeletions involving the PTEN and BMPR1A genes. The sizes of the deletions were analyzed using single nucleotide polymorphism array analysis. All patients had macrocephaly, dysmorphic features, retardation and congenital abnormalities. One patient developed colorectal cancer. However, only one case had disease onset before 2 years of age and severe symptoms requiring colectomy. No clear correlation was found between ages at onset or severity of gastrointestinal symptoms and the sizes of the deletions. We conclude that patients with 10q23 microdeletions involving the PTEN and BMPR1A genes have variable clinical phenotypes, which cannot be explained merely by the deletion sizes. The phenotypes are not restricted to severe infantile juvenile polyposis but include childhood-onset cases with macrocephaly, retardation, mild gastrointestinal symptoms and possibly early-onset colorectal cancer.
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- 2008
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15. Genetic defects underlying Peutz-Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Par1 gene family as potential PJS candidates.
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de Leng WW, Jansen M, Carvalho R, Polak M, Musler AR, Milne AN, Keller JJ, Menko FH, de Rooij FW, Iacobuzio-Donahue CA, Giardiello FM, Weterman MA, and Offerhaus GJ
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- AMP-Activated Protein Kinase Kinases, Exons, Female, Germ-Line Mutation, Humans, Introns, Male, Peutz-Jeghers Syndrome enzymology, Sequence Deletion, Multigene Family, Peutz-Jeghers Syndrome genetics, Protein Serine-Threonine Kinases genetics
- Abstract
LKB1/STK11 germline inactivations are identified in the majority (66-94%) of Peutz-Jeghers syndrome (PJS) patients. Therefore, defects in other genes or so far unidentified ways of LKB1 inactivation may cause PJS. The genes encoding the MARK proteins, homologues of the Par1 polarity protein that associates with Par4/Lkb1, were analyzed in this study because of their link to LKB1 and cell polarity. The genetic defect underlying PJS was determined through analysis of both LKB1 and all four MARK genes. LKB1 point mutations and small deletions were identified in 18 of 23 PJS families using direct sequencing and multiplex ligation-dependent probe amplification analysis identified exon deletions in 3 of 23 families. In total, 91% of the studied families showed LKB1 inactivation. Furthermore, a MARK1, MARK2, MARK3 and MARK4 mutation analysis and an MARK4 quantitative multiplex polymerase chain reaction analysis to identify exon deletions on another eight PJS families without identified LKB1 germline mutation did not identify mutations in the MARK genes. LKB1 defects are the major cause of PJS and genes of the MARK family do not represent alternative PJS genes. Other mechanisms of inactivation of LKB1 may cause PJS in the remaining families.
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- 2007
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16. Is surveillance of the small bowel indicated for Lynch syndrome families?
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ten Kate GL, Kleibeuker JH, Nagengast FM, Craanen M, Cats A, Menko FH, and Vasen HF
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- Adolescent, Adult, Aged, Aged, 80 and over, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, Family Health, Female, Germ-Line Mutation genetics, Heterozygote, Humans, Intestinal Neoplasms pathology, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasms, Multiple Primary pathology, Risk Assessment methods, Risk Factors, Intestinal Neoplasms genetics, Intestine, Small pathology, Neoplasms, Multiple Primary genetics
- Abstract
Background: Small bowel cancer (SBC) is one of the tumours associated with Lynch syndrome (LS). To advise on screening for this tumour it is paramount to be informed about the lifetime risk. The aim of this study was to calculate the lifetime risk of SBC in LS and to identify possible risk factors., Methods: Clinical and pathological data were collected on 1496 proven or putative carriers of a mismatch repair gene mutation from 189 families. Kaplan-Meier survival analysis was used to calculate the lifetime risk and to assess potential risk factors., Results: 28 (1.9%) of the 1496 (putative) mutation carriers were identified with SBC. The median age at diagnosis was 52 years (range 23-69 years). The lifetime risk of developing SBC was 4.2%. There was no difference in risk between males and females (log rank: p = 0.2470), or between MLH1 and MSH2 mutation carriers (log rank: p = 0.2754). SBC was not observed in MSH6 mutation carriers (n = 203). The previous occurrence of colorectal cancer and a family history of SBC did not increase the risk significantly., Conclusions: Approximately, one out of 25 mutation carriers will develop SBC during life. No specific risk factors were identified. The risk appeared to be too low to advise screening by means of an invasive burdensome procedure like double balloon enteroscopy. However, screening by a non-invasive procedure (videocapsule endoscopy) might be considered if future studies will show its cost effectiveness. In patients with unexplained abdominal complaints and/or unexplained iron deficiency anaemia SBC should be considered.
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- 2007
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17. A case of loss of heterozygosity in the BRCA2 gene of a borderline ovarian tumor: case report and review of literature.
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Verbruggen MB, Zweemer RP, Piek JM, van Unnik GA, van Diest PJ, Gille JJ, Menko FH, Dorsman JC, and Verheijen RH
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- DNA Mutational Analysis, Female, Humans, Intracellular Signaling Peptides and Proteins, Middle Aged, Mutation, Ovarian Neoplasms diagnosis, Proteins analysis, Genes, BRCA2, Heterozygote, Loss of Heterozygosity genetics, Ovarian Neoplasms genetics
- Abstract
Germline BRCA1 and BRCA2 mutations highly increase the risk of breast and female adnexal cancer. The role of these genes in the tumorigenesis of other malignancies is still under debate. Borderline ovarian tumors (BOT) are occasionally found in families with a strong history of breast and/or female adnexal cancer with or without proven germline mutations. We investigated whether a BOT arising in a germline BRCA2 mutation carrier could be attributed to this mutation, in which case BOT should be added to the BRCA2 related tumor spectrum. Tumor DNA of a serous borderline ovarian tumor (sBOT) of a 55-year-old female carrier of a pathogenic BRCA2 mutation (6085G>T) was analyzed for loss of heterozygosity (LOH) of BRCA2. The sBOT cells, unexpectedly, revealed loss of the mutant allele of BRCA2, while ovarian stroma cells and peripheral blood lymphocytes contained both wild-type and mutant allele of BRCA2. The finding that no loss of the wild-type BRCA2 allele was found in the tumor tissue but loss of the mutant allele was seen suggests that sBOT are not part of the BRCA2 related tumor spectrum. In the literature BOT's in germline BRCA1 and BRCA2 mutation carriers are described incidentally, while in patients with a BOT a germline BRCA1 or BRCA2 mutation is rarely found. Therefore, we conclude that borderline ovarian tumors are neither part of the BRCA1- nor the BRCA2- related tumor spectrum.
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- 2007
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18. Humoral immune responses to MUC1 in women with a BRCA1 or BRCA2 mutation.
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Hermsen BB, Verheijen RH, Menko FH, Gille JJ, van Uffelen K, Blankenstein MA, Meijer S, van Diest PJ, Kenemans P, and von Mensdorff-Pouilly S
- Subjects
- Adult, Aged, Antibody Formation genetics, Breast Neoplasms genetics, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulin M immunology, Middle Aged, Mutation genetics, Ovarian Neoplasms genetics, Antibodies immunology, Breast Neoplasms immunology, Genes, BRCA1, Genes, BRCA2, Mucin-1 immunology, Ovarian Neoplasms immunology
- Abstract
Introduction: Breast cancer patients with early disease and a natural humoral response to MUC1 have a favourable prognosis, suggesting a possible role of MUC1 antibodies (ab) in controlling haematogenous tumour dissemination and outgrowth. The aim of the study was to evaluate humoral immune responses to MUC1 in women at hereditary high risk of breast cancer to investigate whether this immune response could play a role in the prevention of disease., Materials and Methods: CA15.3 (U/mL), and IgG and IgM ab to MUC1 (arbitrary units per mL, Arb-U/mL) were measured in serum samples obtained from 422 women at hereditary high risk of breast/ovarian cancer, of whom 127 BRCA1/2 carriers, attending the Familial Cancer Clinic of the VU University Medical Centre, and from 370 age-matched healthy controls. Serum samples obtained from women who developed breast cancer (N=12) or breast cancer recurrence (N=17), and from women who underwent prophylactic mastectomy (N=12) and had no breast lesions were also tested., Results: CA15.3 ranked significantly higher in mutation carriers than in controls (P=0.03). MUC1 IgG ab levels ranked significantly lower in BRCA1/2 mutation carriers than in controls (P=0.003). MUC1 IgG levels were not significantly different (P=0.53) between women who developed primary breast cancer (median 0.72Arb-U/ml, range 0.52-2.44Arb-U/ml) and women who underwent prophylactic mastectomy and had no breast lesions (median 1.04Arb-U/ml, range 0.43-2.88Arb-U/ml)., Conclusion: Serum levels of natural IgG ab to MUC1 are lower in BRCA1/2 mutation carriers than in healthy controls. Furthermore, in contrast to previous results in women with sporadic breast cancer, no elevated MUC1 IgG ab were seen in women at hereditary high risk who developed breast cancer. Prophylactic immunotherapy with MUC1 substrates may be a strategy to reduce the risk of breast cancer in BRCA1/2 mutation carriers, strengthening tumour immune surveillance.
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- 2007
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19. [DNA-based diagnosis of hereditary tumour predisposition].
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Menko FH, Ligtenberg MJ, Brouwer T, Hahn DE, and Ausems MG
- Subjects
- Genetic Testing, Humans, Pedigree, DNA, Neoplasm analysis, Genetic Predisposition to Disease, Neoplasms diagnosis, Neoplasms genetics
- Abstract
Of all forms of cancer, approximately 5% are caused by factors leading to a strong genetic predisposition. DNA diagnosis is currently used in families with hereditary tumour syndromes, such as familial adenomatous polyposis, hereditary non-polyposis colorectal carcinoma (Lynch syndrome), and hereditary breast and ovarian cancer. Those persons who have not inherited the predisposition no longer have to undergo regular examinations. DNA diagnosis for a hereditary predisposition is currently also performed in patients with cancer at a relatively young age, even if the family history is unclear or negative. Consideration of the patient in the context of his or her family is important for both medico-technical and psychosocial reasons. This is true of both diagnostic and presymptomatic DNA diagnosis. For these reasons, the clinical application of the DNA diagnosis of hereditary tumours has become an integral part of the work of the multidisciplinary cancer family clinics of the university medical centres and the cancer centres. Guidelines for the management of hereditary tumours have recently been issued, with criteria for referral to the specialised outpatient clinics.
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- 2007
20. STK11 status and intussusception risk in Peutz-Jeghers syndrome.
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Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJ, Keller JJ, Westerman AM, Scott RJ, Lim W, Trimbath JD, Giardiello FM, Gruber SB, Offerhaus GJ, Rooij FW, Wilson JH, Hansmann A, Möslein G, Royer-Pokora B, Vogel T, Phillips RK, Spigelman AD, and Houlston RS
- Subjects
- AMP-Activated Protein Kinase Kinases, Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Risk Factors, Intussusception genetics, Peutz-Jeghers Syndrome genetics, Protein Serine-Threonine Kinases genetics
- Abstract
Background: Peutz-Jeghers syndrome (PJS) is caused by germline STK11 mutations and characterised by gastrointestinal polyposis. Although small bowel intussusception is a recognised complication of PJS, risk varies between patients., Objective: To analyse the time to onset of intussusception in a large series of PJS probands., Methods: STK11 mutation status was evaluated in 225 PJS probands and medical histories of the patients reviewed., Results: 135 (60%) of the probands possessed a germline STK11 mutation; 109 (48%) probands had a history of intussusception at a median age of 15.0 years but with wide variability (range 3.7 to 45.4 years). Median time to onset of intussusception was not significantly different between those with identified mutations and those with no mutation detected, at 14.7 years and 16.4 years, respectively (log-rank test of difference, chi(2) = 0.58, with 1df; p = 0.45). Similarly no differences were observed between patient groups on the basis of the type or site of STK11 mutation., Conclusions: The risk of intussusception in PJS is not influenced by STK11 mutation status.
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- 2006
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21. Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data.
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van der Groep P, Bouter A, van der Zanden R, Siccama I, Menko FH, Gille JJ, van Kalken C, van der Wall E, Verheijen RH, and van Diest PJ
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- Adult, Age Factors, Aged, Aged, 80 and over, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Decision Trees, Diagnosis, Differential, ErbB Receptors metabolism, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Germ-Line Mutation, Heterozygote, Humans, Immunoenzyme Techniques, Ki-67 Antigen metabolism, Middle Aged, Neoplasm Proteins metabolism, Neoplastic Syndromes, Hereditary metabolism, Neoplastic Syndromes, Hereditary pathology, Breast Neoplasms genetics, Neoplastic Syndromes, Hereditary diagnosis
- Abstract
Background: About 5% of all breast cancer cases are attributable to germline mutations in BRCA1 or BRCA2 genes. BRCA mutations in suspected carriers, however, may be missed, which hampers genetic counselling., Materials and Methods: Different clinicopathological features were compared between 22 breast cancers from carriers of proved BRCA1 mutations and 604 cancers from sporadic controls. In addition, 5 BRCA2-related breast cancers and 66 breast cancers of untested patients at intermediate risk and 19 breast cancers of untested patients at high risk of hereditary disease on the basis of family history were evaluated., Results: A "probably sporadic" class (age >or=54 years and epidermal growth factor receptor (EGFR) negative; 68% of cases) with a 0% chance of BRCA1-related breast cancer containing 79% of the sporadic cases was yielded by using a decision tree with age, Ki67 and EGFR. A 75% chance of BRCA1-related breast cancer was shown by the "probably BRCA1-related" class (age <54 years and Ki67 >or=25%; 8% of cases) with 82% of the BRCA1-related cases but only 1.4% of the sporadic cases. Most cases at intermediate or high risk of hereditary disease on the basis of family history could be classified with high probability as either probably BRCA1 related or probably sporadic., Conclusion: Breast carcinomas can be classified with a high level of certainty as sporadic or related to BRCA1 germline mutations by using a decision tree with age, Ki67 and EGFR. This can be clinically useful in mutation analysis in families with a borderline risk of hereditary disease.
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- 2006
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22. STRAD in Peutz-Jeghers syndrome and sporadic cancers.
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de Leng WW, Keller JJ, Luiten S, Musler AR, Jansen M, Baas AF, de Rooij FW, Gille JJ, Menko FH, Offerhaus GJ, and Weterman MA
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- Adaptor Proteins, Vesicular Transport metabolism, Adenocarcinoma metabolism, Chromosomes, Human, Pair 17 genetics, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, DNA, Neoplasm genetics, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Loss of Heterozygosity, Lung Neoplasms genetics, Lung Neoplasms metabolism, Microsatellite Repeats, Mutation, Neoplasm Proteins metabolism, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Peutz-Jeghers Syndrome metabolism, Stomach Neoplasms genetics, Stomach Neoplasms metabolism, Adaptor Proteins, Vesicular Transport genetics, Adenocarcinoma genetics, Neoplasm Proteins genetics, Peutz-Jeghers Syndrome genetics
- Abstract
Background/aims: LKB1 is a tumour suppressor gene that is associated with Peutz-Jeghers syndrome (PJS), a rare autosomal dominant cancer predisposition syndrome. However, germline mutations in the LKB1 gene are found in only about 60% of patients with PJS, suggesting the existence of a second PJS gene. The STRAD gene, encoding an LKB1 interacting protein that activates LKB1, which subsequently leads to polarisation of cells, is an interesting candidate for a second PJS gene and a potential tumour suppressor gene in sporadic carcinomas., Methods: The involvement of STRAD in 42 PJS associated tumours (sporadic lung, colon, gastric, and ovarian adenocarcinomas) was studied using loss of heterozygosity (LOH) analysis of eight microsatellite markers on chromosome 17, including TP53, BRCA1, and STRAD markers., Results: Loss of the marker near the STRAD locus was seen in 13 of 29 informative cases, including all gastric adenocarcinomas. Specific LOH of the STRAD marker was found in four of 29 informative cases. For these patients all exons and exon-intron boundaries of the STRAD gene were sequenced, but no somatic mutations were identified. Furthermore, no germline STRAD mutations were found in 10 patients with PJS and family members without LKB1 germline mutation., Conclusions: Despite the frequent occurrence of LOH in the STRAD region, these results indicate that inactivation of the STRAD gene is not essential in the sporadic adenocarcinomas studied, although it is possible that STRAD may be inactivated in different ways. In addition, no evidence was found for the hypothesis that STRAD is a second PJS susceptibility gene.
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- 2005
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23. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP).
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Nielsen M, Franken PF, Reinards TH, Weiss MM, Wagner A, van der Klift H, Kloosterman S, Houwing-Duistermaat JJ, Aalfs CM, Ausems MG, Bröcker-Vriends AH, Gomez Garcia EB, Hoogerbrugge N, Menko FH, Sijmons RH, Verhoef S, Kuipers EJ, Morreau H, Breuning MH, Tops CM, Wijnen JT, Vasen HF, Fodde R, and Hes FJ
- Subjects
- Adolescent, Adult, Aged, Child, Colorectal Neoplasms genetics, DNA Mutational Analysis, Female, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, Inheritance Patterns genetics, Male, Middle Aged, Netherlands, Phenotype, Risk, Adenomatous Polyposis Coli genetics, DNA Glycosylases genetics
- Abstract
Objective: 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., Methods: 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., Results: 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)., Conclusions: 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.
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- 2005
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24. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.
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van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S, Vasen HF, Ausems MG, Menko FH, Gomez Garcia EB, Klijn JG, Hogervorst FB, van Houwelingen JC, van't Veer LJ, Rookus MA, and van Leeuwen FE
- Subjects
- Adult, Aged, Bone Neoplasms epidemiology, Bone Neoplasms genetics, Breast Neoplasms epidemiology, Cohort Studies, Female, Humans, Male, Middle Aged, Netherlands, Ovarian Neoplasms epidemiology, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms genetics, Pharyngeal Neoplasms epidemiology, Pharyngeal Neoplasms genetics, Prostatic Neoplasms epidemiology, Prostatic Neoplasms genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Ovarian Neoplasms genetics, Risk
- Abstract
Background: In BRCA2 mutation carriers, increased risks have been reported for several cancer sites besides breast and ovary. As most of the families included in earlier reports were selected on the basis of multiple breast/ovarian cancer cases, it is possible that risk estimates may differ in mutation carriers with a less striking family history., Methods: In the Netherlands, 139 BRCA2 families with 66 different pathogenic mutations were included in a nationwide study. To avoid testing bias, we chose not to estimate risk in typed carriers, but rather in male and female family members with a 50% prior probability of being a carrier (n = 1811). The relative risk (RR) for each cancer site with the exception of breast and ovarian cancer was determined by comparing observed numbers with those expected, based on Dutch cancer incidence rates., Results: We observed an excess risk for four cancer sites: pancreas (RR 5.9; 95% confidence interval (CI) 3.2 to 10.0), prostate (2.5; 1.6 to 3.8), bone (14.4; 2.9 to 42.1) and pharynx (7.3; 2.0 to 18.6). A small increase was observed for cancer of the digestive tract (1.5; 1.1 to 1.9). Histological verification was available for 46% of the tumours. Nearly all increased risks reached statistical significance for men only. Cancer risks tended to be higher for people before the age of 65 years. Moreover, families with mutations outside the previously defined ovarian cancer cluster region tended to have a higher cancer risk., Conclusions: We found that BRCA2 carriers are at increased risk for cancers of the prostate and pancreas, and possibly bone and pharynx. Larger databases with extended follow up are needed to provide insight into mutation specific risks of selected carriers in BRCA2 families.
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- 2005
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25. Constitutional rearrangements of chromosome 22 as a cause of neurofibromatosis 2.
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Tsilchorozidou T, Menko FH, Lalloo F, Kidd A, De Silva R, Thomas H, Smith P, Malcolmson A, Dore J, Madan K, Brown A, Yovos JG, Tsaligopoulos M, Vogiatzis N, Baser ME, Wallace AJ, and Evans DG
- Subjects
- Adolescent, Adult, Child, Preschool, Female, Humans, Male, Middle Aged, Retrospective Studies, Ring Chromosomes, Chromosome Disorders complications, Chromosome Disorders genetics, Chromosomes, Human, Pair 22 genetics, Neurofibromatosis 2 etiology, Neurofibromatosis 2 genetics
- Published
- 2004
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26. Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect.
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de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P, Cats A, Menko FH, Griffioen G, Slors JF, Nagengast FM, Kleibeuker JH, and Vasen HF
- Subjects
- Adult, Aged, Base Pair Mismatch, Colectomy mortality, Colorectal Neoplasms genetics, Colorectal Neoplasms mortality, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis mortality, Colorectal Neoplasms, Hereditary Nonpolyposis surgery, Humans, Life Expectancy, Markov Chains, Middle Aged, Neoplasms, Second Primary mortality, Risk Factors, Survival Analysis, Colectomy methods, Colorectal Neoplasms surgery, Decision Support Techniques, Neoplasms, Second Primary prevention & control
- Abstract
Background: In view of the high risk of developing a new primary colorectal carcinoma (CRC), subtotal colectomy rather than segmental resection or hemicolectomy is the preferred treatment in hereditary non-polyposis colorectal cancer (HNPCC) patients. Subtotal colectomy however implies a substantial decrease in quality of life. To date, colonoscopic surveillance has been shown to reduce CRC occurrence., Aims: To compare the potential health effects in terms of life expectancy (LE) for patients undergoing subtotal colectomy or hemicolectomy for CRC., Methods: A decision analysis (Markov) model was created. Information on the 10 year risk of CRC after subtotal colectomy (4%) and hemicolectomy (16%) and stages of CRCs detected within a two year surveillance interval (32% Dukes' A, 54% Dukes' B, and 14% Dukes' C) were derived from two cohort studies. Five year survival rates used for the different Dukes stages (A, B, and C) were 98%, 80%, and 60%, respectively. Remaining LE values were calculated for hypothetical cohorts with an age at CRC diagnosis of 27, 47, and 67 years, respectively. Remaining LE values were also calculated for patients with CRC of Dukes' stage A., Results: The overall LE gain of subtotal colectomy compared with hemicolectomy at ages 27, 47, and 67 was 2.3, 1, and 0.3 years, respectively. Specifically for Dukes' stage A, this would be 3.4, 1.5, and 0.4 years., Conclusions: Unless surveillance results improve, subtotal colectomy still seems the preferred treatment for CRC in HNPCC in view of the difference in LE. For older patients, hemicolectomy may be an option as there is no appreciable difference in LE.
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- 2003
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27. Expression of differentiation and proliferation related proteins in epithelium of prophylactically removed ovaries from women with a hereditary female adnexal cancer predisposition.
- Author
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Piek JM, Verheijen RH, Menko FH, Jongsma AP, Weegenaar J, Gille JJ, Pals G, Kenemans P, and van Diest PJ
- Subjects
- Adnexal Diseases genetics, Adnexal Diseases pathology, Adult, Aged, Biomarkers, Tumor metabolism, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Epithelium metabolism, Epithelium pathology, Fallopian Tubes pathology, Female, Genetic Predisposition to Disease, Humans, Immunoenzyme Techniques, Middle Aged, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Ovariectomy, Ovary pathology, Precancerous Conditions genetics, Precancerous Conditions pathology, Adnexal Diseases metabolism, Cell Transformation, Neoplastic metabolism, Neoplasm Proteins metabolism, Ovarian Neoplasms metabolism, Ovary metabolism, Precancerous Conditions metabolism
- Abstract
Aims: To investigate the occurrence of preinvasive neoplastic lesions in ovarian surface epithelium and ovarian inclusion cyst epithelium of women with a hereditary predisposition to the development of female adnexal (ovarian and fallopian tube) carcinoma and to assess the expression of differentiation and proliferation related proteins within putative sites of origin of serous ovarian carcinoma, the ovarian surface epithelium and ovarian inclusion cyst epithelium., Methods: Twenty-one ovaries, prophylactically removed from 11 women predisposed to the development of female adnexal cancer (cases) were compared with 22 ovaries from 11 women without such predisposition (controls). Archival histological specimens were screened for hyperplastic and dysplastic epithelial lesions. In both the ovarian surface and inclusion cyst epithelia, the percentage of cells was determined that stained positively for Ki67, p21, p27, p53, cyclin A, cyclin D1, bcl-2 and the presence of HER-2/neu, oestrogen (ER-alpha) and progesterone receptors (PR)., Results: No preinvasive neoplastic lesions were detected. However, hyperplastic areas were found in three cases and in four controls (NS). ER-alpha (P = 0.013), PR (P < 0.001), bcl-2 (P = 0.008), p21 (P = 0.046) and p27 (P = 0.008) were expressed in a significantly higher percentage of cells in inclusion cyst epithelium than in ovarian surface epithelium (both groups). The latter showed higher bcl-2 expression in cases (P = 0.05) compared with controls. The inclusion cyst epithelium of cases showed higher expression of bcl-2 (P = 0.006) and PR (P = 0.039) compared with controls. Proliferation was low in both cases and controls as reflected by low Ki67 expression. Over-expression of p53, cyclin D1 and HER-2/neu was not detected., Conclusions: Premalignant changes are not a common feature of ovaries removed prophylactically from women predisposed to the development of female adnexal carcinoma. Increased expression of p21, p27, and ER-alpha is seen in inclusion cyst compared with ovarian surface epithelium of women with and without an inherited risk of adnexal carcinoma. This is most probably caused by the different intraovarian hormonal milieu of inclusion cyst epithelium. However, the increased expression of bcl-2 and PR in the inclusion cyst epithelium of patients with a hereditary predisposition may reflect early disruption of hormonal balance and growth control.
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- 2003
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28. Rapidly progressive adenomatous polyposis in a patient with germline mutations in both the APC and MLH1 genes: the worst of two worlds.
- Author
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Scheenstra R, Rijcken FE, Koornstra JJ, Hollema H, Fodde R, Menko FH, Sijmons RH, Bijleveld CM, and Kleibeuker JH
- Subjects
- Adaptor Proteins, Signal Transducing, Adenomatous Polyposis Coli pathology, Carrier Proteins, Child, Disease Progression, Follow-Up Studies, Humans, Male, MutL Protein Homolog 1, Nuclear Proteins, Adenomatous Polyposis Coli genetics, Genes, APC, Germ-Line Mutation, Neoplasm Proteins genetics
- Abstract
The two most common inherited forms of colorectal cancer are familial adenomatous polyposis and hereditary non-polyposis colorectal cancer. Simultaneous inheritance of both an APC gene mutation and a mismatch repair gene (for example, MLH1) mutation has never been described. In the present case report, we report rapidly progressive adenomatous polyposis in a 10 year old boy with a germline frame shift mutation in the APC gene and a germline splice site mutation in the MLH1 gene. Immunohistochemical investigations showed abnormal expression of beta-catenin in early adenomas with low grade dysplasia, attributed to the APC gene mutation. Subsequent loss of function of the MLH1 gene, as shown by absent immunostaining of its protein in adenomas with high grade dysplasia, may well have caused the rapid progression to high grade dysplasia in many of the adenomas.
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- 2003
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29. Experience of discharge from colonoscopy of mutation negative HNPCC family members.
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Bleiker EM, Menko FH, Taal BG, Kluijt I, Wever LD, Gerritsma MA, Vasen HF, and Aaronson NK
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- Adult, Anxiety, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Female, Genetic Testing psychology, Heterozygote, Humans, Male, Middle Aged, Mutation, Retrospective Studies, Surveys and Questionnaires, Colonoscopy psychology, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis psychology, Genetic Predisposition to Disease, Mass Screening psychology
- Published
- 2003
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30. [Recommendations for the management of women with an increased genetic risk of gynaecological cancer].
- Author
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Verheijen RH, Boonstra H, Menko FH, de Graaff J, Vasen HF, and Kenter GG
- Subjects
- Breast Neoplasms prevention & control, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Endometrial Neoplasms prevention & control, Female, Germ-Line Mutation, Humans, Ovarian Neoplasms prevention & control, Risk Factors, Women's Health, BRCA2 Protein genetics, Breast Neoplasms genetics, Endometrial Neoplasms genetics, Genes, BRCA1, Genetic Predisposition to Disease, Ovarian Neoplasms genetics
- Abstract
About 5% of all ovarian-cancer cases are caused by a genetic predisposition, in particular as a component of the autosomal dominant hereditary breast-ovarian-cancer syndrome. This syndrome is usually due to germline mutations in the BRCA1- or BRCA2-gene. Ovarian and endometrial cancer also occur in families with hereditary non-polyposis colorectal cancer (HNPCC). This syndrome is caused by germline mutations in DNA mismatch-repair genes. Women at high risk of gynaecological cancer based upon familial clustering of disease or a demonstrated pathogenic germ-line mutation are candidates for surveillance: annual gynaecological examinations, including vaginal echoscopy and serum carcinoma antigen CA125 testing. Prophylactic surgery in the form of adnexectomy leads to a marked, but not complete, reduction of ovarian-cancer risk in high-risk cases. There is insufficient evidence to advise against the use of oral contraceptives or hormonal substitution after adnexectomy for healthy women with a genetic predisposition to breast cancer. Recommendations for surveillance and prevention should only be given after genetic-risk counselling, based on a detailed family study and DNA-based diagnosis.
- Published
- 2002
31. Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach.
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Gille JJ, Hogervorst FB, Pals G, Wijnen JT, van Schooten RJ, Dommering CJ, Meijer GA, Craanen ME, Nederlof PM, de Jong D, McElgunn CJ, Schouten JP, and Menko FH
- Subjects
- Adaptor Proteins, Signal Transducing, Base Pair Mismatch genetics, Carrier Proteins, Cohort Studies, DNA Repair genetics, Family, Female, Germ-Line Mutation, Humans, Male, MutL Protein Homolog 1, MutS Homolog 2 Protein, Nuclear Proteins, Pedigree, Polymerase Chain Reaction, Colorectal Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins, Gene Deletion, Neoplasm Proteins genetics, Proto-Oncogene Proteins genetics
- Abstract
Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatch-repair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer., (Copyright 2002 Cancer Research UK)
- Published
- 2002
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32. Histopathologic features of genetically determined ovarian cancer.
- Author
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Shaw PA, McLaughlin JR, Zweemer RP, Narod SA, Risch H, Verheijen RH, Ryan A, Menko FH, Kenemans P, and Jacobs IJ
- Subjects
- Female, Genes, BRCA1, Genes, BRCA2, Humans, Prognosis, Risk Factors, Genetic Predisposition to Disease, Germ-Line Mutation genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Inheritance of germline mutations of BRCA1 or BRCA2 genes account for approximately 10% of ovarian carcinomas, but the characterization of these genetically determined cancers is incomplete. The objective of our study was to characterize the histologic features of ovarian carcinomas associated with germline mutations of BRCA1 and BRCA2. Thirty-two ovarian carcinomas associated with germline BRCA1 or BRCA2 mutations and 40 ovarian carcinomas from patients screened as negative for germline mutations were obtained from three centers. A gynecologic pathologist, blinded to mutation status, reviewed each case, with documentation of the histologic type, Gynecologic Oncology Group (GOG) grade, architectural and nuclear grade, Silverberg grade, and mitotic activity. All BRCA1 and BRCA2 mutation-associated cases were invasive serous carcinomas, and of these 50% were GOG grade 3, 41% had an architectural grade of 3 (predominant solid architecture), 84% a nuclear grade of 3, 72% a mitotic score of 3 (>25 mitoses per 10 HPF), and 75% a Silverberg grade of 3. The differences in histologic type (p = 0.001) and Silverberg grade (p = 0.002) between these tumors and the control group were statistically significant and remained so when comparisons between BRCA carriers and noncarriers were restricted to carcinomas of serous histology alone. Ovarian carcinomas associated with germline mutations of BRCA1/BRCA2 are, in this study, invasive serous carcinomas, with a statistically significant higher histologic grade than ovarian carcinomas without BRCA mutations when using the recently proposed Silverberg grading system.
- Published
- 2002
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33. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer.
- Author
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Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, and Verheijen RH
- Subjects
- Adult, Aged, Case-Control Studies, Cyclin A metabolism, Cyclin D1 metabolism, Female, Genes, BRCA1 physiology, Genes, bcl-2 physiology, Humans, Ki-67 Antigen metabolism, Loss of Heterozygosity, Middle Aged, Ovarian Neoplasms genetics, Polymerase Chain Reaction, Precancerous Conditions genetics, Proliferating Cell Nuclear Antigen metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Tumor Suppressor Protein p53 metabolism, rho GTP-Binding Proteins metabolism, Fallopian Tubes pathology, Ovarian Neoplasms pathology, Precancerous Conditions pathology
- Abstract
The aim of this study was to investigate the occurrence of (pre)neoplastic lesions in overtly normal Fallopian tubes from women predisposed to developing ovarian carcinoma. The presence of (pre)neoplastic lesions was scored in histological specimens from 12 women with a genetically determined predisposition for ovarian cancer, of whom seven tested positive for a germline BRCA1 mutation. A control group included 13 women. Immunohistochemistry was used to determine the expression of p21, p27, p53, cyclin A, cyclin D1, bcl-2, Ki67, HER-2/neu, and the oestrogen and progesterone receptors. Loss of heterozygosity (LOH) analysis on the BRCA1 locus was also assessed on dysplastic tissue by PCR studies. Of the 12 women with a predisposition for ovarian cancer, six showed dysplasia, including one case of severe dysplasia. Five harboured hyperplastic lesions and in one woman no histological aberrations were found in the Fallopian tube. No hyperplastic, dysplastic or neoplastic lesions were detected in the Fallopian tubes of control subjects. In the cases studied, morphologically normal tubal epithelium contained a higher proportion of Ki67-expressing cells (p=0.005) and lower fractions of cells expressing p21 (p<0.0001) and p27 (p=0.006) than in the control group. Even higher fractions of proliferating cells were found in dysplastic areas (p=0.07) and accumulation of p53 was observed in the severely dysplastic lesion. Expression patterns of other proteins studied, including the hormone receptors, were similar in cases and controls. One subject, a germline BRCA1 mutation carrier, showed loss of the wild-type BRCA1 allele in the severely dysplastic lesion. In conclusion, the Fallopian tubes of women predisposed to developing ovarian cancer frequently harbour dysplastic changes, accompanied by changes in cell-cycle and apoptosis-related proteins, indicating an increased risk of developing tubal cancer., (Copyright 2001 John Wiley & Sons, Ltd.)
- Published
- 2001
- Full Text
- View/download PDF
34. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families.
- Author
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Vasen HF, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, Taal BG, Moller P, and Wijnen JT
- Subjects
- Adaptor Proteins, Signal Transducing, Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Base Pair Mismatch genetics, Carrier Proteins, Child, Child, Preschool, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, DNA Repair genetics, Female, Heterozygote, Humans, Male, Middle Aged, MutL Protein Homolog 1, MutS Homolog 2 Protein, Netherlands epidemiology, Nuclear Proteins, Registries, Risk Factors, Sex Factors, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins, Mutation, Neoplasm Proteins genetics, Proto-Oncogene Proteins genetics
- Abstract
Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations., Patients and Methods: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives., Results: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant., Conclusion: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.
- Published
- 2001
- Full Text
- View/download PDF
35. Survival analysis in familial ovarian cancer, a case control study.
- Author
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Zweemer RP, Verheijen RH, Coebergh JW, Jacobs IJ, van Diest PJ, Gille JJ, Skates S, Menko FH, Ten Kate LP, and Kenemans P
- Subjects
- BRCA1 Protein genetics, BRCA2 Protein genetics, Case-Control Studies, Female, Germ-Line Mutation, Humans, Middle Aged, Pedigree, Survival Rate, Ovarian Neoplasms genetics, Ovarian Neoplasms mortality
- Abstract
Objective: familial ovarian cancer patients have been found to differ from sporadic cases, clinically as well as in the molecular make-up of the tumour. Here, a case control study is performed to analyse potential differences in survival., Study Design: 31 families with a strong history of ovarian and/or breast cancer presenting to a family cancer clinic 44 ovarian cancer patients were included. Each patient was matched for age and stage with controls from a cancer registry. Survival rates and the effect of several prognostic factors were analysed., Results: median survival in the study group differed significantly from controls. A survival benefit for familial cases was maintained up to 5 years after diagnosis. Long-term survival was equally poor in both groups., Conclusion: the difference in survival between familial ovarian cancer cases and matched controls may reflect differences in biological behaviour. This may have important implications for the management and prevention of familial ovarian cancer.
- Published
- 2001
- Full Text
- View/download PDF
36. Comparative genomic hybridization of microdissected familial ovarian carcinoma: two deleted regions on chromosome 15q not previously identified in sporadic ovarian carcinoma.
- Author
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Zweemer RP, Ryan A, Snijders AM, Hermsen MA, Meijer GA, Beller U, Menko FH, Jacobs IJ, Baak JP, Verheijen RH, Kenemans P, and van Diest PJ
- Subjects
- BRCA2 Protein genetics, Female, Genes, BRCA1, Genetic Markers, Humans, Nucleic Acid Hybridization, Chromosomes, Human, Pair 15, Ovarian Neoplasms genetics, Sequence Deletion
- Abstract
The vast majority of familial ovarian cancers harbor a germline mutation in either the breast cancer gene BRCA1 or BRCA2 tumor suppressor genes. However, mutations of these genes in sporadic ovarian cancer are rare. This suggests that in contrast to hereditary disease, BRCA1 and BRCA2 are not commonly involved in sporadic ovarian cancer and may indicate that there are two distinct pathways for the development of ovarian cancer. To characterize further differences between hereditary and sporadic cancers, the comparative genomic hybridization technique was employed to analyze changes in copy number of genetic material in a panel of 36 microdissected hereditary ovarian cancers. Gains at 8q23-qter (18 of 36, 5 cases with high-level amplifications), 3q26.3-qter (18 of 36, 2 cases with high-level amplifications), 11q22 (11 of 36) and 2q31-32 (8 of 36) were most frequent. Losses most frequently occurred (in decreasing order of frequency) on 8p21-pter (23 of 36), 16q22-pter (19 of 36), 22q13 (19 of 36), 9q31-33 (16 of 36), 12q24 (16 of 36), 15q11-15 (16 of 36), 17p12-13 (14 of 36), Xp21-22 (14 of 36), 20q13 (13 of 36), 15q24-25 (12 of 36), and 18q21 (12 of 36). Comparison with the literature revealed that the majority of these genetic alterations are also common in sporadic ovarian cancer. Deletions of 15q11-15, 15q24-25, 8p21-ter, 22q13, 12q24 and gains at 11q22, 13q22, and 17q23-25, however, appear to be specific to hereditary ovarian cancer. Aberrations at 15q11-15 and 15q24-25 have not yet been described in familial ovarian cancer. In these regions, important tumor suppressor genes, including the hRAD51 gene, are located. These and other yet unknown suppressor genes may be involved in a specific carcinogenic pathway for familial ovarian cancer and may explain the distinct clinical presentation and behavior of familial ovarian cancer.
- Published
- 2001
- Full Text
- View/download PDF
37. Jan Peutz, Harold Jeghers and a remarkable combination of polyposis and pigmentation of the skin and mucous membranes.
- Author
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Keller JJ, Offerhaus GJ, Giardiello FM, and Menko FH
- Subjects
- History, 19th Century, History, 20th Century, Humans, Mucous Membrane pathology, Netherlands, Skin Pigmentation, United States, Peutz-Jeghers Syndrome history
- Published
- 2001
- Full Text
- View/download PDF
38. [Patient with Peutz-Jeghers syndrome and liver metastases from an unknown primary tumor].
- Author
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van der Werf G, Menko FH, Gille JJ, van Diest PJ, and van Groeningen CJ
- Subjects
- Adenocarcinoma etiology, Adenocarcinoma secondary, Adult, Genetic Predisposition to Disease, Hamartoma etiology, Hamartoma pathology, Humans, Intestinal Neoplasms etiology, Intestinal Neoplasms pathology, Liver Neoplasms etiology, Liver Neoplasms secondary, Male, Neoplasms, Unknown Primary genetics, Peutz-Jeghers Syndrome genetics, Thrombophlebitis etiology, Peutz-Jeghers Syndrome complications, Peutz-Jeghers Syndrome pathology
- Abstract
In a 35-year old man with deep venous thrombosis liver metastases of an adenocarcinoma were observed. The primary tumour was not found. The patient had pigmentations on the lips and hamartomatous polyposis of the intestine. These findings indicate Peutz-Jeghers syndrome. In this syndrome there is an increased risk of, notably, gastrointestinal malignancy at an early age. Recent investigations have shown that Peutz-Jeghers syndrome is associated with a mutation in the STK11 gene on chromosome 19.
- Published
- 2000
39. Molecular evidence linking primary cancer of the fallopian tube to BRCA1 germline mutations.
- Author
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Zweemer RP, van Diest PJ, Verheijen RH, Ryan A, Gille JJ, Sijmons RH, Jacobs IJ, Menko FH, and Kenemans P
- Subjects
- Adult, Aged, Fallopian Tube Neoplasms pathology, Female, Humans, Middle Aged, Pedigree, Prognosis, Risk Assessment, Fallopian Tube Neoplasms genetics, Genes, BRCA1 genetics, Genetic Predisposition to Disease, Germ-Line Mutation
- Abstract
Objectives: BRCA1 and BRCA2 germline mutations increase the risk of ovarian and breast cancer. Fallopian tube cancer has occasionally been observed in breast-ovarian cancer families. At our family cancer clinic we recently encountered two cases of Fallopian tube cancer within two families harboring a BRCA1 germline mutation. To study the relationship between Fallopian tube cancer and BRCA1 mutations, a histopathological reevaluation and molecular analysis were performed., Methods: Medical and histopathological reports of the Fallopian tube cancer cases as well as archival tissue blocks were retrieved. The histopathological diagnoses were reevaluated. We investigated whether patients with Fallopian tube cancer had been carriers of a BRCA germline mutation. In addition we investigated whether loss of the wild-type allele had occurred in the tumor., Results: In 2 of 23 families with a known BRCA1 mutation from our family cancer clinic, a case of Fallopian tube cancer was reported. Histological reevaluation confirmed the diagnosis of Fallopian tube cancer in both cases. In one case Fallopian tube cancer may have been part of a multifocal primary malignancy. In both patients the presence of a BRCA1 mutation was confirmed in the germline. Furthermore, we showed loss of the wild-type BRCA1 allele in both tumors., Conclusions: These findings provide the first molecular evidence that Fallopian tube cancer may be due to germline mutations in BRCA1. This may have important consequences for the preferred method of prophylactic oophorectomy in BRCA1 mutation carriers., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
- View/download PDF
40. Familial breast cancer: clinical services in The Netherlands.
- Author
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Menko FH
- Subjects
- Adult, Aged, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Breast Neoplasms prevention & control, Cancer Care Facilities statistics & numerical data, DNA Mutational Analysis, Female, Genetic Counseling statistics & numerical data, Genetics, Medical, Hospitals, University organization & administration, Hospitals, University statistics & numerical data, Humans, Mammography statistics & numerical data, Mass Screening organization & administration, Mass Screening statistics & numerical data, Middle Aged, Neoplastic Syndromes, Hereditary epidemiology, Neoplastic Syndromes, Hereditary genetics, Netherlands, Oncogenes, Pedigree, Referral and Consultation, Risk, Workforce, Breast Neoplasms therapy, Cancer Care Facilities organization & administration, Genetic Counseling organization & administration, Neoplastic Syndromes, Hereditary therapy
- Published
- 1999
- Full Text
- View/download PDF
41. [Two patients with Muir-Torre syndrome].
- Author
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Vermeer MH, Neering H, and Menko FH
- Subjects
- Adenocarcinoma, Sebaceous genetics, Aged, Colorectal Neoplasms complications, Endometrial Neoplasms complications, Female, Humans, Keratoacanthoma diagnosis, Male, Middle Aged, Neoplasms, Multiple Primary genetics, Sebaceous Gland Neoplasms genetics, Skin Diseases diagnosis, Adenocarcinoma, Sebaceous diagnosis, Germ-Line Mutation, Neoplasms, Multiple Primary diagnosis, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics, Sebaceous Gland Neoplasms diagnosis
- Published
- 1999
42. [Periodic colonoscopic examinations of persons with a positive family history for colorectal cancer. Work Group 'Hereditary non-polyposis- colon-rectum cancers'].
- Author
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Vasen HF, Nagengast FM, Griffioen G, Kleibeuker JH, Menko FH, and Taal BG
- Subjects
- Aged, Colorectal Neoplasms epidemiology, Colorectal Neoplasms genetics, Cost-Benefit Analysis, Female, Genetic Predisposition to Disease epidemiology, Humans, Male, Middle Aged, Netherlands epidemiology, Risk, Colonoscopy, Colorectal Neoplasms prevention & control, Mass Screening methods
- Abstract
Individuals with one first-degree relative with colorectal cancer diagnosed before age 45 years and those with two first-degree relatives with colorectal cancer run a significantly increased risk (relative risk: 4-6) of developing colorectal cancer. Based on calculation of the mortality due to colorectal cancer for the age group 50-70 years (which is higher than the mortality due to breast cancer) surveillance may be justified, e.g. by colonoscopy at 5-year intervals from the age of 45-50. The total number of people in the Netherlands in this high risk group is estimated at 10,000. The authors conclude that prospective studies are needed to assess the cost-effectiveness of such a programme.
- Published
- 1999
43. [Genetics of colorectal cancer. II. Hereditary background of sporadic and familial colorectal cancer].
- Author
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Menko FH, Griffioen G, Wijnen JT, Tops CM, Fodde R, and Vasen HF
- Subjects
- Adenoma genetics, Adolescent, Adult, Aged, Base Pair Mismatch, Carcinoma genetics, Child, Child, Preschool, Colorectal Neoplasms epidemiology, Colorectal Neoplasms prevention & control, DNA Mutational Analysis, DNA Repair genetics, Female, Genes, MCC genetics, Humans, Male, Microsatellite Repeats, Middle Aged, Netherlands epidemiology, Syndrome, Uterine Neoplasms genetics, Colorectal Neoplasms genetics, Genetic Predisposition to Disease genetics, Germ-Line Mutation genetics, Neoplasms, Multiple Primary genetics
- Abstract
About 15% of patients with colorectal cancer have a positive family history: 5% have hereditary colorectal cancer (hereditary non-polyposis colorectal carcinoma (HNPCC), familial adenomatous polyposis (FAP) or some other hereditary syndrome), while in 10% no clear hereditary pattern can be recognized ('familial colorectal cancer'). In sporadic and in familial intestinal cancer, a demonstrable hereditary predisposition may undoubtedly exist. HNPCC is often characterized by microsatellite instability, i.e. an increased number of short DNA sequences in the DNA indicating a disorder in DNA repair and a mutation in a DNA 'mismatch repair' (MMR) gene. Indicative of hereditary bowel cancer on the basis of such an MMR gene mutation are: (a) presence of bowel cancer in > or = 3 relatives, (b) early age at the time of the diagnosis of 'bowel cancer', (c) multiple primary bowel tumours, (d) uterine cancer in the family and (e) bowel and uterine cancer in a woman. Recent data demand a new subdivision of hereditary bowel cancer, based upon both the clinical picture and the results of DNA-tests. The genetic alterations in colonic adenomas and carcinomas are known to a large extent. In future these insights may be important in clinical practice, such as a more individual determination of the patient's prognosis and accordingly, of the treatment and follow-up.
- Published
- 1999
44. [Genetics of colorectal cancer. I. Non-polyposis and polyposis forms of hereditary colorectal cancer].
- Author
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Menko FH, Griffioen G, Wijnen JT, Tops CM, Fodde R, and Vasen HF
- Subjects
- Adenomatous Polyposis Coli epidemiology, Adenomatous Polyps genetics, Adenomatous Polyps surgery, Adolescent, Adult, Aged, Aged, 80 and over, Brain Neoplasms genetics, Child, Child, Preschool, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, Female, Genes, APC genetics, Genetic Carrier Screening, Germ-Line Mutation genetics, Hamartoma Syndrome, Multiple epidemiology, Hamartoma Syndrome, Multiple genetics, Humans, Male, Middle Aged, Netherlands epidemiology, Peutz-Jeghers Syndrome epidemiology, Adenomatous Polyposis Coli genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Neoplasms, Multiple Primary genetics, Peutz-Jeghers Syndrome genetics
- Abstract
About 5% of colorectal cancer cases are due to an autosomal dominant genetic predisposition with high penetrance. In this condition, the patient is carrier of a pathogenic gene mutation present in all body cells which can be transmitted to descendants, a so-called germ line mutation. The mutation is usually present in a tumour suppressor gene. Three subgroups of hereditary colorectal cancer can be distinguished on the basis of the clinical characteristics: (a) syndromes without polyposis (mostly hereditary non-polyposis colorectal carcinoma; HNPCC), (b) syndromes with adenomatous polyposis (mostly familial adenomatous polyposis; FAP) and (c) syndromes with hamartomatous polyposis. Recently, the main gene defects which underlie these syndromes were identified. Consequently, it is possible in approximately half the families with HNPCC or FAP in patients with colorectal cancer to demonstrate the causative gene defect and subsequently, by blood testing of healthy relatives to determine who is and is not a carrier of this hereditary condition. Thus, preventive measures can be directed toward family members with a demonstrable high risk of large bowel cancer.
- Published
- 1999
45. Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations.
- Author
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Zweemer RP, Shaw PA, Verheijen RM, Ryan A, Berchuck A, Ponder BA, Risch H, McLaughlin JR, Narod SA, Menko FH, Kenemans P, and Jacobs IJ
- Subjects
- BRCA2 Protein, Female, Germ-Line Mutation, Humans, Neoplastic Syndromes, Hereditary genetics, Ovarian Neoplasms genetics, Genes, BRCA1, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Ovarian Neoplasms metabolism, Transcription Factors genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Background: Mutations in the BRCA1 or BRCA2 genes are responsible for up to 95% of hereditary ovarian cancer cases. Both genes function as tumour suppressor genes, and development of a cancer is thought to require an accumulation of somatic genetic events in addition to the inherited germline predisposition. It is unknown whether these somatic events in BRCA associated ovarian cancer are similar to or distinct from those in sporadic cases. The most frequent somatic genetic event in ovarian cancer is a mutation of the p53 gene., Aim: To study the role of p53 in hereditary ovarian cancer, by analysing accumulation of the p53 protein in ovarian cancers which occurred in BRCA1 or BRCA2 germline mutation carriers and comparing the results with a panel of ovarian cancers from patients who tested negative for both BRCA1 and BRCA2., Methods: The study group consisted of 39 ovarian cancer patients in whom a BRCA mutation had been confirmed previously. p53 Immunohistochemistry was performed on archival tissue using a standard microwave antigen retrieval technique. The rate of p53 accumulation was compared with 40 ovarian cancer cases who tested negative for BRCA1 and BRCA2 germline mutations., Results: P53 Accumulation was similar in BRCA related ovarian cancers and BRCA negative controls. Overall 27 of 39 BRCA1 or BRCA2 positive cases (69%) had evidence of p53 accumulation, compared with 24 of 40 invasive ovarian cancer cases (60%) which tested negative for BRCA1 and BRCA2 germline mutations. BRCA1 related ovarian cancers showed p53 accumulation in 22 of 30 cases (73%); p53 accumulation was present in five of nine BRCA2 related ovarian cancers., Conclusions: In addition to germline BRCA1 and BRCA2 mutations, somatic p53 alterations leading to p53 accumulation are an important event in hereditary ovarian cancer and are as frequent as in non-BRCA-related ovarian cancer.
- Published
- 1999
- Full Text
- View/download PDF
46. Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2.
- Author
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Ligtenberg MJ, Hogervorst FB, Willems HW, Arts PJ, Brink G, Hageman S, Bosgoed EA, Van der Looij E, Rookus MA, Devilee P, Vos EM, Wigbout G, Struycken PM, Menko FH, Rutgers EJ, Hoefsloot EH, Mariman EC, Brunner HG, and Van 't Veer LJ
- Subjects
- Adult, BRCA2 Protein, Breast Neoplasms pathology, DNA Mutational Analysis, Family, Female, Genes, BRCA1, Genetic Markers genetics, Genetic Predisposition to Disease, Humans, Middle Aged, Breast Neoplasms genetics, Germ-Line Mutation, Neoplasm Proteins genetics, Ovarian Neoplasms genetics, Transcription Factors genetics
- Abstract
For families with a small number of cases of breast and/or ovarian cancer, limited data are available to predict the likelihood of genetic predisposition due to mutations in BRCA1 or BRCA2. In 104 families with three or more affected individuals (average 3.8) seeking counselling at family cancer clinics, mutation analysis was performed in the open reading frame of BRCA1 and BRCA2 by the protein truncation test and mutation-specific assays. In 31 of the 104 families tested, mutations were detected (30%). The majority of these mutations (25) occurred in BRCA1. Mutations were detected in 15 out of 25 families (60%) with both breast and ovarian cancer and in 16 out of 79 families (20%) with exclusively cases of breast cancer. Thus, an ovarian cancer case strongly predicted finding a mutation (P < 0.001). Within the group of small breast-cancer-only families, a bilateral breast cancer case or a unilateral breast cancer case diagnosed before age 40 independently predicted finding a BRCA1 or BRCA2 mutation (P = 0.005 and P = 0.02, respectively). Therefore, even small breast/ovarian cancer families with at least one case of ovarian cancer, bilateral breast cancer, or a case of breast cancer diagnosed before age 40, should be referred for mutation screening.
- Published
- 1999
- Full Text
- View/download PDF
47. Differences between hereditary and sporadic ovarian cancer.
- Author
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Zweemer RP, Verheijen RH, Menko FH, Gille JJ, van Diest PJ, Coebergh JW, Shaw PA, Jacobs IJ, and Kenemans P
- Subjects
- Age Factors, BRCA2 Protein, Female, Genes, BRCA1 genetics, Genes, p53 genetics, Humans, Mutation, Neoplasm Proteins genetics, Neoplasm Staging, Ovarian Neoplasms epidemiology, Registries, Survival Rate, Transcription Factors genetics, Ovarian Neoplasms genetics
- Abstract
Approximately 5% of ovarian cancer cases can be attributed to an autosomal dominant inheritance factor. The majority of these cases are due to germline mutations in the BRCA1 or BRCA2 tumoursupressor genes. Patients with hereditary disease do not exhibit pathognomonic features that would allow distinction from non-hereditary (sporadic) cases of ovarian cancer. Our studies are aimed at identifying clinical, histopathological as well as molecular genetic differences between hereditary and sporadic ovarian cancer. Clinical studies of the ovarian cancer cases in 31 families revealed differences regarding age at onset and stage as well as in survival compared with cancer registry controls. The molecular studies of hereditary ovarian cancer are still underway and some preliminary data is discussed.
- Published
- 1999
- Full Text
- View/download PDF
48. A cost-effectiveness analysis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers.
- Author
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Vasen HF, van Ballegooijen M, Buskens E, Kleibeuker JK, Taal BG, Griffioen G, Nagengast FM, Menko FH, and Meera Khan P
- Subjects
- Adult, Aged, Colonoscopy economics, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis economics, Cost-Benefit Analysis, Heterozygote, Humans, Male, Middle Aged, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Genetic Testing economics
- Abstract
Background: It has been estimated that the prevalence of carriers of a mutated mismatch repair (MMR) gene among the general population in Western countries is between 5 and 50 per 10,000. These carriers have a risk of >85% of developing colorectal carcinoma (CRC) and therefore need careful follow-up. The objective of this study was to analyze the cost-effectiveness of CRC surveillance of carriers of a mutated MMR gene., Methods: The authors constructed a model to estimate the potential health effects (life expectancy) and healthcare costs of two strategies: 1) surveillance, with colonoscopy every 2-3 years, and 2) no CRC surveillance. Estimates of the lifetime risk of developing CRC and the stage distribution of CRC for symptomatic patients were derived from the Dutch hereditary nonpolyposis colorectal carcinoma (HNPCC) registry. The CRC stage specific relative survival rates and the effectiveness of surveillance in preventing or detecting cancer early were based on Finnish studies. The costs of surveillance and treatment were derived from recent American studies., Results: The results showed that 1) surveillance of gene carriers led to an increase in life expectancy of 7 years, and 2) the costs of surveillance under a wide range of assumptions are less than the costs of no CRC surveillance., Conclusions: CRC surveillance of HNPCC gene carriers appears to be effective and considerably less costly than no CRC surveillance and therefore deserves to be supported by governmental agencies and health insurance organizations.
- Published
- 1998
49. Clinical and genetic evaluation of thirty ovarian cancer families.
- Author
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Zweemer RP, Verheijen RH, Gille JJ, van Diest PJ, Pals G, and Menko FH
- Subjects
- Adenocarcinoma epidemiology, Alleles, Chromosome Mapping, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 17, Cluster Analysis, DNA Mutational Analysis, DNA Primers analysis, DNA Primers chemistry, DNA Primers genetics, DNA, Neoplasm analysis, DNA, Neoplasm chemistry, DNA, Neoplasm genetics, Exons genetics, Female, Humans, Male, Middle Aged, Neoplasm Staging, Ovarian Neoplasms epidemiology, Pedigree, Prevalence, Adenocarcinoma genetics, Adenocarcinoma pathology, Family Health, Germ-Line Mutation genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Objectives: Our purpose was to determine the prevalence of BRCA1 and BRCA2 germline mutations among patients from ovarian cancer families and to evaluate age at diagnosis, histologic diagnosis, and International Federation of Gynecology and Obstetrics stage in this group., Study Design: We reviewed 50 ovarian cancer patients from 30 ovarian cancer families and compared relevant clinical characteristics with those of a cancer registry reference group. BRCA1 (exons 2 to 24) and BRCA2 (exon 11) germline mutations were detected by a protein truncation test and sequencing of BRCA1 exon 2 (185delAG mutation) in 25 of the 30 families., Results: Ten (40%) of 25 families tested revealed a germline BRCA1 or BRCA2 mutation. Patients with ovarian cancer from the study group were young with an advanced International Federation of Gynecology and Obstetrics stage at diagnosis and had a relatively high frequency of serous adenocarcinoma., Conclusion: Direct mutation analysis of BRCA1 and BRCA2 revealed a high frequency of germline mutations in ovarian cancer families. Some clinical characteristics of hereditary ovarian cancer may differ from those of sporadic disease.
- Published
- 1998
- Full Text
- View/download PDF
50. Familial and hereditary non-polyposis colorectal cancer: issues relevant for surgical practice.
- Author
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Menko FH, Wijnen JT, Vasen HF, Sijmons RH, and Khan PM
- Subjects
- Adenomatous Polyps diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, DNA, Neoplasm analysis, Female, Humans, Male, Pedigree, Adenomatous Polyps surgery, Colorectal Neoplasms, Hereditary Nonpolyposis surgery
- Abstract
About 15% of patients with colorectal cancer report a family history of this disease. An estimated 1%-5% of patients have hereditary non-polyposis colorectal cancer (HNPCC). Recently, DNA mismatch repair genes associated with this syndrome were identified. For about 50% of families in which HNPCC occurs, DNA-based diagnosis and presymptomatic DNA testing are now feasible. Diagnosis of a hereditary tumour syndrome is relevant for both the patient with cancer and his or her close relatives. The complexities of family studies warrant the forming of a multidisciplinary team which may choose to work within a specialized cancer family clinic.
- Published
- 1998
- Full Text
- View/download PDF
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