23 results on '"Letteboer, Tom G W"'
Search Results
2. Delineating genotype and parent‐of‐origin effect on the phenotype in MSH6‐associated Lynch syndrome.
- Author
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van der Werf‐'t Lam, Anne‐Sophie, Rodriguez‐Girondo, Mar, Villasmil, Mandy, Tops, Carli M., van Hest, Liselotte, Gille, Hans J. P., Duijkers, Floor A. M., Wagner, Anja, Eikenboom, Ellis, Letteboer, Tom G. W., de Jong, Mirjam M., Bajwa‐ten Broeke, Sanne W., Bleeker, Fonnet, Gomez Garcia, Encarna B., Dominguez‐Valentin, Mev, Møller, Pal, Suerink, Manon, and Nielsen, Maartje
- Published
- 2024
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3. SNP association study in PMS2-associated Lynch syndrome
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ten Broeke, Sanne W., Elsayed, Fadwa A., Pagan, Lisa, Olderode-Berends, Maran J. W., Garcia, Encarna Gomez, Gille, Hans J. P., van Hest, Liselot P., Letteboer, Tom G. W., van der Kolk, Lizet E., Mensenkamp, Arjen R., van Os, Theo A., Spruijt, Liesbeth, Redeker, Bert J. W., Suerink, Manon, Vos, Yvonne J., Wagner, Anja, Wijnen, Juul T., Steyerberg, E. W., Tops, Carli M. J., van Wezel, Tom, and Nielsen, Maartje
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- 2018
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4. Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans
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Kawasaki, Kyoko, Freimuth, Julia, Meyer, Dominique S., Lee, Marie M., Tochimoto-Okamoto, Akiko, Benzinou, Michael, Clermont, Frederic F., Wu, Gloria, Roy, Ritu, Letteboer, Tom G. W., van Amstel, Johannes Kristian Ploos, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaeten, Westermann, Cornelius J. J., Coffey, Robert J., and Akhurst, Rosemary J.
- Published
- 2014
5. Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis
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Hes, Frederik J, Ruano, Dina, Nieuwenhuis, Marry, Tops, Carli M, Schrumpf, Melanie, Nielsen, Maartje, Huijts, Petra E A, Wijnen, Juul T, Wagner, Anja, García, Encarna B Gómez, Sijmons, Rolf H, Menko, Fred H, Letteboer, Tom G W, Hoogerbrugge, Nicoline, Harryvan, Jan, Kampman, Ellen, Morreau, Hans, Vasen, Hans F A, and van Wezel, Tom
- Published
- 2014
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6. A Pulmonary Right-to-Left Shunt in Patients With Hereditary Hemorrhagic Telangiectasia Is Associated With an Increased Prevalence of Migraine*
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Post, Martijn C., Letteboer, Tom G. W., Mager, Johannes J., Plokker, Thijs H., Kelder, Johannes C., and Westermann, Cornelius J. J.
- Published
- 2005
7. CORRIGENDUM: The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers
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Suerink, Manon, Van Der Klift, Heleen M., Ten Broeke, Sanne W., Dekkers, Olaf M., Bernstein, Inge, Munar, Gabriel Capell, Gomez Garcia, Encarna, Hoogerbrugge, Nicoline, Letteboer, Tom G W, Menko, Fred H., Lindblom, Annika, Mensenkamp, Arjen, Moller, Pal, Van Os, Theo A., Rahner, Nils, Redeker, Bert J W, Olderode-Berends, M. J W, Spruijt, Liesbeth, Vos, Yvonne J., Wagner, Anja, Morreau, Hans, Hes, Frederik J., Vasen, Hans F A, Tops, Carli M., Wijnen, Juul T., and Nielsen, Maartje
- Subjects
Published Erratum ,Genetics(clinical) - Published
- 2016
8. The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect.
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ten Broeke, Sanne W., Rodríguez-Girondo, Mar, Suerink, Manon, Aretz, Stefan, Bernstein, Inge, Capellá, Gabriel, Engel, Christoph, Gomez-Garcia, Encarna B., van Hest, Liselot P., von Knebel Doeberitz, Magnus, Lagerstedt-Robinson, Kristina, Letteboer, Tom G. W., Moller, Pal, van Os, Theo A., Pineda, Marta, Rahner, Nils, Olderode-Berends, Maran J. W., von Salomé, Jenny, Schackert, Hans K., and Spruijt, Liesbeth
- Abstract
Background: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. Methods: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. Results: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. Conclusions: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. Impact: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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9. Cancer Risks for PMS2-Associated Lynch Syndrome.
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ten Broeke, Sanne W., van der Klift, Heleen M., Tops, Carli M.J., Aretz, Stefan, Bernstein, Inge, Buchanan, Daniel D., de la Chapelle, Albert, Capella, Gabriel, Clendenning, Mark, Engel, Christoph, Gallinger, Steven, Gomez Garcia, Encarna, Figueiredo, Jane C., Haile, Robert, Hampel, Heather L., Hopper, John L., Hoogerbrugge, Nicoline, von Knebel Doeberitz, Magnus, Le Marchand, Loic, and Letteboer, Tom G. W.
- Published
- 2018
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10. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.
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Jansen, Anne M. L., Geilenkirchen, Marije A., van Wezel, Tom, Jagmohan-Changur, Shantie C., Ruano, Dina, van der Klift, Heleen M., van den Akker, Brendy E. W. M., Laros, Jeroen F. J., van Galen, Michiel, Wagner, Anja, Letteboer, Tom G. W., Gómez-García, Encarna B., Tops, Carli M. J., Vasen, Hans F., Devilee, Peter, Hes, Frederik J., Morreau, Hans, and Wijnen, Juul T.
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HEREDITARY nonpolyposis colorectal cancer ,COLON cancer ,GENOMICS ,DNA ,SOMATIC cells ,GENETICS - Abstract
Background and Aims: Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. Methods: Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. Results: Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). Conclusions: This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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11. Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14.
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Letteboer, Tom G. W., Benzinou, Michael, Merrick, Christopher B., Quigley, David A., Kechen Zhau, Kim, Il-Jin, To, Minh D., Jablons, David M., van Amstel, Johannes K. P., Westermann, Cornelius J. J., Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Berg, Jonathan H., Balmain, Allan, and Akhurst, Rosemary J.
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HUMAN genetic variation ,HUMAN variation (Biology) ,ALLELES ,ARTERIOVENOUS malformation ,BLOOD-vessel abnormalities - Abstract
HHT shows clinical variability within and between families. Organ site and prevalence of arteriovenous malformations (AVMs) depend on the HHT causative gene and on environmental and genetic modifiers. We tested whether variation in the functional ENG allele, inherited from the unaffected parent, alters risk for pulmonary AVM in HHT1 mutation carriers who are ENG haploinsufficient. Genetic association was found between rs10987746 of the wild type ENG allele and presence of pulmonary AVM [relative risk = 1.3 (1.0018-1.7424)]. The rs10987746-C at-risk allele associated with lower expression of ENG RNA in a panel of human lymphoblastoid cell lines (P = 0.004). Moreover, in angiogenically active human lung adenocarcinoma tissue, but not in uninvolved quiescent lung, rs10987746-C was correlated with expression of PTPN14 (P = 0.004), another modifier of HHT. Quantitative TAQMAN expression analysis in a panel of normal lung tissues from 69 genetically heterogeneous inter-specific backcross mice, demonstrated strong correlation between expression levels of Eng, Acvrl1, and Ptpn14 (r2 12 = 0.75-0.9, P < 1 x 10
-12 ), further suggesting a direct or indirect interaction between these three genes in lung in vivo. Our data indicate that genetic variation within the single functional ENG gene influences quantitative and/or qualitative differences in ENG expression that contribute to risk of pulmonary AVM in HHT1, and provide correlative support for PTPN14 involvement in endoglin/ALK1 lung biology in vivo. PTPN14 has been shown to be a negative regulator of Yap/Taz signaling, which is implicated in mechanotransduction, providing a possible molecular link between endoglin/ALK1 signaling and mechanical stress. EMILIN2, which showed suggestive genetic association with pulmonary AVM, is also reported to interact with Taz in angiogenesis. Elucidation of the molecular mechanisms regulating these interactions in endothelial cells may ultimately provide more rational choices for HHT therapy. [ABSTRACT FROM AUTHOR]- Published
- 2015
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12. Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk.
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ten Broeke, Sanne W., Brohet, Richard M., Tops, Carli M., van der Klift, Heleen M., Velthuizen, Mary E., Bernstein, Inge, Munar, Gabriel Capellá, Gomez Garcia, Encarna, Hoogerbrugge, Nicoline, Letteboer, Tom G. W., Menko, Fred H., Lindblom, Annika, Mensenkamp, Arjen R., Moller, Pal, van Os, Theo A., Rahner, Nils, Redeker, Bert J. W., Sijmons, Rolf H., Spruijt, Liesbeth, and Suerink, Manon
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- 2015
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13. Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans.
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Kyoko Kawasaki, Freimuth, Julia, Meyer, Dominique S., Lee, Marie M., Akiko Tochimoto-Okamoto, Benzinou, Michael, Clermont, Frederic F., Wu, Gloria, Roy, Ritu, Letteboer, Tom G. W., van Amstel, Johannes Kristian Ploos, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaeten, Westermann, Cornelius J. J., Coffey Jr., Robert J., and Akhurst, Rosemary J.
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HAPLOTYPES ,GERM cells ,PROGENITOR cells ,HUMAN genetic variation ,MICE genetics ,GENETIC polymorphisms ,NEOVASCULARIZATION - Abstract
Outcome of TGFβ1 signaling is context dependent and differs between individuals due to germ-line genetic variation. To explore innate genetic variants that determine differential outcome of reduced TGFβ1 signaling, we dissected the modifier locus Tgfbm3, on mouse chromosome 12. On a NIH/OlaHsd genetic background, the Tgfbm3b
C57 haplotype suppresses prenatal lethality of Tgfb1-/- embryos and enhances nuclear accumulation of mothers against decapentaplegic homolog 2 (Smad2) in embryonic cells. Amino acid polymorphisms within a disintegrin and metalloprotease 17 (Adam17) can account, at least in part, for this Tgfbm3b effect. ADAM17 is known to down-regulate Smad2 signaling by shedding the extracellular domain of TGFβRI, and we show that the C57 variant is hypomorphic for down-regulation of Smad2/3-driven transcription. Genetic variation at Tgfbm3 or pharmacological inhibition of ADAM17, modulates postnatal circulating endothelial progenitor cell (CEPC) numbers via effects on TGFβRI activity. Because CEPC numbers correlate with angiogenic potential, this suggests that variant Adam17 is an innate modifier of adult angiogenesis, acting through TGFβR1. To determine whether human ADAM17 is also polymorphic and interacts with TGFβ signaling in human vascular disease, we investigated hereditary hemorrhagic telangiectasia (HHT), which is caused by mutations in TGFβ/bone morphogenetic protein receptor genes, ENG, encoding endoglin (HHT1), or ACVRL1 encoding ALK1 (HHT2), and considered a disease of excessive abnormal angiogenesis. HHT manifests highly variable incidence and severity of clinical features, ranging from small mucocutaneous telangiectases to life-threatening visceral and cerebral arteriovenous malformations (AVMs). We show that ADAM17 SNPs associate with the presence of pulmonary AVM in HHT1 but not HHT2, indicating genetic variation in ADAM17 can potentiate a TGFβ-regulated vascular disease. [ABSTRACT FROM AUTHOR]- Published
- 2014
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14. Risks of Less Common Cancers in Proven Mutation Carriers With Lynch Syndrome.
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Engel, Christoph, Loeffler, Markus, Steinke, Verena, Rahner, Nils, Holinski-Feder, Elke, Dietmaier, Wolfgang, Schackert, Hans K., Goergens, Heike, von Knebel Doeberitz, Magnus, Goecke, Timm O., Schmiegel, Wolff, Buettner, Reinhard, Moeslein, Gabriela, Letteboer, Tom G. W., García, Encarna Gómez, Hes, Frederik J., Hoogerbrugge, Nicoline, Menko, Fred H., van Os, Theo A. M., and Sijmons, Rolf H.
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- 2012
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15. Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers.
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van der Werf-'t Lam AS, Terlouw D, Tops CM, van Kan MS, van Hest LP, Gille HJP, Duijkers FAM, Wagner A, Eikenboom EL, Letteboer TGW, de Jong MM, Bajwa-Ten Broeke SW, Bleeker FE, Gomez Garcia EB, de Wind N, van Wezel JT, Morreau H, Suerink M, and Nielsen M
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- Female, Humans, Microsatellite Repeats, Microsatellite Instability, DNA Mismatch Repair genetics, DNA-Binding Proteins genetics, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, Colonic Neoplasms genetics, Endometrial Neoplasms genetics, Colorectal Neoplasms pathology
- Abstract
Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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16. Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2.
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Ten Broeke SW, van Bavel TC, Jansen AML, Gómez-García E, Hes FJ, van Hest LP, Letteboer TGW, Olderode-Berends MJW, Ruano D, Spruijt L, Suerink M, Tops CM, van Eijk R, Morreau H, van Wezel T, and Nielsen M
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- Adult, Aged, DNA Mismatch Repair, DNA-Binding Proteins genetics, Epithelial Cell Adhesion Molecule genetics, Female, Humans, Male, Middle Aged, MutL Protein Homolog 1 genetics, beta Catenin genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Germ-Line Mutation, Mismatch Repair Endonuclease PMS2 genetics
- Abstract
Background & Aims: Germline variants in mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in older patients than CRCs with variants in other mismatch repair genes., Methods: We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3,000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher exact test., Results: None of the PMS2-associated CRCs contained any somatic variants in the catenin-β
1 gene (CTNNB1), which encodes β-catenin, whereas 14 of 24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half the PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%; P = .44) and MSH2 (71.4%; P = .035) than in those associated with variants in PMS2., Conclusions: In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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17. Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation.
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Postema FAM, Hopman SMJ, Aalfs CM, Berger LPV, Bleeker FE, Dommering CJ, Jongmans MCJ, Letteboer TGW, Olderode-Berends MJW, Wagner A, Hennekam RC, and Merks JHM
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- Child, Humans, Incidence, Referral and Consultation, Genetic Counseling, Genetic Predisposition to Disease, Neoplastic Syndromes, Hereditary epidemiology
- Abstract
Introduction: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic consultation., Methods: We performed a PubMed search to review the incidence of TPSs in children for 85 tumour types listed in the International Classification of Childhood Cancer third edition (ICCC-3). The results were discussed during a national consensus meeting with representative clinical geneticists from all six academic paediatric oncology centres in The Netherlands. A TPS incidence of 5% or more was considered a high probability and therefore in itself a reason for referral to a clinical geneticist., Results: The literature search resulted in data on the incidence of a TPS in 26 tumours. For 23/26 tumour types, a TPS incidence of 5% or higher was reported. In addition, during the consensus meeting the experts agreed that children with any carcinoma should always be referred for clinical genetic consultation as well, as it may point to a TPS., Conclusion: We present an overview of 23 paediatric tumours with a high probability of a TPS; this will facilitate paediatric oncologists to decide which patients should be referred for genetic consultation merely based on type of tumour., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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18. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome.
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van der Klift HM, Mensenkamp AR, Drost M, Bik EC, Vos YJ, Gille HJ, Redeker BE, Tiersma Y, Zonneveld JB, García EG, Letteboer TG, Olderode-Berends MJ, van Hest LP, van Os TA, Verhoef S, Wagner A, van Asperen CJ, Ten Broeke SW, Hes FJ, de Wind N, Nielsen M, Devilee P, Ligtenberg MJ, Wijnen JT, and Tops CM
- Subjects
- Brain Neoplasms metabolism, Cohort Studies, Colorectal Neoplasms metabolism, Colorectal Neoplasms, Hereditary Nonpolyposis metabolism, Genetic Predisposition to Disease, Genetic Variation, Germ-Line Mutation, Humans, Microsatellite Instability, Mismatch Repair Endonuclease PMS2 metabolism, Neoplastic Syndromes, Hereditary metabolism, Netherlands, Brain Neoplasms genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA Mutational Analysis methods, Mismatch Repair Endonuclease PMS2 genetics, Neoplastic Syndromes, Hereditary genetics
- Abstract
Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/MSI (immunohistochemistry/microsatellite instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro mismatch repair assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor prescreening methods will however miss some PMS2 germline mutation carriers., (© 2016 WILEY PERIODICALS, INC.)
- Published
- 2016
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19. The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers.
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Suerink M, van der Klift HM, Ten Broeke SW, Dekkers OM, Bernstein I, Capellá Munar G, Gomez Garcia E, Hoogerbrugge N, Letteboer TG, Menko FH, Lindblom A, Mensenkamp A, Moller P, van Os TA, Rahner N, Redeker BJ, Olderode-Berends MJ, Spruijt L, Vos YJ, Wagner A, Morreau H, Hes FJ, Vasen HF, Tops CM, Wijnen JT, and Nielsen M
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- Adult, Age of Onset, Aged, Aged, 80 and over, Cohort Studies, Female, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, Male, Middle Aged, Neoplasms epidemiology, Risk, Heterozygote, Mismatch Repair Endonuclease PMS2 genetics, Mutation, Neoplasms genetics
- Abstract
Purpose: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype., Methods: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally., Results: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC., Conclusions: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409.
- Published
- 2016
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20. Hereditary hemorrhagic telangiectasia: how accurate are the clinical criteria?
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van Gent MW, Velthuis S, Post MC, Snijder RJ, Westermann CJ, Letteboer TG, and Mager JJ
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- Adolescent, Adult, Aged, Antigens, CD genetics, DNA Mutational Analysis, Endoglin, Female, Genetic Testing, Humans, Male, Middle Aged, Molecular Diagnostic Techniques, Radiography, Receptors, Cell Surface genetics, Telangiectasia, Hereditary Hemorrhagic classification, Telangiectasia, Hereditary Hemorrhagic genetics, Young Adult, Telangiectasia, Hereditary Hemorrhagic diagnostic imaging
- Abstract
The clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on the Curaçao criteria. Three out of four criteria are required for a definite clinical diagnosis HHT, two criteria are considered "possible" HHT, and 0 or 1 criterion makes the diagnosis unlikely. However, these consensus diagnostic criteria have not been validated. We report on the diagnostic accuracy of the clinical criteria. A total of 450 consecutive persons ≥16 years of age were screened for HHT between May 2004 and September 2009, including a chest CT to screen for pulmonary arteriovenous malformations (AVMs). We selected 263 first-degree relatives of disease-causing mutation carriers who underwent mutation analysis. Genetic test results were considered the gold standard. The family mutation was present in 186 patients (mean age 42.9 ± 14.6 yr; 54.8% female). A clinical diagnosis was definite, "possible", and unlikely in 168 (90.3%), 17 (9.1%), and 1 (0.5%) patient, respectively. In 77 persons the family mutation was absent (mean age 37.1 ± 12.3 yr, 59.7% female). In this group a clinical diagnosis was definite, possible, and unlikely in 0, 35 (45.5%), and 42 (54.5%) persons, respectively. The positive predictive value of a definite clinical diagnosis was 100% (95% CI 97.8-100), the negative predictive value of an unlikely diagnosis 97.7% (95% CI 87.9-99.6). Of 52 patients with "possible" HHT, 17 (32.7%) displayed an HHT-causing mutation. The Curaçao clinical criteria have a good diagnostic performance. Genetic testing is particularly helpful in patients with a "possible" clinical diagnosis HHT., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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21. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.
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Benzinou M, Clermont FF, Letteboer TG, Kim JH, Espejel S, Harradine KA, Arbelaez J, Luu MT, Roy R, Quigley D, Higgins MN, Zaid M, Aouizerat BE, van Amstel JK, Giraud S, Dupuis-Girod S, Lesca G, Plauchu H, Hughes CC, Westermann CJ, and Akhurst RJ
- Subjects
- Activin Receptors, Type I metabolism, Activin Receptors, Type II metabolism, Animals, Chromosome Mapping, Ephrin-B2 metabolism, Exons, Female, Genetic Variation, Haplotypes, Humans, Male, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Transgenic, Models, Genetic, Mutation, Phenotype, Protein Tyrosine Phosphatases, Non-Receptor genetics, Species Specificity, Transforming Growth Factor beta metabolism, Protein Tyrosine Phosphatases, Non-Receptor physiology, Telangiectasia, Hereditary Hemorrhagic genetics
- Abstract
Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-β pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1(-/-) mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, [corrected] as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HHT [corrected] in particular and to angiogenesis in general.
- Published
- 2012
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- View/download PDF
22. Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia.
- Author
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Letteboer TG, Mager HJ, Snijder RJ, Lindhout D, Ploos van Amstel HK, Zanen P, and Westermann KJ
- Subjects
- Activin Receptors, Type II genetics, Adolescent, Adult, Age Factors, Aged, Antigens, CD genetics, Child, Child, Preschool, Endoglin, Female, Genotype, Humans, Male, Middle Aged, Mouth Mucosa blood supply, Mouth Mucosa pathology, Nasal Mucosa blood supply, Nasal Mucosa pathology, Phenotype, Receptors, Cell Surface genetics, Sex Factors, Skin blood supply, Skin pathology, Telangiectasia, Hereditary Hemorrhagic classification, Telangiectasia, Hereditary Hemorrhagic genetics, Telangiectasia, Hereditary Hemorrhagic pathology
- Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations (AVMs) ranging from telangiectases to larger AVMs. Mutations in two genes cause HHT; ENG (HHT1) and ACVRL1 (HHT2). Although the hallmark for clinical diagnosis is the presence of telangiectases, there are few publications reporting the relative distribution and frequency of these features between HHT1 and HHT2. Here, the results of such analysis of telangiectases in 268 patients with HHT1 and 130 patients with HHT2 are described. Localization of the telangiectases is reported, and patients were clustered by age to estimate the site prevalence for different age categories. We show that telangiectases of the nasal mucosa are present at a higher prevalence and start to appear earlier in life than those of the oral mucosa or dermal sites in patients with either HHT1 or HHT2. Oral and nasal mucosal telangiectases are present earlier in life in patients with HHT1 compared to patients with HHT2, whereas dermal lesions are more frequent and appear earlier in life in patients with HHT2. In patients with either HHT1 or HHT2, the number of sites affected increases with age. In patients with HHT1, more women than men had skin telangiectases, particularly on the face. These results confirm that the frequency of AVMs differ between patients with HHT1 and HHT2, and that these differences can be detected on physical examination., (Copyright 2008 Wiley-Liss, Inc.)
- Published
- 2008
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23. Assessment of intestinal vascular malformations in patients with hereditary hemorrhagic teleangiectasia and anemia.
- Author
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van Tuyl SA, Letteboer TG, Rogge-Wolf C, Kuipers EJ, Snijder RJ, Westermann CJ, and Stolk MF
- Subjects
- Adolescent, Adult, Aged, Arteriovenous Malformations etiology, Capsule Endoscopy, Colonic Diseases diagnosis, Female, Gastrointestinal Hemorrhage etiology, Genotype, Humans, Intestinal Diseases complications, Intestine, Small pathology, Liver Diseases diagnosis, Male, Middle Aged, Phenotype, Stomach Diseases diagnosis, Telangiectasia, Hereditary Hemorrhagic complications, Anemia etiology, Arteriovenous Malformations diagnosis, Intestinal Diseases diagnosis, Telangiectasia, Hereditary Hemorrhagic diagnosis
- Abstract
Introduction: Hereditary hemorrhagic teleangiectasia (HHT) is an autosomal dominant disorder with mucocutaneous teleangiectasia and visceral arteriovenous malformations. Mutations of endoglin and Activin A receptor like kinase-1 have different phenotypes, HHT1 and HHT2, respectively. The gastrointestinal tract is frequently affected, but limited information is available on the relationship with genotype., Aim: To determine whether different genotypes have different phenotypes with respect to intestinal teleangiectasia., Methods: HHT patients, referred for anemia, underwent videocapsule endoscopy. Chart review was performed for information on genotype and HHT manifestations., Results: Twenty-five patients were analyzed (men/women 13/9, mean age 49+/-15 years.), 14 HHT1, eight HHT2 and three without known mutation. Epistaxis occurred in 96% of patients. Gastroduodenoscopy revealed teleangiectasia in 7/12 (58%) HHT1 and 3/8 (38%) HHT2 patients. Videocapsule endoscopy found teleangiectasia in all HHT1 and 5/8 (63%) HHT2 patients. In 9/14 HHT1 patients, teleangiectasia were large. Teleangiectasia in the colon was restricted to 6/11 (55%) HHT1 patients. Hepatic arteriovenous malformations were present in 1/7 HHT1 and 5/6 HHT2 patients., Conclusion: Large teleangiectasia in small intestine and colon appear to occur predominantly in HHT1. Hepatic arteriovenous malformations are mainly found in HHT2. In HHT patients with unexplained anemia, videocapsule endoscopy should be considered to determine the size and extent of teleangiectasia and exclude other abnormalities.
- Published
- 2007
- Full Text
- View/download PDF
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