44 results on '"Letteboer, Tom G W"'
Search Results
2. Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study
- Author
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Postema, Floor A. M., Hopman, Saskia M. J., de Borgie, Corianne A. J. M., Aalfs, Cora M., Anninga, Jakob K., Berger, Lieke P. V., Bleeker, Fonnet E., Dommering, Charlotte J., van Eijkelenburg, Natasha K. A., Hammond, Peter, van den Heuvel-Eibrink, Marry M., Hol, Janna A., Kors, Wijnanda A., Letteboer, Tom G. W., Loeffen, Jan L. C. M., Meijer, Lisethe, Olderode-Berends, Maran J. W., Wagner, Anja, Hennekam, Raoul C., and Merks, Johannes H. M.
- Published
- 2021
- Full Text
- View/download PDF
3. SNP association study in PMS2-associated Lynch syndrome
- Author
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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
- Published
- 2018
- Full Text
- View/download PDF
4. Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans
- Author
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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. Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study
- Author
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Genetica Klinische Genetica, Child Health, PMC Medisch specialisten, Speerpunt, Zorg en O&O, Postema, Floor A M, Hopman, Saskia M J, de Borgie, Corianne A J M, Aalfs, Cora M, Anninga, Jakob K, Berger, Lieke P V, Bleeker, Fonnet E, Dommering, Charlotte J, van Eijkelenburg, Natasha K A, Hammond, Peter, van den Heuvel-Eibrink, Marry M, Hol, Janna A, Kors, Wijnanda A, Letteboer, Tom G W, Loeffen, Jan L C M, Meijer, Lisethe, Olderode-Berends, Maran J W, Wagner, Anja, Hennekam, Raoul C, Merks, Johannes H M, Genetica Klinische Genetica, Child Health, PMC Medisch specialisten, Speerpunt, Zorg en O&O, Postema, Floor A M, Hopman, Saskia M J, de Borgie, Corianne A J M, Aalfs, Cora M, Anninga, Jakob K, Berger, Lieke P V, Bleeker, Fonnet E, Dommering, Charlotte J, van Eijkelenburg, Natasha K A, Hammond, Peter, van den Heuvel-Eibrink, Marry M, Hol, Janna A, Kors, Wijnanda A, Letteboer, Tom G W, Loeffen, Jan L C M, Meijer, Lisethe, Olderode-Berends, Maran J W, Wagner, Anja, Hennekam, Raoul C, and Merks, Johannes H M
- Published
- 2021
6. Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis
- Author
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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
- Full Text
- View/download PDF
7. A Pulmonary Right-to-Left Shunt in Patients With Hereditary Hemorrhagic Telangiectasia Is Associated With an Increased Prevalence of Migraine*
- Author
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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
8. SNP association study in PMS2-associated Lynch syndrome
- Author
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ten Broeke, Sanne W., primary, Elsayed, Fadwa A., additional, Pagan, Lisa, additional, Olderode-Berends, Maran J. W., additional, Garcia, Encarna Gomez, additional, Gille, Hans J. P., additional, van Hest, Liselot P., additional, Letteboer, Tom G. W., additional, van der Kolk, Lizet E., additional, Mensenkamp, Arjen R., additional, van Os, Theo A., additional, Spruijt, Liesbeth, additional, Redeker, Bert J. W., additional, Suerink, Manon, additional, Vos, Yvonne J., additional, Wagner, Anja, additional, Wijnen, Juul T., additional, Steyerberg, E. W., additional, Tops, Carli M. J., additional, van Wezel, Tom, additional, and Nielsen, Maartje, additional
- Published
- 2017
- Full Text
- View/download PDF
9. Validation of a clinical screening instrument for tumour predisposition syndromes in patients with childhood cancer (TuPS) : Protocol for a prospective, observational, multicentre study
- Author
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Postema, Floor A M, Hopman, Saskia M J, De Borgie, Corianne A J M, Hammond, Peter, Hennekam, Raoul C., Merks, Johannes H M, Aalfs, Cora M., Anninga, Jakob K., Berger, Lieke P V, Bleeker, Fonnet E., De Bont, Eveline S J M, Dommering, Charlotte J., Van Eijkelenburg, Natasha K A, Van Den Heuvel-Eibrink, Marry M., Jongmans, Marjolijn C J, Kors, Wijnanda A., Letteboer, Tom G W, Loeffen, Jan L C M, Olderode-Berends, Maran J W, Wagner, Anja, Postema, Floor A M, Hopman, Saskia M J, De Borgie, Corianne A J M, Hammond, Peter, Hennekam, Raoul C., Merks, Johannes H M, Aalfs, Cora M., Anninga, Jakob K., Berger, Lieke P V, Bleeker, Fonnet E., De Bont, Eveline S J M, Dommering, Charlotte J., Van Eijkelenburg, Natasha K A, Van Den Heuvel-Eibrink, Marry M., Jongmans, Marjolijn C J, Kors, Wijnanda A., Letteboer, Tom G W, Loeffen, Jan L C M, Olderode-Berends, Maran J W, and Wagner, Anja
- Published
- 2017
10. Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation
- Author
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Postema, Floor A M, Hopman, Saskia M J, Aalfs, Cora M, Berger, Lieke P V, Bleeker, Fonnet E, Dommering, Charlotte J, Jongmans, Marjolijn C J, Letteboer, Tom G W, Olderode-Berends, Maran J W, Wagner, Anja, Hennekam, Raoul C, Merks, Johannes H M, Postema, Floor A M, Hopman, Saskia M J, Aalfs, Cora M, Berger, Lieke P V, Bleeker, Fonnet E, Dommering, Charlotte J, Jongmans, Marjolijn C J, Letteboer, Tom G W, Olderode-Berends, Maran J W, Wagner, Anja, Hennekam, Raoul C, and Merks, Johannes H M
- Published
- 2017
11. Childhood tumours with a high probability of being part of a tumour predisposition syndrome; reason for referral for genetic consultation
- Author
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Genetica Klinische Genetica, Child Health, Genetica Sectie Oncogenetica, Cancer, Postema, Floor A M, Hopman, Saskia M J, Aalfs, Cora M, Berger, Lieke P V, Bleeker, Fonnet E, Dommering, Charlotte J, Jongmans, Marjolijn C J, Letteboer, Tom G W, Olderode-Berends, Maran J W, Wagner, Anja, Hennekam, Raoul C, Merks, Johannes H M, Genetica Klinische Genetica, Child Health, Genetica Sectie Oncogenetica, Cancer, Postema, Floor A M, Hopman, Saskia M J, Aalfs, Cora M, Berger, Lieke P V, Bleeker, Fonnet E, Dommering, Charlotte J, Jongmans, Marjolijn C J, Letteboer, Tom G W, Olderode-Berends, Maran J W, Wagner, Anja, Hennekam, Raoul C, and Merks, Johannes H M
- Published
- 2017
12. Validation of a clinical screening instrument for tumour predisposition syndromes in patients with childhood cancer (TuPS): Protocol for a prospective, observational, multicentre study
- Author
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Genetica, UMC Utrecht, Genetica Klinische Genetica, Child Health, PMC Medisch specialisten, Genetica Sectie Oncogenetica, Cancer, Postema, Floor A M, Hopman, Saskia M J, De Borgie, Corianne A J M, Hammond, Peter, Hennekam, Raoul C., Merks, Johannes H M, Aalfs, Cora M., Anninga, Jakob K., Berger, Lieke P V, Bleeker, Fonnet E., De Bont, Eveline S J M, Dommering, Charlotte J., Van Eijkelenburg, Natasha K A, Van Den Heuvel-Eibrink, Marry M., Jongmans, Marjolijn C J, Kors, Wijnanda A., Letteboer, Tom G W, Loeffen, Jan L C M, Olderode-Berends, Maran J W, Wagner, Anja, Genetica, UMC Utrecht, Genetica Klinische Genetica, Child Health, PMC Medisch specialisten, Genetica Sectie Oncogenetica, Cancer, Postema, Floor A M, Hopman, Saskia M J, De Borgie, Corianne A J M, Hammond, Peter, Hennekam, Raoul C., Merks, Johannes H M, Aalfs, Cora M., Anninga, Jakob K., Berger, Lieke P V, Bleeker, Fonnet E., De Bont, Eveline S J M, Dommering, Charlotte J., Van Eijkelenburg, Natasha K A, Van Den Heuvel-Eibrink, Marry M., Jongmans, Marjolijn C J, Kors, Wijnanda A., Letteboer, Tom G W, Loeffen, Jan L C M, Olderode-Berends, Maran J W, and Wagner, Anja
- Published
- 2017
13. CORRIGENDUM: The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers
- Author
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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
14. The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect.
- Author
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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
- Full Text
- View/download PDF
15. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome
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van der Klift, Heleen M, Mensenkamp, Arjen R, Drost, Mark, Bik, Elsa C, Vos, Yvonne J, Gille, Hans J J P, Redeker, Bert E J W, Tiersma, Yvonne, Zonneveld, José B M, García, Encarna Gómez, Letteboer, Tom G W, Olderode-Berends, Maran J W, van Hest, Liselotte P, van Os, Theo A, Verhoef, Senno, Wagner, Anja, van Asperen, Christi J, Ten Broeke, Sanne W, Hes, Frederik J, de Wind, Niels, Nielsen, Maartje, Devilee, Peter, Ligtenberg, Marjolijn J L, Wijnen, Juul T, Tops, Carli M J, van der Klift, Heleen M, Mensenkamp, Arjen R, Drost, Mark, Bik, Elsa C, Vos, Yvonne J, Gille, Hans J J P, Redeker, Bert E J W, Tiersma, Yvonne, Zonneveld, José B M, García, Encarna Gómez, Letteboer, Tom G W, Olderode-Berends, Maran J W, van Hest, Liselotte P, van Os, Theo A, Verhoef, Senno, Wagner, Anja, van Asperen, Christi J, Ten Broeke, Sanne W, Hes, Frederik J, de Wind, Niels, Nielsen, Maartje, Devilee, Peter, Ligtenberg, Marjolijn J L, Wijnen, Juul T, and Tops, Carli M J
- Published
- 2016
16. The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers
- Author
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Suerink, Manon, van der Klift, Heleen M, Ten Broeke, Sanne W, Dekkers, Olaf M, Bernstein, Inge, Capellá Munar, Gabriel, 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, Maran, Spruijt, Liesbeth, Vos, Yvonne J, Wagner, Anja, Morreau, Hans, Hes, Frederik J, Vasen, Hans F A, Tops, Carli M, Wijnen, Juul T, Nielsen, Maartje, Suerink, Manon, van der Klift, Heleen M, Ten Broeke, Sanne W, Dekkers, Olaf M, Bernstein, Inge, Capellá Munar, Gabriel, 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, Maran, 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
- Published
- 2016
17. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients
- Author
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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, Wijnen, Juul T, 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
- Published
- 2016
18. Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome
- Author
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Genetica Sectie Oncogenetica, Child Health, van der Klift, Heleen M, Mensenkamp, Arjen R, Drost, Mark, Bik, Elsa C, Vos, Yvonne J, Gille, Hans J J P, Redeker, Bert E J W, Tiersma, Yvonne, Zonneveld, José B M, García, Encarna Gómez, Letteboer, Tom G W, Olderode-Berends, Maran J W, van Hest, Liselotte P, van Os, Theo A, Verhoef, Senno, Wagner, Anja, van Asperen, Christi J, Ten Broeke, Sanne W, Hes, Frederik J, de Wind, Niels, Nielsen, Maartje, Devilee, Peter, Ligtenberg, Marjolijn J L, Wijnen, Juul T, Tops, Carli M J, Genetica Sectie Oncogenetica, Child Health, van der Klift, Heleen M, Mensenkamp, Arjen R, Drost, Mark, Bik, Elsa C, Vos, Yvonne J, Gille, Hans J J P, Redeker, Bert E J W, Tiersma, Yvonne, Zonneveld, José B M, García, Encarna Gómez, Letteboer, Tom G W, Olderode-Berends, Maran J W, van Hest, Liselotte P, van Os, Theo A, Verhoef, Senno, Wagner, Anja, van Asperen, Christi J, Ten Broeke, Sanne W, Hes, Frederik J, de Wind, Niels, Nielsen, Maartje, Devilee, Peter, Ligtenberg, Marjolijn J L, Wijnen, Juul T, and Tops, Carli M J
- Published
- 2016
19. The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers
- Author
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Genetica Sectie Oncogenetica, Child Health, Suerink, Manon, van der Klift, Heleen M, Ten Broeke, Sanne W, Dekkers, Olaf M, Bernstein, Inge, Capellá Munar, Gabriel, 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, Maran, Spruijt, Liesbeth, Vos, Yvonne J, Wagner, Anja, Morreau, Hans, Hes, Frederik J, Vasen, Hans F A, Tops, Carli M, Wijnen, Juul T, Nielsen, Maartje, Genetica Sectie Oncogenetica, Child Health, Suerink, Manon, van der Klift, Heleen M, Ten Broeke, Sanne W, Dekkers, Olaf M, Bernstein, Inge, Capellá Munar, Gabriel, 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, Maran, 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
- Published
- 2016
20. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients
- Author
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Genetica Sectie Oncogenetica, Child Health, 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, Wijnen, Juul T, Genetica Sectie Oncogenetica, Child Health, 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
- Published
- 2016
21. CORRIGENDUM: The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers
- Author
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Genetica Sectie Oncogenetica, Child Health, 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., Nielsen, Maartje, Genetica Sectie Oncogenetica, Child Health, 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
- Published
- 2016
22. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients
- Author
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Jansen, Anne M. L., primary, Geilenkirchen, Marije A., additional, van Wezel, Tom, additional, Jagmohan-Changur, Shantie C., additional, Ruano, Dina, additional, van der Klift, Heleen M., additional, van den Akker, Brendy E. W. M., additional, Laros, Jeroen F. J., additional, van Galen, Michiel, additional, Wagner, Anja, additional, Letteboer, Tom G. W., additional, Gómez-García, Encarna B., additional, Tops, Carli M. J., additional, Vasen, Hans F., additional, Devilee, Peter, additional, Hes, Frederik J., additional, Morreau, Hans, additional, and Wijnen, Juul T., additional
- Published
- 2016
- Full Text
- View/download PDF
23. Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14
- Author
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Letteboer, Tom G W, Benzinou, Michael, Merrick, Christopher, Quigley, David, Zhau, Kechen, Kim, Il Jin, To, Minh D., Jablons, David, Van Amstel, Johannes Kristian Ploos, Westermann, Cornelius, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Berg, Jonathan, Balmain, Allan, Akhurst, Rosemary J., Letteboer, Tom G W, Benzinou, Michael, Merrick, Christopher, Quigley, David, Zhau, Kechen, Kim, Il Jin, To, Minh D., Jablons, David, Van Amstel, Johannes Kristian Ploos, Westermann, Cornelius, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Berg, Jonathan, Balmain, Allan, and Akhurst, Rosemary J.
- Published
- 2015
24. Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14
- Author
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Genetica Sectie Oncogenetica, Child Health, Genetica Sectie Genoomdiagnostiek, Letteboer, Tom G W, Benzinou, Michael, Merrick, Christopher, Quigley, David, Zhau, Kechen, Kim, Il Jin, To, Minh D., Jablons, David, Van Amstel, Johannes Kristian Ploos, Westermann, Cornelius, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Berg, Jonathan, Balmain, Allan, Akhurst, Rosemary J., Genetica Sectie Oncogenetica, Child Health, Genetica Sectie Genoomdiagnostiek, Letteboer, Tom G W, Benzinou, Michael, Merrick, Christopher, Quigley, David, Zhau, Kechen, Kim, Il Jin, To, Minh D., Jablons, David, Van Amstel, Johannes Kristian Ploos, Westermann, Cornelius, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Berg, Jonathan, Balmain, Allan, and Akhurst, Rosemary J.
- Published
- 2015
25. Cancer Risks for PMS2-Associated Lynch Syndrome.
- Author
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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
- Full Text
- View/download PDF
26. 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
- Author
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Letteboer, Tom G. W., primary, Benzinou, Michael, additional, Merrick, Christopher B., additional, Quigley, David A., additional, Zhau, Kechen, additional, Kim, Il-Jin, additional, To, Minh D., additional, Jablons, David M., additional, van Amstel, Johannes K. P., additional, Westermann, Cornelius J. J., additional, Giraud, Sophie, additional, Dupuis-Girod, Sophie, additional, Lesca, Gaetan, additional, Berg, Jonathan H., additional, Balmain, Allan, additional, and Akhurst, Rosemary J., additional
- Published
- 2015
- Full Text
- View/download PDF
27. Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis
- Author
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Hes, Frederik J, primary, Ruano, Dina, additional, Nieuwenhuis, Marry, additional, Tops, Carli M, additional, Schrumpf, Melanie, additional, Nielsen, Maartje, additional, Huijts, Petra E A, additional, Wijnen, Juul T, additional, Wagner, Anja, additional, García, Encarna B Gómez, additional, Sijmons, Rolf H, additional, Menko, Fred H, additional, Letteboer, Tom G W, additional, Hoogerbrugge, Nicoline, additional, Harryvan, Jan, additional, Kampman, Ellen, additional, Morreau, Hans, additional, Vasen, Hans F A, additional, and van Wezel, Tom, additional
- Published
- 2013
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28. Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.
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Clermont, Frédéric, Benzinou, Michael, Letteboer, Tom G W, Kim, Jai-Hyun, Espejel, Silvia, Harradine, Kelly A, Arbelaez, Juan, Luu, Minh Thu, Roy, Ritu, Quigley, David, Higgins, Mamie Nakayama, Zaid, Musa, Aouizerat, Bradley E, van Amstel, Johannes Kristian Ploos, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Plauchu, Henri, Hughes, Christopher C W, Westermann, Cornelius J J, Akhurst, Rosemary J, Clermont, Frédéric, Benzinou, Michael, Letteboer, Tom G W, Kim, Jai-Hyun, Espejel, Silvia, Harradine, Kelly A, Arbelaez, Juan, Luu, Minh Thu, Roy, Ritu, Quigley, David, Higgins, Mamie Nakayama, Zaid, Musa, Aouizerat, Bradley E, van Amstel, Johannes Kristian Ploos, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Plauchu, Henri, Hughes, Christopher C W, Westermann, Cornelius J J, and Akhurst, Rosemary J
- Abstract
Hereditary haemorrhagic telangiectasia (HTT) is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HTT 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 HTT, 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 HTT in particular and to angiogenesis in general., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published
- Published
- 2012
29. Risks of Less Common Cancers in Proven Mutation Carriers With Lynch Syndrome
- Author
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Engel, Christoph, Loeffler, Markus, Steinke, Verena, Rahner, Nils, Holinski-Feder, Elke, Dietmaier, Wolfgang, Schackert, Hans K., Goergens, Heike, Doeberitz, Magnus von Knebel, Goecke, Timm O., Schmiegel, Wolff, Buettner, Reinhard, Moeslein, Gabriela, Letteboer, Tom G. W., Garcia, Encarna Gomez, Hes, Frederik J., Hoogerbrugge, Nicoline, Menko, Fred H., van Os, Theo A. M., Sijmons, Rolf H., Wagner, Anja, Kluijt, Irma, Propping, Peter, Vasen, Hans F. A., Engel, Christoph, Loeffler, Markus, Steinke, Verena, Rahner, Nils, Holinski-Feder, Elke, Dietmaier, Wolfgang, Schackert, Hans K., Goergens, Heike, Doeberitz, Magnus von Knebel, Goecke, Timm O., Schmiegel, Wolff, Buettner, Reinhard, Moeslein, Gabriela, Letteboer, Tom G. W., Garcia, Encarna Gomez, Hes, Frederik J., Hoogerbrugge, Nicoline, Menko, Fred H., van Os, Theo A. M., Sijmons, Rolf H., Wagner, Anja, Kluijt, Irma, Propping, Peter, and Vasen, Hans F. A.
- Abstract
Purpose Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. Patients and Methods Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex-and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. Results The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. Conclusion The sex-and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome. J Clin Oncol 30: 4409-4415. (C) 2012 by American Society of Clinical Oncology
- Published
- 2012
30. Erratum: Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia.
- Author
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Clermont, Frédéric, Benzinou, Michael, Letteboer, Tom G W, Kim, Jai-Hyun, Espejel, Silvia, Harradine, Kelly A, Arbelaez, Juan, Luu, Minh Thu, Roy, Ritu, Quigley, David, Higgins, Mamie Nakayama, Zaid, Musa, Aouizerat, Bradley E, van Amstel, Johannes Kristian Ploos, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Plauchu, Henri, Hughes, Christopher C W, Westermann, Cornelius J J, Akhurst, Rosemary J, Clermont, Frédéric, Benzinou, Michael, Letteboer, Tom G W, Kim, Jai-Hyun, Espejel, Silvia, Harradine, Kelly A, Arbelaez, Juan, Luu, Minh Thu, Roy, Ritu, Quigley, David, Higgins, Mamie Nakayama, Zaid, Musa, Aouizerat, Bradley E, van Amstel, Johannes Kristian Ploos, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaetan, Plauchu, Henri, Hughes, Christopher C W, Westermann, Cornelius J J, and Akhurst, Rosemary J
- Abstract
Journal Article, info:eu-repo/semantics/published
- Published
- 2012
31. Erratum: Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia
- Author
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Benzinou, Michael, primary, Clermont, Frederic F., additional, Letteboer, Tom G W., additional, Kim, Jai-hyun, additional, Espejel, Silvia, additional, Harradine, Kelly A., additional, Arbelaez, Juan, additional, Luu, Minh Thu, additional, Roy, Ritu, additional, Quigley, David, additional, Higgins, Mamie Nakayama, additional, Zaid, Musa, additional, Aouizerat, Bradley E., additional, van Amstel, Johannes Kristian Ploos, additional, Giraud, Sophie, additional, Dupuis-Girod, Sophie, additional, Lesca, Gaetan, additional, Plauchu, Henri, additional, Hughes, Christopher C W., additional, Westermann, Cornelius J.J., additional, and Akhurst, Rosemary J., additional
- Published
- 2012
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32. 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
- Published
- 2015
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33. 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.
- Subjects
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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34. 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
- Subjects
- 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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35. 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
- Subjects
- 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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36. 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
- Subjects
- 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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37. 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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38. The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers.
- Author
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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
- Subjects
- 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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39. 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
- Subjects
- 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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40. Risks of less common cancers in proven mutation carriers with lynch syndrome.
- Author
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Engel C, Loeffler M, Steinke V, Rahner N, Holinski-Feder E, Dietmaier W, Schackert HK, Goergens H, von Knebel Doeberitz M, Goecke TO, Schmiegel W, Buettner R, Moeslein G, Letteboer TG, Gómez García E, Hes FJ, Hoogerbrugge N, Menko FH, van Os TA, Sijmons RH, Wagner A, Kluijt I, Propping P, and Vasen HF
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adult, Aged, Cohort Studies, DNA-Binding Proteins genetics, Female, Germany epidemiology, Humans, Male, Middle Aged, MutL Protein Homolog 1, MutS Homolog 2 Protein genetics, Mutation, Netherlands epidemiology, Nuclear Proteins genetics, Registries, Retrospective Studies, Risk Factors, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Neoplasms epidemiology, Neoplasms genetics
- Abstract
Purpose: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6., Patients and Methods: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk., Results: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers., Conclusion: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.
- Published
- 2012
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41. 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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42. [Diagnosis of fetal alcohol spectrum disorders].
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van Wieringen H, Letteboer TG, Pereira RR, de Ruiter S, Balemans WA, and Lindhout D
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple etiology, Alcohol Drinking adverse effects, Alcoholism complications, Congenital Abnormalities etiology, Female, Fetal Alcohol Spectrum Disorders epidemiology, Humans, Netherlands epidemiology, Pregnancy, Prenatal Exposure Delayed Effects, Prevalence, Risk Factors, Congenital Abnormalities diagnosis, Ethanol adverse effects, Ethanol blood, Fetal Alcohol Spectrum Disorders diagnosis, Practice Guidelines as Topic
- Abstract
Prenatal alcohol exposure may cause decreased growth of the child, congenital abnormalities, specific facial characteristics, and, most importantly, mental retardation and behavioural disorders, all known as fetal alcohol spectrum disorders (FASD). A significant number of pregnant women in the Netherlands drink alcohol, but the prevalence of FASD in our country is unknown. Repeated and high peak blood alcohol concentrations, for example in the case of binge drinking by the mother, result in more severe abnormalities; a safe limit for alcohol consumption in pregnancy cannot be defined. In 2007 and 2008, Dutch paediatricians reported a total of 56 diagnosed cases of FASD, mostly adopted and foster children. Possibly the condition has not always been diagnosed. Use of international guidelines for diagnosis by the medical profession may improve detection. The guidelines of the Canadian Public Health Agency provide a useful and generally accepted classification, with strict cut-off points to avoid overdiagnosis; attention should always be paid to the broad differential diagnosis.
- Published
- 2010
43. 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
- Full Text
- View/download PDF
44. 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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