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151. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Author

Vogelaar, Ingrid P., van der Post, Rachel S., Van Krieken, J. Han J M, Spruijt, Liesbeth, van Zelst-Stams, Wendy A. G., Kets, C. Marleen, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M., Van Hest, Liselotte P., Pinheiro, Hugo, Oliveira, Carla, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R, De Ligt, Joep, Vissers, Lisenka E L M, Hoischen, Alexander, Gilissen, Christian, Van De Vorst, Maartje, Goeman, Jelle J., Schackert, Hans K, Ranzani, Guglielmina N., Molinaro, Valeria, García, Encarna B.Gómez, Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G.E.M., Sijmons, Rolf H., Wagner, Anja, Van Der Kolk, Lizet E., Bjørnevoll, Inga, Høberg Vetti, Hildegunn, van Kessel, Ad Geurts, Kuiper, Roland P., Ligtenberg, Marjolijn J. L., Hoogerbrugge, Nicoline, Vogelaar, Ingrid P., van der Post, Rachel S., Van Krieken, J. Han J M, Spruijt, Liesbeth, van Zelst-Stams, Wendy A. G., Kets, C. Marleen, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M., Van Hest, Liselotte P., Pinheiro, Hugo, Oliveira, Carla, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R, De Ligt, Joep, Vissers, Lisenka E L M, Hoischen, Alexander, Gilissen, Christian, Van De Vorst, Maartje, Goeman, Jelle J., Schackert, Hans K, Ranzani, Guglielmina N., Molinaro, Valeria, García, Encarna B.Gómez, Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G.E.M., Sijmons, Rolf H., Wagner, Anja, Van Der Kolk, Lizet E., Bjørnevoll, Inga, Høberg Vetti, Hildegunn, van Kessel, Ad Geurts, Kuiper, Roland P., Ligtenberg, Marjolijn J. L., and Hoogerbrugge, Nicoline

Published
2017

152. Novel algorithms for improved sensitivity in non-invasive prenatal testing

Author

Johansson, Lennart F., De Boer, E. N., De Weerd, H. A., van Dijk, F., Elferink, M. G., Schuring-Blom, G. H., Suijkerbuijk, Ron F, Sinke, Richard J., Te Meerman, G. J., Sijmons, Rolf H., Swertz, Morris A., Sikkema-Raddatz, B., Johansson, Lennart F., De Boer, E. N., De Weerd, H. A., van Dijk, F., Elferink, M. G., Schuring-Blom, G. H., Suijkerbuijk, Ron F, Sinke, Richard J., Te Meerman, G. J., Sijmons, Rolf H., Swertz, Morris A., and Sikkema-Raddatz, B.

Published
2017

153. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance:first report from the prospective Lynch syndrome database

Author

Møller, Pål, Seppälä, Toni, Bernstein, Inge, Holinski-Feder, Elke, Sala, Paola, Evans, D. Gareth, Lindblom, Annika, Macrae, Finlay, Blanco, Ignacio, Sijmons, Rolf, Jeffries, Jacqueline, Vasen, Hans, Burn, John, Nakken, Sigve, Hovig, Eivind, Rødland, Einar Andreas, Tharmaratnam, Kukatharmini, de Vos Tot Nederveen Cappel, Wouter H., Hill, James, Wijnen, Juul, Green, Kate, Lalloo, Fiona, Sunde, Lone, Mints, Miriam, Bertario, Lucio, Pineda, Marta, Navarro, Matilde, Morak, Monika, Renkonen-Sinisalo, Laura, Frayling, Ian M., Plazzer, John-Paul, Pylvanainen, Kirsi, Sampson, Julian R., Capella, Gabriel, Mecklin, Jukka-Pekka, Möslein, Gabriela, Mallorca Group (http://mallorca-group.eu), Møller, Pål, Seppälä, Toni, Bernstein, Inge, Holinski-Feder, Elke, Sala, Paola, Evans, D. Gareth, Lindblom, Annika, Macrae, Finlay, Blanco, Ignacio, Sijmons, Rolf, Jeffries, Jacqueline, Vasen, Hans, Burn, John, Nakken, Sigve, Hovig, Eivind, Rødland, Einar Andreas, Tharmaratnam, Kukatharmini, de Vos Tot Nederveen Cappel, Wouter H., Hill, James, Wijnen, Juul, Green, Kate, Lalloo, Fiona, Sunde, Lone, Mints, Miriam, Bertario, Lucio, Pineda, Marta, Navarro, Matilde, Morak, Monika, Renkonen-Sinisalo, Laura, Frayling, Ian M., Plazzer, John-Paul, Pylvanainen, Kirsi, Sampson, Julian R., Capella, Gabriel, Mecklin, Jukka-Pekka, Möslein, Gabriela, and Mallorca Group (http://mallorca-group.eu)

Abstract

OBJECTIVE: Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. DESIGN: We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. RESULTS: 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. CONCLUSIONS: The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Published
2017

154. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Author

CMM Groep De Ridder, Cancer, Genetica, UMC Utrecht, Genetica Sectie Oncogenetica, Child Health, Vogelaar, Ingrid P., van der Post, Rachel S., Van Krieken, J. Han J M, Spruijt, Liesbeth, van Zelst-Stams, Wendy A. G., Kets, C. Marleen, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M., Van Hest, Liselotte P., Pinheiro, Hugo, Oliveira, Carla, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R, De Ligt, Joep, Vissers, Lisenka E L M, Hoischen, Alexander, Gilissen, Christian, Van De Vorst, Maartje, Goeman, Jelle J., Schackert, Hans K, Ranzani, Guglielmina N., Molinaro, Valeria, García, Encarna B.Gómez, Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G.E.M., Sijmons, Rolf H., Wagner, Anja, Van Der Kolk, Lizet E., Bjørnevoll, Inga, Høberg Vetti, Hildegunn, van Kessel, Ad Geurts, Kuiper, Roland P., Ligtenberg, Marjolijn J. L., Hoogerbrugge, Nicoline, CMM Groep De Ridder, Cancer, Genetica, UMC Utrecht, Genetica Sectie Oncogenetica, Child Health, Vogelaar, Ingrid P., van der Post, Rachel S., Van Krieken, J. Han J M, Spruijt, Liesbeth, van Zelst-Stams, Wendy A. G., Kets, C. Marleen, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M., Van Hest, Liselotte P., Pinheiro, Hugo, Oliveira, Carla, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R, De Ligt, Joep, Vissers, Lisenka E L M, Hoischen, Alexander, Gilissen, Christian, Van De Vorst, Maartje, Goeman, Jelle J., Schackert, Hans K, Ranzani, Guglielmina N., Molinaro, Valeria, García, Encarna B.Gómez, Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G.E.M., Sijmons, Rolf H., Wagner, Anja, Van Der Kolk, Lizet E., Bjørnevoll, Inga, Høberg Vetti, Hildegunn, van Kessel, Ad Geurts, Kuiper, Roland P., Ligtenberg, Marjolijn J. L., and Hoogerbrugge, Nicoline

Published
2017

155. Novel algorithms for improved sensitivity in non-invasive prenatal testing

Author

UMC Utrecht, Genetica, Genetica Medische Informatica, Child Health, Genetica Sectie Genoomdiagnostiek, Cancer, Johansson, Lennart F., De Boer, E. N., De Weerd, H. A., van Dijk, F., Elferink, M. G., Schuring-Blom, G. H., Suijkerbuijk, Ron F, Sinke, Richard J., Te Meerman, G. J., Sijmons, Rolf H., Swertz, Morris A., Sikkema-Raddatz, B., UMC Utrecht, Genetica, Genetica Medische Informatica, Child Health, Genetica Sectie Genoomdiagnostiek, Cancer, Johansson, Lennart F., De Boer, E. N., De Weerd, H. A., van Dijk, F., Elferink, M. G., Schuring-Blom, G. H., Suijkerbuijk, Ron F, Sinke, Richard J., Te Meerman, G. J., Sijmons, Rolf H., Swertz, Morris A., and Sikkema-Raddatz, B.

Published
2017

157. Prevalence and Progression of Pancreatic Cystic Precursor Lesions Differ Between Groups at High Risk of Developing Pancreatic Cancer

Author

MS MDL Oncologie, Cancer, MS MDL 1, Genetica Sectie Oncogenetica, Child Health, Konings, Ingrid C A W, Harinck, Femme, Poley, Jan-Werner, Aalfs, Cora M, van Rens, Anja, Krak, Nanda C, Wagner, Anja, Nio, C Yung, Sijmons, Rolf H, van Dullemen, Hendrik M, Vleggaar, Frank P, Ausems, Margreet G E M, Fockens, Paul, van Hooft, Jeanin E, Bruno, Marco J, Dutch Research Group on Pancreatic Cancer Surveillance in High-Risk Individuals, MS MDL Oncologie, Cancer, MS MDL 1, Genetica Sectie Oncogenetica, Child Health, Konings, Ingrid C A W, Harinck, Femme, Poley, Jan-Werner, Aalfs, Cora M, van Rens, Anja, Krak, Nanda C, Wagner, Anja, Nio, C Yung, Sijmons, Rolf H, van Dullemen, Hendrik M, Vleggaar, Frank P, Ausems, Margreet G E M, Fockens, Paul, van Hooft, Jeanin E, Bruno, Marco J, and Dutch Research Group on Pancreatic Cancer Surveillance in High-Risk Individuals

Published
2017

158. GAVIN: Gene-Aware Variant INterpretation for medical sequencing

Author

van der Velde, K. Joeri, primary, de Boer, Eddy N., additional, van Diemen, Cleo C., additional, Sikkema-Raddatz, Birgit, additional, Abbott, Kristin M., additional, Knopperts, Alain, additional, Franke, Lude, additional, Sijmons, Rolf H., additional, de Koning, Tom J., additional, Wijmenga, Cisca, additional, Sinke, Richard J., additional, and Swertz, Morris A., additional

Published
2017
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161. Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

Author

Genetica Sectie Oncogenetica, Child Health, Cancer, Vogelaar, Ingrid P., Ligtenberg, Marjolijn J L, van der Post, Rachel S., de Voer, Richarda M., Kets, C. Marleen, Jansen, Trees J G, Jacobs, Liesbeth, Schreibelt, Gerty, de Vries, I. Jolanda M, Netea, Mihai G., Hoogerbrugge, Nicoline, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Schackert, Hans K., Aalfs, Cora M., Gómez García, Encarna B., Ranzani, Guglielmina N., Molinaro, Valeria, van Hest, Liselotte P., Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G E M, Sijmons, Rolf H., Wagner, Anja, van der Kolk, Lizet E., Pinheiro, Hugo, Oliveira, Carla, Bjørnevoll, Inga, Høberg Vetti, Hildegunn, Van Krieken, J. Han J M, Genetica Sectie Oncogenetica, Child Health, Cancer, Vogelaar, Ingrid P., Ligtenberg, Marjolijn J L, van der Post, Rachel S., de Voer, Richarda M., Kets, C. Marleen, Jansen, Trees J G, Jacobs, Liesbeth, Schreibelt, Gerty, de Vries, I. Jolanda M, Netea, Mihai G., Hoogerbrugge, Nicoline, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Schackert, Hans K., Aalfs, Cora M., Gómez García, Encarna B., Ranzani, Guglielmina N., Molinaro, Valeria, van Hest, Liselotte P., Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G E M, Sijmons, Rolf H., Wagner, Anja, van der Kolk, Lizet E., Pinheiro, Hugo, Oliveira, Carla, Bjørnevoll, Inga, Høberg Vetti, Hildegunn, and Van Krieken, J. Han J M

Published
2016

163. GAVIN - Gene-Aware Variant INterpretation for medical sequencing

Author

van der Velde, K. Joeri, primary, de Boer, Eddy N., additional, van Diemen, Cleo C., additional, Sikkema-Raddatz, Birgit, additional, Abbott, Kristin M., additional, Knopperts, Alain, additional, Franke, Lude, additional, Sijmons, Rolf H., additional, de Koning, Tom J., additional, Wijmenga, Cisca, additional, Sinke, Richard J., additional, and Swertz, Morris A., additional

Published
2016
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165. Charles Buys (1942-2014) OBITUARY

Author

Sijmons, Rolf H., te Meerman, Gerard J., Hofstra, Robert M. W., Clinical Genetics, Ethical, Legal, Social Issues in Genetics (ELSI), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
CARCINOMA, MUTATION, REGION
Published
2014

166. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database.

Author

Møller, Pål, Seppälä, Toni T., Bernstein, Inge, Holinski-Feder, Elke, Sala, Paulo, Evans, D. Gareth, Lindblom, Annika, Macrae, Finlay, Blanco, Ignacio, Sijmons, Rolf H., Jeffries, Jacqueline, Vasen, Hans F. A., Burn, John, Nakken, Sigve, Hovig, Eivind, Rødland, Einar Andreas, Tharmaratnam, Kukatharmini, de Vos tot Nederveen Cappel, Wouter H., Hill, James, and Wijnen, Juul T.

Subjects
HEREDITARY nonpolyposis colorectal cancer, CANCER risk factors, GENES, GENDER, GASTROINTESTINAL cancer
Published
2018
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167. Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1

Author

Genetica Sectie Oncogenetica, Child Health, Cancer, Van Der Post, Rachel S., Vogelaar, Ingrid P., Manders, Peggy, Van Der Kolk, Lizet E., Cats, Annemieke, Van Hest, Liselotte P., Sijmons, Rolf, Aalfs, Cora M., Ausems, Margreet G E M, Gómez García, Encarna B., Wagner, Anja, Hes, Frederik J., Arts, Neeltje, Mensenkamp, Arjen R., Van Krieken, J. Han, Hoogerbrugge, Nicoline, Ligtenberg, Marjolijn J L, Genetica Sectie Oncogenetica, Child Health, Cancer, Van Der Post, Rachel S., Vogelaar, Ingrid P., Manders, Peggy, Van Der Kolk, Lizet E., Cats, Annemieke, Van Hest, Liselotte P., Sijmons, Rolf, Aalfs, Cora M., Ausems, Margreet G E M, Gómez García, Encarna B., Wagner, Anja, Hes, Frederik J., Arts, Neeltje, Mensenkamp, Arjen R., Van Krieken, J. Han, Hoogerbrugge, Nicoline, and Ligtenberg, Marjolijn J L

Published
2015

168. Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1

Author

van der Post, Rachel S., primary, Vogelaar, Ingrid P., additional, Manders, Peggy, additional, van der Kolk, Lizet E., additional, Cats, Annemieke, additional, van Hest, Liselotte P., additional, Sijmons, Rolf, additional, Aalfs, Cora M., additional, Ausems, Margreet G.E.M., additional, Gómez García, Encarna B., additional, Wagner, Anja, additional, Hes, Frederik J., additional, Arts, Neeltje, additional, Mensenkamp, Arjen R., additional, van Krieken, J. Han, additional, Hoogerbrugge, Nicoline, additional, and Ligtenberg, Marjolijn J.L., additional

Published
2015
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169. 294 Higher Prevalence of Cystic Lesions of the Pancreas in First Degree Relatives of Familial Pancreatic Cancer Cases Than in Carriers of Pancreatic Cancer-Prone Gene Mutations

Author

Konings, Ingrid C., primary, Harinck, Femme, additional, Poley, Jan-Werner, additional, Aalfs, Cora M., additional, van Rens, Anja, additional, Krak, Nanda, additional, Wagner, Anja, additional, Nio, Chung Y., additional, Sijmons, Rolf H., additional, Dullemen, Hendrik V., additional, Vleggaar, Frank P., additional, Ausems, Margreet G., additional, Fockens, Paul, additional, van Hooft, Jeanin E., additional, and Bruno, Marco J., additional

Published
2015
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170. Mononucleotide precedes dinucleotide repeat instability during colorectal tumour development in Lynch syndrome patients

Author

Ferreira, Ana M., Westers, Helga, Sousa, Sonia, Wu, Ying, Niessen, Renee C., Olderode-Berends, Maran, van der Sluis, Tineke, Reuvekamp, Peter T. W., Seruca, Raquel, Kleibeuker, Jan H., Hollema, Harry, Sijmons, Rolf H., Hofstra, Robert M. W., Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Targeted Gynaecologic Oncology (TARGON)

Subjects
colorectal adenoma, congenital, hereditary, and neonatal diseases and abnormalities, LEVEL MICROSATELLITE INSTABILITY, MUTATIONS, colorectal cancer, MMR, digestive system diseases, mononucleotide repeats, TRANSFORMATION, mismatch repair, HOMOLOG, Lynch syndrome, CARCINOMAS, ADENOMAS, TUMORIGENESIS, microsatellite instability, dinucleotide repeats, NONPOLYPOSIS COLON-CANCER, MSI, REPEATED SEQUENCES, GENOMIC INSTABILITY
Abstract

A progressive accumulation of genetic alterations underlies the adenoma-carcinoma sequence of colorectal cancer. This accumulation of mutations is driven by genetic instability, of which there are different types. Microsatellite instability (MSI) is the predominant type present in the tumours of Lynch syndrome patients and in a subset of sporadic tumours. It is generally accepted that MSI can be found in the early stages of tumour progression, such as adenomas; however, the frequencies reported vary widely among studies. Moreover, data on the qualitative differences between adenomas and carcinomas, or between tumours of hereditary and sporadic origin, are scarce. We compared MSI in samples of colorectal adenoma and colorectal carcinoma in order to identify possible differences along the adenoma-carcinoma sequence. We compared germline mismatch repair (MMR) gene mutation carriers and non-carriers, to address possible differences of instability patterns between Lynch syndrome patients and patients with sporadic tumours. We found a comparable relative frequency of mono- and dinucleotide instability in sporadic colorectal adenomas and carcinomas, dinucleotide instability being observed most frequently in these sporadic tumours. In MMR gene truncating mutation carriers, the profile was different: colorectal adenomas showed predominantly mononucleotide instability and in colorectal carcinomas, also more mononucleotide than dinucleotide instability was detected. We conclude that MSI profiles differ between sporadic and Lynch syndrome tumours, and that mononucleotide marker instability precedes dinucleotide marker instability during colorectal tumour development in Lynch syndrome patients. As mononucleotide MSI proves to be highly sensitive for detecting mutation carriers, we propose the use of mononucleotide markers for the identification of possible Lynch syndrome patients. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Published
2009

171. Clinical Vignette: Early-Onset Head and Neck Cancer: Beware of Fanconi Anaemia!

Author

Sijmons, Rolf H. and Stulp, Rein P.

Subjects
Diagnosis, Care and treatment, Genetic aspects, Research, Risk factors, Health aspects, Fanconi's anemia -- Genetic aspects -- Risk factors -- Research -- Diagnosis -- Care and treatment, Chemotherapy -- Health aspects -- Research, Radiotherapy -- Health aspects -- Research, Head and neck cancer -- Diagnosis -- Care and treatment -- Research -- Genetic aspects -- Risk factors, Cancer -- Chemotherapy
Abstract

Authors: Rolf H Sijmons (corresponding author) [1]; Rein P Stulp [1] Introduction Our department recently received a letter of referral from an otolaryngologist concerning a 31-year-old Caucasian male with inoperable [...]

Published
2004
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172. Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report.

Author

Seppälä, Toni, Pylvänäinen, Kirsi, Gareth Evans, Dafydd, Järvinen, Heikki, Renkonen-Sinisalo, Laura, Bernstein, Inge, Holinski-Feder, Elke, Sala, Paola, Lindblom, Annika, Macrae, Finlay, Blanco, Ignacio, Sijmons, Rolf, Jeffries, Jacqueline, Vasen, Hans, Burn, John, Nakken, Sigve, Hovig, Eivind, Rødland, Einar Andreas, Tharmaratnam, Kukatharmini, and de Vos tot Nederveen Cappel, Wouter H.

Subjects
COLON cancer risk factors, DISEASE incidence, HEREDITARY nonpolyposis colorectal cancer, POLYPECTOMY, COLONOSCOPY
Abstract

Background: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. Methods: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results: Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). Conclusions: The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval. [ABSTRACT FROM AUTHOR]

Published
2017
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173. Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database.

Author

Møller, Pål, Seppälä, Toni, Bernstein, Inge, Holinski-Feder, Elke, Sala, Paola, Gareth Evans, D., Lindblom, Annika, Macrae, Finlay, Blanco, Ignacio, Sijmons, Rolf, Jeffries, Jacqueline, Vasen, Hans, Burn, John, Nakken, Sigve, Hovig, Eivind, Rødland, Einar Andreas, Tharmaratnam, Kukatharmini, de Vos tot Nederveen Cappel, Wouter H., Hill, James, and Wijnen, Juul

Subjects
HEREDITARY nonpolyposis colorectal cancer, MEDICAL databases
Published
2017
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174. Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk

Author

ten Broeke, Sanne W., primary, Brohet, Richard M., additional, Tops, Carli M., additional, van der Klift, Heleen M., additional, Velthuizen, Mary E., additional, Bernstein, Inge, additional, Capellá Munar, Gabriel, additional, Gomez Garcia, Encarna, additional, Hoogerbrugge, Nicoline, additional, Letteboer, Tom G.W., additional, Menko, Fred H., additional, Lindblom, Annika, additional, Mensenkamp, Arjen R., additional, Moller, Pal, additional, van Os, Theo A., additional, Rahner, Nils, additional, Redeker, Bert J.W., additional, Sijmons, Rolf H., additional, Spruijt, Liesbeth, additional, Suerink, Manon, additional, Vos, Yvonne J., additional, Wagner, Anja, additional, Hes, Frederik J., additional, Vasen, Hans F., additional, Nielsen, Maartje, additional, and Wijnen, Juul T., additional

Published
2015
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175. SORTA: a system for ontology-based re-coding and technical annotation of biomedical phenotype data

Author

Pang, Chao, primary, Sollie, Annet, additional, Sijtsma, Anna, additional, Hendriksen, Dennis, additional, Charbon, Bart, additional, de Haan, Mark, additional, de Boer, Tommy, additional, Kelpin, Fleur, additional, Jetten, Jonathan, additional, van der Velde, Joeri K., additional, Smidt, Nynke, additional, Sijmons, Rolf, additional, Hillege, Hans, additional, and Swertz, Morris A., additional

Published
2015
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176. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

Author

Thompson, Bryony A, Spurdle, Amanda B, Plazzer, John-Paul, Greenblatt, Marc S, Akagi, Kiwamu, Al-Mulla, Fahd, Bapat, Bharati, Bernstein, Inge, Capellá, Gabriel, den Dunnen, Johan T, du Sart, Desiree, Fabre, Aurelie, Farrell, Michael P, Farrington, Susan M, Frayling, Ian M, Frebourg, Thierry, Goldgar, David E, Heinen, Christopher D, Holinski-Feder, Elke, Kohonen-Corish, Maija, Robinson, Kristina Lagerstedt, Leung, Suet Yi, Martins, Alexandra, Moller, Pal, Morak, Monika, Nystrom, Minna, Peltomaki, Paivi, Pineda, Marta, Qi, Ming, Ramesar, Rajkumar, Rasmussen, Lene Juel, Royer-Pokora, Brigitte, Scott, Rodney J, Sijmons, Rolf, Tavtigian, Sean V, Tops, Carli M, Weber, Thomas, Wijnen, Juul, Woods, Michael O, Macrae, Finlay, Genuardi, Maurizio, Castillejo, Adela, Sexton, Adrienne, Chan, Anthony K W, Viel, Alessandra, Blanco, Amie, French, Amy, Laner, Andreas, Wagner, Anja, van den Ouweland, Ans, Thompson, Bryony A, Spurdle, Amanda B, Plazzer, John-Paul, Greenblatt, Marc S, Akagi, Kiwamu, Al-Mulla, Fahd, Bapat, Bharati, Bernstein, Inge, Capellá, Gabriel, den Dunnen, Johan T, du Sart, Desiree, Fabre, Aurelie, Farrell, Michael P, Farrington, Susan M, Frayling, Ian M, Frebourg, Thierry, Goldgar, David E, Heinen, Christopher D, Holinski-Feder, Elke, Kohonen-Corish, Maija, Robinson, Kristina Lagerstedt, Leung, Suet Yi, Martins, Alexandra, Moller, Pal, Morak, Monika, Nystrom, Minna, Peltomaki, Paivi, Pineda, Marta, Qi, Ming, Ramesar, Rajkumar, Rasmussen, Lene Juel, Royer-Pokora, Brigitte, Scott, Rodney J, Sijmons, Rolf, Tavtigian, Sean V, Tops, Carli M, Weber, Thomas, Wijnen, Juul, Woods, Michael O, Macrae, Finlay, Genuardi, Maurizio, Castillejo, Adela, Sexton, Adrienne, Chan, Anthony K W, Viel, Alessandra, Blanco, Amie, French, Amy, Laner, Andreas, Wagner, Anja, and van den Ouweland, Ans

Abstract

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

Published
2014

178. New Target Genes in Endometrial Tumors Show a Role for the Estrogen-Receptor Pathway in Microsatellite-Unstable Cancers

Author

Ferreira, Ana M., primary, Tuominen, Iina, additional, Sousa, Sónia, additional, Gerbens, Frans, additional, van Dijk-Bos, Krista, additional, Osinga, Jan, additional, Kooi, Krista A., additional, Sanjabi, Bahram, additional, Esendam, Chris, additional, Oliveira, Carla, additional, Terpstra, Peter, additional, Hardonk, Menno, additional, van der Sluis, Tineke, additional, Zazula, Monika, additional, Stachura, Jerzy, additional, van der Zee, Ate G., additional, Hollema, Harry, additional, Sijmons, Rolf H., additional, Aaltonen, Lauri A., additional, Seruca, Raquel, additional, Hofstra, Robert M. W., additional, and Westers, Helga, additional

Published
2014
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179. High Frequency ofRPL22Mutations in Microsatellite-Unstable Colorectal and Endometrial Tumors

Author

Ferreira, Ana M., primary, Tuominen, Iina, additional, van Dijk-Bos, Krista, additional, Sanjabi, Bahram, additional, van der Sluis, Tineke, additional, van der Zee, Ate G., additional, Hollema, Harry, additional, Zazula, Monika, additional, Sijmons, Rolf H., additional, Aaltonen, Lauri A., additional, Westers, Helga, additional, and Hofstra, Robert M.W., additional

Published
2014
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180. 673 A Comparative Prospective Blinded Analysis of the Effectiveness of EUS and MRI As Screening Tools for Pancreatic Cancer

Author

Harinck, Femme, primary, Konings, Ingrid C., additional, Poley, Jan-Werner, additional, Krak, Nanda, additional, Biermann, Katharina, additional, Van Hooft, Jeanin E., additional, Nio, Chung Y., additional, Aalfs, Cora M., additional, Van Rens, Anja, additional, Van Eijck, Casper H., additional, Gouma, Dirk, additional, Dijkgraaf, Marcel G., additional, Dullemen, Hendrik V., additional, Sijmons, Rolf H., additional, Fockens, Paul, additional, and Brun, Marco J., additional

Published
2014
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181. Risks of Less Common Cancers in Proven Mutation Carriers With Lynch Syndrome

Author

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

182. Capturing all disease-causing mutations for clinical and research use: Toward an effortless system for the Human Variome Project

Author

Cotton, Richard G.H., Al Aqeel, Aida I., Al-Mulla, Fahd, Carrera, Paola, Claustres, Mireille, Ekong, Rosemary, Hyland, Valentine J., Macrae, Finlay A., Marafie, Makia J., Paalman, Mark H., Patrinos, George P., Qi, Ming, Ramesar, Rajkumar S., Scott, Rodney J., Sijmons, Rolf H., Sobrido, María-Jesús, and Vihinen, Mauno

Published
2009
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183. Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non-polyposis colorectal cancer

Author

Sijmons, Rolf, Hofstra, Roelof, Hollema, Harmen, Mensink, R, VANDERHOUT, A, Hoekstra, Harald, Kleibeuker, Jan, Molenaar, Willemina, Wijnen, Juul, Fodde, R, Vasen, H, Buys, Carolus, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Targeted Gynaecologic Oncology (TARGON)

Subjects
RISK, congenital, hereditary, and neonatal diseases and abnormalities, MUTATIONS, INSTABILITY, SURVIVAL, nutritional and metabolic diseases, HNPCC, neoplasms, digestive system diseases
Abstract

Sarcomas, including the malignant fibrous histiocytomas (MFHs), are not known to be part of the tumour spectrum of hereditary non-polyposis colorectal cancer (HNPCC) as epidemiologically established. Therefore, occurrence of MFH in an HNPCC family may very well be coincidental. HNPCC is associated with germline mutations in DNA mismatch repair genes, including the MSH2 gene. We analysed an MFH diagnosed in a 45-year-old male HNPCC patient carrying a germline MSH2 mutation for HNPCC-associated molecular characteristics, to investigate a possible relationship between the tumour and that mutation. DNA analysis revealed microsatellite instability and loss of one MSH2 copy, and immunohistochemistry showed absence of nuclear MSH2 protein staining. To investigate whether this is a common finding in MFH, microsatellite instability and nuclear MSH2 protein staining was tested for in 5 and 6 sporadic MFHs, respectively. None showed microsatellite instability and all stained positively for MSH2. Together, these findings show that in rare cases, MFH may be part of the HNPCC tumour spectrum. (C) 2000 Wiley-Liss, Inc.

Published
2000

184. Malignant peritoneal mesothelioma in a patient with Li-Fraumeni syndrome

Author

Ghent University Hospital - Department of Pathology, Ceelen, Wim P, Van Dalen, Thijs, Van Bockstal, Mieke, Libbrecht, Louis, Sijmons, Rolf H, Ghent University Hospital - Department of Pathology, Ceelen, Wim P, Van Dalen, Thijs, Van Bockstal, Mieke, Libbrecht, Louis, and Sijmons, Rolf H

Abstract

A 60-year-old Caucasian woman who was known to carry a germline c.473GA (p.Arg158His) mutation in the TP53 gene, which causes Li-Fraumeni syndrome (LFS), was scheduled for surgery for an umbilical hernia in another hospital. The patient’s history included a cholecystectomy for symptomatic lithiasis 20 years earlier; there was no identifiable exposure to asbestos. During surgery, pathologic thickening of the peritoneum was noted along with small soft, pinkish nodules on the visceral and parietal peritoneal surfaces. Biopsies of these lesions demonstrated a malignant peritoneal mesothelioma of the epithelioid type. Additional staging was performed using positron emission tomography– computed tomography scanning, which showed extensive [18F]fluorodeoxyglucose-avid lesions in the greater omentum and pelvis (Figs 1A and 1B) and a small amount of ascites, but no extra-abdominal disease. [...]

Published
2011

185. Deciphering the colon cancer genes--report of the InSiGHT-Human Variome Project Workshop, UNESCO, Paris 2010

Author

Kohonen-Corish, Maija R J, Macrae, Finlay, Genuardi, Maurizio, Aretz, Stefan, Bapat, Bharati, Bernstein, Inge T, Burn, John, Cotton, Richard G H, den Dunnen, Johan T, Frebourg, Thierry, Greenblatt, Marc S, Hofstra, Robert, Holinski-Feder, Elke, Lappalainen, Ilkka, Lindblom, Annika, Maglott, Donna, Møller, Pål, Morreau, Hans, Möslein, Gabriela, Sijmons, Rolf, Spurdle, Amanda B, Tavtigian, Sean, Tops, Carli M J, Weber, Thomas K, de Wind, Niels, Woods, Michael O, Kohonen-Corish, Maija R J, Macrae, Finlay, Genuardi, Maurizio, Aretz, Stefan, Bapat, Bharati, Bernstein, Inge T, Burn, John, Cotton, Richard G H, den Dunnen, Johan T, Frebourg, Thierry, Greenblatt, Marc S, Hofstra, Robert, Holinski-Feder, Elke, Lappalainen, Ilkka, Lindblom, Annika, Maglott, Donna, Møller, Pål, Morreau, Hans, Möslein, Gabriela, Sijmons, Rolf, Spurdle, Amanda B, Tavtigian, Sean, Tops, Carli M J, Weber, Thomas K, de Wind, Niels, and Woods, Michael O

Abstract

The Human Variome Project (HVP) has established a pilot program with the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) to compile all inherited variation affecting colon cancer susceptibility genes. An HVP-InSiGHT Workshop was held on May 10, 2010, prior to the HVP Integration and Implementation Meeting at UNESCO in Paris, to review the progress of this pilot program. A wide range of topics were covered, including issues relating to genotype-phenotype data submission to the InSiGHT Colon Cancer Gene Variant Databases (chromium.liacs.nl/LOVD2/colon_cancer/home.php). The meeting also canvassed the recent exciting developments in models to evaluate the pathogenicity of unclassified variants using in silico data, tumor pathology information, and functional assays, and made further plans for the future progress and sustainability of the pilot program.

Published
2011

186. Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome

Author

Ou, Jianghua, Rasmussen, Merete, Westers, Helga, Andersen, Sofie D, Jager, Paul O, Kooi, Krista A, Niessen, Renée C, Eggen, Bart J L, Nielsen, Finn C, Kleibeuker, Jan H, Sijmons, Rolf H, Rasmussen, Lene J, Hofstra, Robert M W, Ou, Jianghua, Rasmussen, Merete, Westers, Helga, Andersen, Sofie D, Jager, Paul O, Kooi, Krista A, Niessen, Renée C, Eggen, Bart J L, Nielsen, Finn C, Kleibeuker, Jan H, Sijmons, Rolf H, Rasmussen, Lene J, and Hofstra, Robert M W

Abstract

Udgivelsesdato: 2009-Apr, So far 18 MLH3 germline mutations/variants have been identified in familial colorectal cancer cases. Sixteen of these variants are amino acid substitutions of which the pathogenic nature is still unclear. These substitutions are known as unclassified variants or UVs. To clarify a possible role for eight of these MLH3 UVs identified in suspected Lynch syndrome patients, we performed several biochemical tests. We determined the protein expression and stability, protein localization and interaction of the mutant MLH3 proteins with wildtype MLH1. All eight MLH3 UVs gave protein expression levels comparable with wildtype MLH3. Furthermore, the UV-containing proteins, in contrast to previous studies, were all localized normally in the nucleus and they interacted normally with wildtype MLH1. Our different biochemical assays yielded no evidence that the eight MLH3 UVs tested are the cause of hereditary colorectal cancer, including Lynch syndrome.

Published
2009

187. Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis

Author

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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188. Reusability of coded data in the primary care electronic medical record: A dynamic cohort study concerning cancer diagnoses.

Author

Sollie, Annet, Sijmons, Rolf H., Helsper, Charles, and Numans, Mattijs E.

Subjects
*CANCER diagnosis, *ELECTRONIC health records, *PRIMARY care, *COHORT analysis, *MEDICAL databases, *TUMOR diagnosis, *DATABASES, *LONGITUDINAL method, *PRIMARY health care, *TUMORS, *DISEASE incidence, *ACQUISITION of data, *STANDARDS
Abstract

Objectives: To assess quality and reusability of coded cancer diagnoses in routine primary care data. To identify factors that influence data quality and areas for improvement.Methods: A dynamic cohort study in a Dutch network database containing 250,000 anonymized electronic medical records (EMRs) from 52 general practices was performed. Coded data from 2000 to 2011 for the three most common cancer types (breast, colon and prostate cancer) was compared to the Netherlands Cancer Registry.Measurements: Data quality is expressed in Standard Incidence Ratios (SIRs): the ratio between the number of coded cases observed in the primary care network database and the expected number of cases based on the Netherlands Cancer Registry. Ratios were multiplied by 100% for readability.Results: The overall SIR was 91.5% (95%CI 88.5-94.5) and showed improvement over the years. SIRs differ between cancer types: from 71.5% for colon cancer in males to 103.9% for breast cancer. There are differences in data quality (SIRs 76.2% - 99.7%) depending on the EMR system used, with SIRs up to 232.9% for breast cancer. Frequently observed errors in routine healthcare data can be classified as: lack of integrity checks, inaccurate use and/or lack of codes, and lack of EMR system functionality.Conclusions: Re-users of coded routine primary care Electronic Medical Record data should be aware that 30% of cancer cases can be missed. Up to 130% of cancer cases found in the EMR data can be false-positive. The type of EMR system and the type of cancer influence the quality of coded diagnosis registry. While data quality can be improved (e.g. through improving system design and by training EMR system users), re-use should only be taken care of by appropriately trained experts. [ABSTRACT FROM AUTHOR]

Published
2017
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189. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.

Author

Møller, Pål, Seppälä, Toni, Bernstein, Inge, Holinski-Feder, Elke, Sala, Paola, Evans, D. Gareth, Lindblom, Annika, Macrae, Finlay, Blanco, Ignacio, Sijmons, Rolf, Jeffries, Jacqueline, Vasen, Hans, Burn, John, Nakken, Sigve, Hovig, Eivind, Rødland, Einar Andreas, Tharmaratnam, Kukatharmini, de Vos tot Nederveen Cappel, Wouter H., Hill, James, and Wijnen, Juul

Subjects
HEREDITARY nonpolyposis colorectal cancer, CANCER risk factors, DISEASE incidence, SURVIVAL analysis (Biometry), LONGITUDINAL method, PATIENTS
Published
2017
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191. Design and Feasibility of an Intervention to Support Cancer Genetic Counselees in Informing their At-Risk Relatives.

Author

Geus, Eveline, Eijzenga, Willem, Menko, Fred, Sijmons, Rolf, Haes, Hanneke, Aalfs, Cora, and Smets, Ellen

Abstract

Cancer genetic counselees receive individualized information regarding heightened risks and medical recommendations which is also relevant for their at-risk relatives. Unfortunately, counselees often insufficiently inform these relatives. We designed an intervention aimed at improving counselees' knowledge regarding which at-risk relatives to inform and what information to disclose, their motivation to disclose, and their self-efficacy. The intervention, offered by telephone by trained psychosocial workers, is based on the principles of Motivational Interviewing. Phase 1 of the intervention covers agenda setting, exploration, and evaluation, and phase 2 includes information provision, enhancing motivation and self-efficacy, and brainstorming for solutions to disseminate information within the family. Fidelity and acceptability of the intervention were assessed using recordings of intervention sessions and by counselee self-report. A total of 144 counselees participated. Psychosocial workers ( n = 5) delivered the intervention largely as intended. Counselees highly appreciated the content of the intervention and the psychosocial workers who delivered the intervention. In the sessions, psychosocial workers provided additional and/or corrective information, and brainstorming for solutions was performed in 70 %. These results indicate that this intervention is feasible and warrants testing in clinical practice. For this, a randomized controlled trial is currently in progress to test the intervention's efficacy. [ABSTRACT FROM AUTHOR]

Published
2016
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192. CoNVaDING: Single Exon Variation Detection in Targeted NGS Data.

Author

Johansson, Lennart F., Dijk, Freerk, Boer, Eddy N., Dijk‐Bos, Krista K., Jongbloed, Jan D.H., der Hout, Annemieke H., Westers, Helga, Sinke, Richard J., Swertz, Morris A., Sijmons, Rolf H., and Sikkema‐Raddatz, Birgit

Abstract

ABSTRACT We have developed a tool for detecting single exon copy-number variations (CNVs) in targeted next-generation sequencing data: CoNVaDING (Copy Number Variation Detection In Next-generation sequencing Gene panels). CoNVaDING includes a stringent quality control (QC) metric, that excludes or flags low-quality exons. Since this QC shows exactly which exons can be reliably analyzed and which exons are in need of an alternative analysis method, CoNVaDING is not only useful for CNV detection in a research setting, but also in clinical diagnostics. During the validation phase, CoNVaDING detected all known CNVs in high-quality targets in 320 samples analyzed, giving 100% sensitivity and 99.998% specificity for 308,574 exons. CoNVaDING outperforms existing tools by exhibiting a higher sensitivity and specificity and by precisely identifying low-quality samples and regions. [ABSTRACT FROM AUTHOR]

Published
2016
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195. Risks of Less Common Cancers in Proven Mutation Carriers With Lynch Syndrome

Author

Engel, Christoph, primary, Loeffler, Markus, additional, Steinke, Verena, additional, Rahner, Nils, additional, Holinski-Feder, Elke, additional, Dietmaier, Wolfgang, additional, Schackert, Hans K., additional, Goergens, Heike, additional, von Knebel Doeberitz, Magnus, additional, Goecke, Timm O., additional, Schmiegel, Wolff, additional, Buettner, Reinhard, additional, Moeslein, Gabriela, additional, Letteboer, Tom G.W., additional, García, Encarna Gómez, additional, Hes, Frederik J., additional, Hoogerbrugge, Nicoline, additional, Menko, Fred H., additional, van Os, Theo A.M., additional, Sijmons, Rolf H., additional, Wagner, Anja, additional, Kluijt, Irma, additional, Propping, Peter, additional, and Vasen, Hans F.A., additional

Published
2012
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196. Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions

Author

Thompson, Bryony A., primary, Greenblatt, Marc S., additional, Vallee, Maxime P., additional, Herkert, Johanna C., additional, Tessereau, Chloe, additional, Young, Erin L., additional, Adzhubey, Ivan A., additional, Li, Biao, additional, Bell, Russell, additional, Feng, Bingjian, additional, Mooney, Sean D., additional, Radivojac, Predrag, additional, Sunyaev, Shamil R., additional, Frebourg, Thierry, additional, Hofstra, Robert M.W., additional, Sijmons, Rolf H., additional, Boucher, Ken, additional, Thomas, Alun, additional, Goldgar, David E., additional, Spurdle, Amanda B., additional, and Tavtigian, Sean V., additional

Published
2012
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197. Indication forCDKN2A-mutation analysis in familial pancreatic cancer families without melanomas

Author

Harinck, Femme, primary, Kluijt, Irma, additional, van der Stoep, Nienke, additional, Oldenburg, Rogier A, additional, Wagner, Anja, additional, Aalfs, Cora M, additional, Sijmons, Rolf H, additional, Poley, Jan-Werner, additional, Kuipers, Ernst J, additional, Fockens, Paul, additional, van Os, Theo A M, additional, and Bruno, Marco J, additional

Published
2012
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198. Su1816 Prospective Evaluation of Psychological Impact of Pancreatic Cancer Surveillance in High-Risk Individuals

Author

Harinck, Femme, primary, Nagtegaal, Tanja, additional, Kluijt, Irma, additional, Aalfs, Cora M., additional, Smets, Ellen, additional, Poley, Jan-Werner, additional, Wagner, Anja, additional, Sidharta, Grace N., additional, van Hooft, Jeanin E., additional, van Dullemen, Hendrik, additional, Sijmons, Rolf H., additional, Fockens, Paul, additional, Bruno, Marco J., additional, and Bleiker, Eveline, additional

Published
2012
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200. Role of germline aberrations affecting CTNNA1, MAP3K6and MYD88in gastric cancer susceptibility

Author

Weren, Robbert D A, van der Post, Rachel S, Vogelaar, Ingrid P, van Krieken, J Han, Spruijt, Liesbeth, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M, van Hest, Liselotte P, Oliveira, Carla, Kamping, Eveline J, Schackert, Hans K, Ranzani, Guglielmina N, Gómez Garcóía, Encarna B, Hes, Frederik J, Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G E M, Sijmons, Rolf H, Wagner, Anja, van der Kolk, Lizet E, Cats, Annemieke, Bjørnevoll, Inga, Hoogerbrugge, Nicoline, and Ligtenberg, Marjolijn J L

Abstract

BackgroundIn approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6or MYD88.MethodsWe sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6and MYD88using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.ResultsPredicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1(n=2) and MAP3K6(n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6also occur frequently in the general population.ConclusionsBased on our results MAP3K6should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

Published
2018
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