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201. Erratum: Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia

Author

Schubert, Stephanie A, primary, Ruano, Dina, additional, Elsayed, Fadwa A, additional, Boot, Arnoud, additional, Crobach, Stijn, additional, Sarasqueta, Arantza Farina, additional, Wolffenbuttel, Bruce, additional, van der Klauw, Melanie M, additional, Oosting, Jan, additional, Tops, Carli M, additional, van Eijk, Ronald, additional, Vasen, Hans FA, additional, Vossen, Rolf HAM, additional, Nielsen, Maartje, additional, Castellví-Bel, Sergi, additional, Ruiz-Ponte, Clara, additional, Tomlinson, Ian, additional, Dunlop, Malcolm G, additional, Vodicka, Pavel, additional, Wijnen, Juul T, additional, Hes, Frederik J, additional, Morreau, Hans, additional, de Miranda, Noel FCC, additional, Sijmons, Rolf H, additional, and van Wezel, Tom, additional

Published
2017
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203. Statin Use After Diagnosis of Colon Cancer and Patient Survival

Author

Voorneveld, Philip W., primary, Reimers, Marlies S., additional, Bastiaannet, Esther, additional, Jacobs, Rutger J., additional, van Eijk, Ronald, additional, Zanders, Marjolein M.J., additional, Herings, Ron M.C., additional, van Herk-Sukel, Myrthe P.P., additional, Kodach, Liudmila L., additional, van Wezel, Tom, additional, Kuppen, Peter J.K., additional, Morreau, Hans, additional, van de Velde, Cornelis J.H., additional, Hardwick, James C.H., additional, and Liefers, Gerrit Jan, additional

Published
2017
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204. Diagnostic value of ultra-deep targeted next-generation sequencing in patients with suspect pancreatic and periampullary lesions

Author

Mulder, Babs Sibinga, primary, Mieog, Sven, additional, Sarasqueta, Akin Farina, additional, Handgraaf, Henricus, additional, Vasen, Hans, additional, Swijnenburg, Rutger-Jan, additional, Luelmo, Saskia, additional, Feshtali, Shirin, additional, Inderson, Akin, additional, Vahrmeijer, Alexander, additional, Bonsing, Bert, additional, van Wezel, Tom, additional, and Morreau, Hans, additional

Published
2017
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205. POLEandPOLD1screening in 155 patients with multiple polyps and early-onset colorectal cancer

Author

Esteban-Jurado, Clara, primary, Giménez-Zaragoza, David, additional, Muñoz, Jenifer, additional, Franch-Expósito, Sebastià, additional, Álvarez-Barona, Miriam, additional, Ocaña, Teresa, additional, Cuatrecasas, Miriam, additional, Carballal, Sabela, additional, López-Cerón, María, additional, Marti-Solano, Maria, additional, Díaz-Gay, Marcos, additional, van Wezel, Tom, additional, Castells, Antoni, additional, Bujanda, Luis, additional, Balmaña, Judith, additional, Gonzalo, Victoria, additional, Llort, Gemma, additional, Ruiz-Ponte, Clara, additional, Cubiella, Joaquín, additional, Balaguer, Francesc, additional, Aligué, Rosa, additional, and Castellví-Bel, Sergi, additional

Published
2017
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206. Distinct Patterns of Somatic Mosaicism in the APC Gene in Neoplasms From Patients With Unexplained Adenomatous Polyposis

Author

Jansen, Anne M.L., primary, Crobach, Stijn, additional, Geurts-Giele, Willemina R.R., additional, van den Akker, Brendy E.W.M., additional, Garcia, Marina Ventayol, additional, Ruano, Dina, additional, Nielsen, Maartje, additional, Tops, Carli M.J., additional, Wijnen, Juul T., additional, Hes, Frederik J., additional, van Wezel, Tom, additional, Dinjens, Winand N.M., additional, and Morreau, Hans, additional

Published
2017
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207. The Influence of BRAF and KRAS Mutation Status on the Association between Aspirin Use and Survival after Colon Cancer Diagnosis

Author

Frouws, Martine A., primary, Reimers, Marlies S., additional, Swets, Marloes, additional, Bastiaannet, Esther, additional, Prinse, Bianca, additional, van Eijk, Ronald, additional, Lemmens, Valery E. P. P., additional, van Herk-Sukel, Myrthe P. P., additional, van Wezel, Tom, additional, Kuppen, Peter J. K., additional, Morreau, Hans, additional, van de Velde, Cornelis J. H., additional, and Liefers, Gerrit-Jan, additional

Published
2017
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209. The complexity of screening PMS2 in DNA isolated from formalin-fixed paraffin-embedded material

Author

Jansen, Anne M. L., Tops, Carli M. J., Ruano, Dina, van Eijk, Ronald, Wijnen, Juul T., ten Broeke, Sanne, Nielsen, Maartje, Hes, Frederik J., van Wezel, Tom, and Morreau, Hans

Abstract

Germline variants in the DNA mismatch repair (MMR) gene PMS2cause 1–14% of all Lynch Syndrome cancers. Correct variant analysis of PMS2is complex due to the presence of multiple pseudogenes and the occurrence of gene conversion. The analysis complexity increases in highly fragmented DNA from formalin-fixed paraffin-embedded (FFPE) tissue. Here we describe a reliable approach to detect true PMS2variants in fragmented DNA. A custom NGS panel designed for FFPE tissue was used targeting four MMR genes, POLEand POLD1. Amplicon design for PMS2was based on the position of paralogous sequence variants (PSVs) that distinguish PMS2from its pseudogenes. PMS2variants in exons 1–11 can be correctly curated based on this information. For exons 12–15 this is less reliable as these undergo gene conversion. Using this method, we screened PMS2variants in 125 MMR-deficient tumors. Of the 125 tumors tested, six were unexplained MMR-deficient tumors with solitary PMS2 protein expression loss. In these six tumors two unclassified variants (class 3) and five variants likely affecting function (class 4/5) were detected in PMS2. One microsatellite unstable tumor with positive staining for all MMR proteins was found to carry a frameshift PMS2variant (class 5). No class 4 or class 5 PMS2variants were detected in tumors with other patterns of MMR protein expression loss.

Published
2020
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210. Declining detection rates for APCand biallelic MUTYHvariants in polyposis patients, implications for DNA testing policy

Author

Terlouw, Diantha, Suerink, Manon, Singh, Sunny S., Gille, Hans J. J. P., Hes, Frederik J., Langers, Alexandra M. J., Morreau, Hans, Vasen, Hans F. A., Vos, Yvonne J., van Wezel, Tom, Tops, Carli. M., ten Broeke, Sanne W., and Nielsen, Maartje

Abstract

This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APCand MUTYHvariant analysis between 1992 and 2017 were collected (n= 2082). Using the data provided on the application form, the APCand biallelic MUTYHprevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APCgene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50–99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged <60 and >20 adenomas aged <70. Patients with variants outside these criteria had FAP-related extracolonic manifestations, colorectal cancer aged <40, somatic KRASc.34G > T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APCand MUTYHtesting in patients with >10 adenomas aged <60 and with >20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing.

Published
2020
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211. Targeted next generation sequencing screening of Lynch syndrome in Tunisian population.

Author

Ben Sghaier, Rihab, Jansen, Anne Maria Lucia, Bdioui, Ahlem, Van Wezel, Tom, ksiaa, Mehdi, Elgolli, Lamia, Ben Fatma, Leila, Ben Ahmed, Slim, Azzouz, Mohamed Msaddak, Hellara, Olfa, Elghali, Amine, Darbel, Fathi, Skandrani, Karim, Mokkni, Moncef, Gdissa, Ameni, Ltaief, Rached, Saad, Ali, Hmila, Fahmi, Gribaa, Moez, and Morreau, Hans

Subjects
HEREDITARY nonpolyposis colorectal cancer, IMMUNOSTAINING, DNA mismatch repair, COLON cancer
Abstract

A high colorectal cancer (CRC) incidence is observed in Tunisia, with a relatively high proportion of patients developing CRC before the age of 40. While this suggests a genetic susceptibility, only a few Tunisian Lynch Syndrome families have been described. In this study we aimed to identify the underlying genetic cause in 32 patients with early onset CRC and/or a positive family history. Of twenty-four patients' tumor or biopsies could be analyzed with immunohistochemical staining to detect loss of expression of one of the MMR proteins. Ten tumors showed loss of expression, of which one tumor was from a patient where a germline pathogenic MSH2 variant was detected previously with Sanger sequencing. Next generation sequencing of the MMR, POLE and POLD1 genes was performed in leukocyte and tumor DNA of the remaining nine patients, as well as in two patients with MMR-proficient tumors, but with severe family history. In six of 11 patients a germline variant was detected in MLH1 (n = 5) or MSH2 (n = 1). Two of six patients were from the same family and both were found to carry a novel in-frame MLH1 deletion, predicted to affect MLH1 function. All MLH1 variant carriers had loss of heterozygosity with retention of the variant in the tumors, while a somatic pathogenic variant was detected in the patient with the germline MSH2 variant. [ABSTRACT FROM AUTHOR]

Published
2019
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212. Recurrent CLTC::SYKfusions and CSF1Rmutations in juvenile xanthogranuloma of soft tissue

Author

Kemps, Paul G., Baelde, Hans J., Vorderman, Ruben H. P., Stelloo, Ellen, Swennenhuis, Joost F., Szuhai, Karoly, Lamers, Meindert H., Kenkhuis, Boyd, Al-Hussaini, Maysa, Briaire-de Bruijn, Inge H., Lam, Suk Wai, Bovée, Judith V. M. G., Cleven, Arjen H. G., Verdijk, Robert M., van Noesel, Carel J. M., van Dijk, Marijke R., Scheijde-Vermeulen, Marijn A., Bruggink, Annette H., van Laar, Jan A. M., de Vries, Andrica C. H., Tissing, Wim J. E., van den Bos, Cor, von Deimling, Andreas, van Wezel, Tom, van Halteren, Astrid G. S., and Hogendoorn, Pancras C. W.

Abstract

•CLTC::SYKfusions and CSF1Rmutations are recurrent genetic alterations in JXG of soft tissue.•BRAF, MAP2K1, or NTRK1alterations may be detected in CNS- or systemic JXG, enabling targeted therapy when necessary.

Published
2024
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213. Recurrent ETV3::NCOA2fusions and MAPK pathway mutations in indeterminate dendritic cell histiocytosis

Author

Kemps, Paul G., Woei-A-Jin, F. J. Sherida H., Quint, Koen D., van den Bos, Cor, Naeije, Leonie, van Laar, Jan A. M., Vanden Bempt, Isabelle, Koudijs, Marco J., Vorderman, Ruben H. P., Stelloo, Ellen, Swennenhuis, Joost F., Bruggink, Annette H., Hebeda, Konnie M., Scheijde-Vermeulen, Marijn A., Diercks, Gilles F. H., Verdijk, Robert M., Jansen, Patty M., Hauben, Esther, Tousseyn, Thomas, Cleven, Arjen H. G., van Wezel, Tom, van Halteren, Astrid G. S., and Hogendoorn, Pancras C. W.

Published
2024
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214. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

Author

Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, Morreau, Hans, Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, and Morreau, Hans

Published
2016

215. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

Author

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

216. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

Author

Genetica Sectie Oncogenetica, Child Health, Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, Morreau, Hans, Genetica Sectie Oncogenetica, Child Health, Jansen, Anne Ml, van Wezel, Tom, van den Akker, Brendy Ewm, Ventayol Garcia, Marina, Ruano, Dina, Tops, Carli Mj, Wagner, Anja, Letteboer, Tom Gw, Gómez-García, Encarna B, Devilee, Peter, Wijnen, Juul T, Hes, Frederik J, and Morreau, Hans

Published
2016

217. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

Author

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

218. The MLH1 c.1852_1853delinsGC (p.K618A) Variant in Colorectal Cancer: Genetic Association Study in 18,723 Individuals

Author

Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, Castellví-Bel, Sergi, and Universitat de Barcelona

Subjects
Male, tumors, Heredity, BIOCHEMISTRY AND MOLECULAR BIOLOGY, Genetic Linkage, Colorectal cancer, Epidemiology, lcsh:Medicine, Genome-wide association study, HEREDITARY, Bioinformatics, Cohort Studies, INDEL Mutation, lynch syndrome, Gastrointestinal Cancers, Medicine and Health Sciences, PMS2, Malalties hereditàries, Molecular genetics, lcsh:Science, Càncer -- Aspectes genètics, Mismatch Repair Endonuclease PMS2, risk, Adenosine Triphosphatases, RISK, Multidisciplinary, Cancer Risk Factors, LYNCH SYNDROME, Nuclear Proteins, Genomics, TUMORS, Lynch syndrome, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, Oncology, classification, Còlon -- Càncer, AGRICULTURAL AND BIOLOGICAL SCIENCES, Female, Colorectal Neoplasms, MutL Protein Homolog 1, hereditary, Research Article, Genetic diseases, metaanalysis, congenital, hereditary, and neonatal diseases and abnormalities, SUSCEPTIBILITY LOCI, Genetic Causes of Cancer, Mutation, Missense, Gastroenterology and Hepatology, Biology, MLH1, CLASSIFICATION, Genètica molecular, Familial adenomatous polyposis, Genomic Medicine, Càncer colorectal, Genetics, Cancer Genetics, medicine, Humans, Genetic Testing, GENOME-WIDE ASSOCIATION, Epidemiologia, Genetic Association Studies, Germ-Line Mutation, METAANALYSIS, Adaptor Proteins, Signal Transducing, IDENTIFICATION, MUTATIONS, MEDICINE, lcsh:R, Biology and Life Sciences, Human Genetics, medicine.disease, mutations, digestive system diseases, susceptibility loci, MSH6, DNA Repair Enzymes, Amino Acid Substitution, MSH2, Genetics of Disease, genome-wide association, identification, lcsh:Q, Genètica
Abstract

Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance'', being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome. This work was supported by COST Action BM1206. Groups 1, 4, 5, 6, 7, 8, 10 and 13 are active members of this consortium. Edinburgh: This work was supported by a Cancer Research UK Programme Grant (C348/A12076) and a Centre Grant from the CORE Charity. Epicolon: SCB is supported by a contract from the Fondo de Investigacion Sanitaria (CP 03-0070). JM and CEJ are supported by contracts from the CIBERehd. CIBERehd and CIBERER are funded by the Instituto de Salud Carlos III. This work was supported by grants from the Fondo de Investigacion Sanitaria/FEDER (11/00219, 11/00681), Instituto de Salud Carlos III (Accion Transversal de Cancer), Xunta de Galicia (07PXIB9101209PR), Ministerio de Ciencia e Innovacion (SAF2010-19273), Asociacion Espanola contra el Cancer (Fundacion Cientifica GCB13131592CAST y Junta de Barcelona), Fundacio Olga Torres (SCB and CRP) and FP7 CHIBCHA Consortium (SCB and ACar). Kiel: This work was supported by the German Ministry for Education and Research through the German National Genome Research Network (NGFNplus) Colon Cancer Network (CCN). Leiden: This work was supported by the Dutch Cancer Society with grant KWF-UL-2005-3247. Stockholm: The Swedish sample and data resource were funded by the Swedish Cancer Society, the Swedish Scientific Research Council and the Stockholm Cancer Foundation. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Published
2014

219. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study

Author

Domingo, Enric, primary, Freeman-Mills, Luke, additional, Rayner, Emily, additional, Glaire, Mark, additional, Briggs, Sarah, additional, Vermeulen, Louis, additional, Fessler, Evelyn, additional, Medema, Jan Paul, additional, Boot, Arnoud, additional, Morreau, Hans, additional, van Wezel, Tom, additional, Liefers, Gerrit-Jan, additional, Lothe, Ragnhild A, additional, Danielsen, Stine A, additional, Sveen, Anita, additional, Nesbakken, Arild, additional, Zlobec, Inti, additional, Lugli, Alessandro, additional, Koelzer, Viktor H, additional, Berger, Martin D, additional, Castellví-Bel, Sergi, additional, Muñoz, Jenifer, additional, de Bruyn, Marco, additional, Nijman, Hans W, additional, Novelli, Marco, additional, Lawson, Kay, additional, Oukrif, Dahmane, additional, Frangou, Eleni, additional, Dutton, Peter, additional, Tejpar, Sabine, additional, Delorenzi, Mauro, additional, Kerr, Rachel, additional, Kerr, David, additional, Tomlinson, Ian, additional, and Church, David N, additional

Published
2016
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220. Targeted next-generation sequencing of FNA-derived DNA in pancreatic cancer

Author

Sibinga Mulder, Babs G, primary, Mieog, J Sven D, additional, Handgraaf, Henricus J M, additional, Farina Sarasqueta, Arantza, additional, Vasen, Hans F A, additional, Potjer, Thomas P, additional, Swijnenburg, Rutger-Jan, additional, Luelmo, Saskia A C, additional, Feshtali, Shirin, additional, Inderson, Akin, additional, Vahrmeijer, Alexander L, additional, Bonsing, Bert A, additional, van Wezel, Tom, additional, and Morreau, Hans, additional

Published
2016
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223. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients

Author

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
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224. Correspondence: SEMA4A variation and risk of colorectal cancer

Author

Kinnersley, Ben, primary, Chubb, Daniel, additional, Dobbins, Sara E., additional, Frampton, Matthew, additional, Buch, Stephan, additional, Timofeeva, Maria N., additional, Castellví-Bel, Sergi, additional, Farrington, Susan M., additional, Forsti, Asta, additional, Hampe, Jochen, additional, Hemminki, Kari, additional, Hofstra, Robert M. W., additional, Northwood, Emma, additional, Palles, Claire, additional, Pinheiro, Manuela, additional, Ruiz-Ponte, Clara, additional, Schafmayer, Clemens, additional, Teixeira, Manuel R., additional, Westers, Helga, additional, van Wezel, Tom, additional, Timothy Bishop, D., additional, Tomlinson, Ian, additional, Dunlop, Malcolm G., additional, and Houlston, Richard S., additional

Published
2016
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227. Transforming Growth Factor beta Signaling in Colorectal Cancer Cells With Microsatellite Instability Despite Biallelic Mutations in TGFBR2

Author

de Miranda, Noel F. C. C., van Dinther, Maarten, van den Akker, Brendy E. W. M., van Wezel, Tom, ten Dijke, Peter, Morreau, Hans, de Miranda, Noel F. C. C., van Dinther, Maarten, van den Akker, Brendy E. W. M., van Wezel, Tom, ten Dijke, Peter, and Morreau, Hans

Abstract

BACKGROUND & AIMS: Most colorectal cancer (CRC) cells with high levels of microsatellite instability (MSI-H) accumulate mutations at a microsatellite sequence in the gene encoding transforming growth factor beta receptor II (TGFBR2). TGF beta signaling therefore is believed to be defective in these tumors, although CRC cells with TGFBR2 mutations have been reported to remain sensitive to TGF beta. We investigated how TGF beta signaling might continue in MSI-H CRC cells. METHODS: We sequenced the 10-adenines microsatellite sequence in the TGFBR2 gene of 32 MSI-H colon cancer tissues and 6 cell lines (HCT116, LS180, LS411N, RKO, SW48, and SW837). Activation of TGF beta signaling was detected by SMAD2 phosphorylation and through use of a TGF beta-responsive reporter construct in all CRC cell lines. Transcripts of TGFBR2 were knocked-down in CRC cells using short hairpin RNA. Full-length and mutant forms of TGFBR2 were expressed in LS411N cells, which do not respond to TGF beta, and their activities were measured. RESULTS: SMAD2 was phosphorylated in most MSI-H CRC tissues (strong detection in 44% and weak detection in 34% of MSI-H tumors). Phosphorylation of SMAD2 in MSI-H cells required TGFBR2-even the form encoding a frameshift mutation. Transcription and translation of TGFBR2 with a 1-nucleotide deletion at its microsatellite sequence still produced a full-length TGFBR2 protein. However, protein expression required preservation of the TGFBR2 microsatellite sequence; cells in which this sequence was replaced with a synonymous nonmicrosatellite sequence did not produce functional TGFBR2 protein. CONCLUSION: TGF beta signaling remains active in some MSI-H CRC cells despite the presence of frameshift mutations in the TGFBR2 gene because the mutated gene still expresses a functional protein. Strategies to reactivate TGF beta signaling in colorectal tumors might not be warranted, and the functional effects of mutations at other regions of microsatellite instability sh

Published
2015
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228. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers

Author

Jansen, Anne ML, primary, van Wezel, Tom, additional, van den Akker, Brendy EWM, additional, Ventayol Garcia, Marina, additional, Ruano, Dina, additional, Tops, Carli MJ, additional, Wagner, Anja, additional, Letteboer, Tom GW, additional, Gómez-García, Encarna B, additional, Devilee, Peter, additional, Wijnen, Juul T, additional, Hes, Frederik J, additional, and Morreau, Hans, additional

Published
2015
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229. A novel RET/PTC variant detected in a pediatric patient with papillary thyroid cancer without ionization history

Author

Halkova, Tereza, primary, Dvorakova, Sarka, additional, Vaclavikova, Eliska, additional, Sykorova, Vlasta, additional, Vcelak, Josef, additional, Sykorova, Pavla, additional, Vlcek, Petr, additional, Reboun, Martin, additional, Katra, Rami, additional, Kodetova, Daniela, additional, Schrumpf, Melanie, additional, van Wezel, Tom, additional, Morreau, Hans, additional, and Bendlova, Bela, additional

Published
2015
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230. SNP association study in PMS2-associated Lynch syndrome.

Author

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., and van Wezel, Tom

Abstract

Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2-3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5-4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients. [ABSTRACT FROM AUTHOR]

Published
2018
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231. Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2.

Author

ten Broeke, Sanne W., van Bavel, Tom C., Jansen, Anne M.L., Gómez-García, Encarnca, Hes, Frederik J., van Hest, Liselot P., Letteboer, Tom G.W., Olderode-Berends, Maran J.W., Ruano, Dina, Spruijt, Liesbeth, Suerink, Manon, Tops, Carli M., van Eijk, Ronald, Morreau, Hans, van Wezel, Tom, and Nielsen, Maartje

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. [ABSTRACT FROM AUTHOR]

Published
2018
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232. Excluding Lynch syndrome in a female patient with metachronous DNA mismatch repair deficient colon- and ovarian cancer.

Author

Crobach, Stijn, Jansen, Anne M. L., Ligtenberg, Marjolein J. L., Koopmans, Marije, Nielsen, Maartje, Hes, Frederik J., Wijnen, Juul T., Dinjens, Winand N. M., van Wezel, Tom, and Morreau, Hans

Abstract

Patients synchronously or metachronously presenting with ovarian and colon cancer can pose diagnostic challenges. A primary colon carcinoma can metastasize to one or both ovaries, two independent primary tumors can arise or an ovarian carcinoma can metastasize to the colon. Clinical and immunohistochemical characterization can aid the diagnosis. Recently, we reported that in difficult cases finding pathogenic APC variants supports a colonic origin.In this case report we describe the clinical history of a female patient suspected for Lynch syndrome. She was diagnosed with a bilateral ovarian cancer at age 44, followed by the detection of a colon carcinoma 12.5 months later. Lesions of both sites showed a DNA mismatch repair deficiency with immunohistochemical loss of MLH1 and PMS2 expression without MLH1 promoter hypermethylation. In absence of germline MMR gene variants identical somatic MLH1 and CTNNB1 gene variants were found, indicating a clonal relation. MMR germline mosaicism was made unlikely by ultra deep sequencing of the MLH1 variant in DNA isolated from normal mucosa, blood, urine and saliva. Although initially being suspect for Lynch syndrome it was eventually concluded that a metachronously diagnosed colon carcinoma that metastasized to both ovaries was most likely. [ABSTRACT FROM AUTHOR]

Published
2018
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233. Diagnostic value of targeted next-generation sequencing in patients with suspected pancreatic or periampullary cancer.

Author

Sibinga Mulder, Babs G., Mieog, J. Sven D., Sarasqueta, Arantza Farina, Handgraaf, Henricus J. M., Vasen, Hans F. A., Swijnenburg, Rutger-Jan, Luelmo, Saskia A. C., Feshtali, Shirin, Inderson, Akin, Vahrmeijer, Alexander L., Bonsing, Bert A., van Wezel, Tom, and Morreau, Hans

Subjects
PANCREATIC cancer diagnosis, CANCER patients, PANCREATIC cancer, TUMOR diagnosis, PRECANCEROUS conditions, INFLAMMATORY bowel diseases
Published
2018
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234. ROS-induced near-homozygous genomes in thyroid cancer.

Author

Corver, Willem E., Demmers, Joris, Oosting, Jan, Sahraeian, Shima, Boot, Arnoud, Ruano, Dina, van Wezel, Tom, and Morreau, Hans

Subjects
GENOMES, THYROID cancer treatment, THYROID cancer, SINGLE nucleotide polymorphisms, GENETIC overexpression, GENE therapy, THERAPEUTICS
Abstract

A near-homozygous genome (NHG) is especially seen in a subset of follicular thyroid cancer of the oncocytic type (FTC-OV). An NHG was also observed in the metabolically relatively quiescent cell lines XTC.UC1, a model for FTC-OV, and in FTC-133, -236 and -238, the latter three derived from one single patient with follicular thyroid cancer. FTC-236 subclones showed subtle whole-chromosome differences indicative of sustained reciprocal mitotic missegregations. Reactive oxygen species (ROS) scavenger experiments reduced the number of chromosomal missegregations in XTC.UC1 and FTC-236, while pCHK2 was downregulated in these cells. Treatment with antimycin A increased ROS indicated by enhanced MitoSOX Red and pCHK2 fluorescence in metaphase cells. In a selected set of oncocytic follicular thyroid tumors, increasing numbers of wholechromosome losses were observed toward an aggressive phenotype, but with retention of chromosome 7. Together, ROS activates CHK2 and links to the stepwise loss of whole chromosomes during tumor progression in these lesions. We postulate that sequential loss of whole chromosomes is a dominant driver of the oncogenesis of a subset of follicular thyroid tumors. [ABSTRACT FROM AUTHOR]

Published
2018
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235. Clinical and Molecular Characteristics May Alter Treatment Strategies of Thyroid Malignancies in DICER1 Syndrome.

Author

van der Tuin, Karin, de Kock, Leanne, Kamping, Eveline J, Hannema, Sabine E, Pouwels, Marie-Jose M, Niedziela, Marek, van Wezel, Tom, Hes, Frederik J, Jongmans, Marjolijn C, Foulkes, William D, and Morreau, Hans

Abstract

DICER1 syndrome is a rare autosomal-dominantly inherited disorder that predisposes to a variety of cancerous and noncancerous tumors of mostly pediatric and adolescent onset, including differentiated thyroid carcinoma (DTC). DTC has been hypothesized to arise secondarily to the increased prevalence of thyroid hyperplastic nodules in syndromic patients.

Published
2019
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237. Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer

Author

Timofeeva, Maria N., primary, Kinnersley, Ben, additional, Farrington, Susan M., additional, Whiffin, Nicola, additional, Palles, Claire, additional, Svinti, Victoria, additional, Lloyd, Amy, additional, Gorman, Maggie, additional, Ooi, Li-Yin, additional, Hosking, Fay, additional, Barclay, Ella, additional, Zgaga, Lina, additional, Dobbins, Sara, additional, Martin, Lynn, additional, Theodoratou, Evropi, additional, Broderick, Peter, additional, Tenesa, Albert, additional, Smillie, Claire, additional, Grimes, Graeme, additional, Hayward, Caroline, additional, Campbell, Archie, additional, Porteous, David, additional, Deary, Ian J., additional, Harris, Sarah E., additional, Northwood, Emma L., additional, Barrett, Jennifer H., additional, Smith, Gillian, additional, Wolf, Roland, additional, Forman, David, additional, Morreau, Hans, additional, Ruano, Dina, additional, Tops, Carli, additional, Wijnen, Juul, additional, Schrumpf, Melanie, additional, Boot, Arnoud, additional, Vasen, Hans F A, additional, Hes, Frederik J., additional, van Wezel, Tom, additional, Franke, Andre, additional, Lieb, Wolgang, additional, Schafmayer, Clemens, additional, Hampe, Jochen, additional, Buch, Stephan, additional, Propping, Peter, additional, Hemminki, Kari, additional, Försti, Asta, additional, Westers, Helga, additional, Hofstra, Robert, additional, Pinheiro, Manuela, additional, Pinto, Carla, additional, Teixeira, Manuel, additional, Ruiz-Ponte, Clara, additional, Fernández-Rozadilla, Ceres, additional, Carracedo, Angel, additional, Castells, Antoni, additional, Castellví-Bel, Sergi, additional, Campbell, Harry, additional, Bishop, D. Timothy, additional, Tomlinson, Ian P M, additional, Dunlop, Malcolm G., additional, and Houlston, Richard S., additional

Published
2015
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240. Formalin-fixed, paraffin-embedded (FFPE) tissue epigenomics using Infinium HumanMethylation450 BeadChip assays

Author

de Ruijter, Tim C, primary, de Hoon, Joep PJ, additional, Slaats, Jeroen, additional, de Vries, Bart, additional, Janssen, Marjolein JFW, additional, van Wezel, Tom, additional, Aarts, Maureen JB, additional, van Engeland, Manon, additional, Tjan-Heijnen, Vivianne CG, additional, Van Neste, Leander, additional, and Veeck, Jürgen, additional

Published
2015
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244. Tu1976 Statin Use After Diagnosis Improves Survival in Colorectal Cancer Patients

Author

Voorneveld, Philip, primary, Reimers, Marlies S., additional, Jacobs, Rutger J., additional, Bastiaannet, Esther, additional, Van Eijk, Ronald, additional, Kodach, Liudmila L., additional, van Wezel, Tom, additional, Kuppen, Peter J., additional, Morreau, Hans, additional, van de Velde, Cornelis J., additional, Liefers, Gerrit Jan, additional, and Hardwick, James C., additional

Published
2015
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246. Whole-Exome Sequencing Studies of Parathyroid Carcinomas Reveal NovelPRUNE2Mutations, Distinctive Mutational Spectra Related to APOBEC-Catalyzed DNA Mutagenesis and Mutational Enrichment in Kinases Associated With Cell Migration and Invasion

Author

Yu, Willie, primary, McPherson, John R, additional, Stevenson, Mark, additional, van Eijk, Ronald, additional, Heng, Hong Lee, additional, Newey, Paul, additional, Gan, Anna, additional, Ruano, Dina, additional, Huang, Dachuan, additional, Poon, Song Ling, additional, Ong, Choon Kiat, additional, van Wezel, Tom, additional, Cavaco, Branca, additional, Rozen, Steven G, additional, Tan, Patrick, additional, Teh, Bin T, additional, Thakker, Rajesh V, additional, and Morreau, Hans, additional

Published
2015
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247. Loss of SMAD4 alters BMP signaling to promote colorectal cancer cell metastasis via activation of rho and ROCK

Author

Pathologie Pathologen staf, Cancer, Voorneveld, Philip W., Kodach, Liudmila L., Jacobs, Rutger J., Liv, Nalan, Christiaan Zonnevylle, A., Hoogenboom, Jacob P., Biemond, Izak, Verspaget, Hein W., Hommes, Daniel W., De Rooij, Karien, Van Noesel, Carel J.M., Morreau, Hans, Van Wezel, Tom, Offerhaus, G. Johan A., Van Den Brink, Gijs R., Peppelenbosch, Maikel P., Ten Dijke, Peter, Hardwick, James C.H., Pathologie Pathologen staf, Cancer, Voorneveld, Philip W., Kodach, Liudmila L., Jacobs, Rutger J., Liv, Nalan, Christiaan Zonnevylle, A., Hoogenboom, Jacob P., Biemond, Izak, Verspaget, Hein W., Hommes, Daniel W., De Rooij, Karien, Van Noesel, Carel J.M., Morreau, Hans, Van Wezel, Tom, Offerhaus, G. Johan A., Van Den Brink, Gijs R., Peppelenbosch, Maikel P., Ten Dijke, Peter, and Hardwick, James C.H.

Published
2014

248. The MLH1 c.1852_1853delinsGC (p.K618A) Variant in Colorectal Cancer: Genetic Association Study in 18,723 Individuals

Author

Medicina, Medikuntza, Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, Castellví-Bel, Sergi, Medicina, Medikuntza, Abulí, Anna, Bujanda Fernández de Pierola, Luis, Mun, Jenifer, Buch, Stephan, Schafmayer, Clemens, Maiorana, Maria Valeria, Veneroni, Silvia, Van Wezel, Tom, Liu, Tao, Westers, Helga, Esteban-Jurado, Clara, Ocan, Teresa, Pique, Josep M., Andreu, Montserrat, Jover, Rodrigo, Carracedo, Angel, Xicola, Rosa M., Llor, Xavier, Castells, Antoni, The EPICOLON Consortium, Dunlop15, Malcolm, Hofstra, Robert, Lindblom, Annika, Wijnen, Juul, Peterlongo, Paolo, Hampe, Jochen, Ruiz- Ponte, Clara, and Castellví-Bel, Sergi

Abstract

Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance'', being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.

Published
2014

249. Association between CASP8-652 6N Del Polymorphism (rs3834129) and Colorectal Cancer Risk: Results from a Multi-Centric Study

Author

Medicina, Medikuntza, Pardini, Barbara, Verderio, Paolo, Pizzamiglio, Sara, Nici, Carmela, Maiorana, Maria Valeria, Naccarati, Alessio, Vodickova, Ludmila, Vymetalkova, Veronika, Veneroni, Silvia, Daidone, Maria Grazia, Ravagnani, Fernando, Bianchi, Tiziana, Bujanda Fernández de Pierola, Luis, Carracedo, Angel, Castells, Antoni, Ruiz Ponte, Clara, Morreau, Hans, Howarth, Kimberley, Jones, Angela, Castellví-Bel, Sergi, Li, Li, Tomlinson, Ian, Van Wezel, Tom, Vodicka, Pavel, Radice, Paolo, Peterlongo, Paolo, EPICOLON Consortium, Medicina, Medikuntza, Pardini, Barbara, Verderio, Paolo, Pizzamiglio, Sara, Nici, Carmela, Maiorana, Maria Valeria, Naccarati, Alessio, Vodickova, Ludmila, Vymetalkova, Veronika, Veneroni, Silvia, Daidone, Maria Grazia, Ravagnani, Fernando, Bianchi, Tiziana, Bujanda Fernández de Pierola, Luis, Carracedo, Angel, Castells, Antoni, Ruiz Ponte, Clara, Morreau, Hans, Howarth, Kimberley, Jones, Angela, Castellví-Bel, Sergi, Li, Li, Tomlinson, Ian, Van Wezel, Tom, Vodicka, Pavel, Radice, Paolo, Peterlongo, Paolo, and EPICOLON Consortium

Abstract

The common 2652 6N del variant in the CASP8 promoter (rs3834129) has been described as a putative low-penetrance risk factor for different cancer types. In particular, some studies suggested that the deleted allele (del) was inversely associated with CRC risk while other analyses failed to confirm this. Hence, to better understand the role of this variant in the risk of developing CRC, we performed a multi-centric case-control study. In the study, the variant 2652 6N del was genotyped in a total of 6,733 CRC cases and 7,576 controls recruited by six different centers located in Spain, Italy, USA, England, Czech Republic and the Netherlands collaborating to the international consortium COGENT (COlorectal cancer GENeTics). Our analysis indicated that rs3834129 was not associated with CRC risk in the full data set. However, the del allele was under-represented in one set of cases with a family history of CRC (per allele model OR = 0.79, 95% CI = 0.69-0.90) suggesting this allele might be a protective factor versus familial CRC. Since this multi-centric case-control study was performed on a very large sample size, it provided robust clarification of the effect of rs3834129 on the risk of developing CRC in Caucasians.

Published
2014

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