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2. The BMP pathway either enhances or inhibits the Wnt pathway depending on the SMAD4 and p53 status in CRC.

Author

Voorneveld, PW, Kodach, LL, Jacobs, RJ, van Noesel, CJM, Peppelenbosch, MP, Korkmaz, KS, Molendijk, I, Dekker, E, Morreau, H, van Pelt, GW, Tollenaar, RAEM, Mesker, W, Hawinkels, LJAC, Paauwe, M, Verspaget, HW, Geraets, DT, Hommes, DW, Offerhaus, GJA, van den Brink, GR, Ten Dijke, P, and Hardwick, JCH

Subjects
HCT116 Cells, HT29 Cells, Humans, Colorectal Neoplasms, Bone Morphogenetic Proteins, Transfection, Signal Transduction, Tumor Suppressor Protein p53, beta Catenin, Smad4 Protein, HEK293 Cells, Wnt Signaling Pathway, p53, ALK3 inhibitor, 5-FU, beta-catenin, metastasis, chemotherapy, invasive front, colon cancer, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundConstitutive Wnt activation is essential for colorectal cancer (CRC) initiation but also underlies the cancer stem cell phenotype, metastasis and chemosensitivity. Importantly Wnt activity is still modulated as evidenced by higher Wnt activity at the invasive front of clonal tumours termed the β-catenin paradox. SMAD4 and p53 mutation status and the bone morphogenetic protein (BMP) pathway are known to affect Wnt activity. The combination of SMAD4 loss, p53 mutations and BMP signalling may integrate to influence Wnt signalling and explain the β-catenin paradox.MethodsWe analysed the expression patterns of SMAD4, p53 and β-catenin at the invasive front of CRCs using immunohistochemistry. We activated BMP signalling in CRC cells in vitro and measured BMP/Wnt activity using luciferase reporters. MTT assays were performed to study the effect of BMP signalling on CRC chemosensitivity.ResultsEighty-four percent of CRCs with high nuclear β-catenin staining are SMAD4 negative and/or p53 aberrant. BMP signalling inhibits Wnt signalling in CRC only when p53 and SMAD4 are unaffected. In the absence of SMAD4, BMP signalling activates Wnt signalling. When p53 is lost or mutated, BMP signalling no longer influences Wnt signalling. The cytotoxic effects of 5-FU are influenced in a similar manner.ConclusionsThe BMP signalling pathway differentially modulates Wnt signalling dependent on the SMAD4 and p53 status. The use of BMPs in cancer therapy, as has been proposed by previous studies, should be targeted to individual cancers based on the mutational status of p53 and SMAD4.

Published
2015

4. Molecular alterations associated with liver metastases development in colorectal cancer patients

Author

Bruin, SC, He, Y, Mikolajewska-Hanclich, I, Liefers, G-J, Klijn, C, Vincent, A, Verwaal, VJ, de Groot, KA, Morreau, H, van Velthuysen, M-LF, Tollenaar, RAEM, and van ‘t Veer, LJ

Subjects
Cancer, Digestive Diseases, Liver Disease, Colo-Rectal Cancer, Genetics, Clinical Research, Adult, Aged, Aged, 80 and over, Carcinoma, Chromosome Aberrations, Cohort Studies, Colorectal Neoplasms, DNA Mutational Analysis, Disease Progression, Female, Follow-Up Studies, Genome-Wide Association Study, Humans, Liver Neoplasms, Male, Middle Aged, Mutation, colorectal cancer, liver metastases, chromosome 20q, PI(3)K signalling pathway, PIK3CA, KRAS, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundUnderstanding the molecular biology of colorectal cancer (CRC) provides opportunities for effective personalised patient management. We evaluated whether chromosomal aberrations, mutations in the PI(3)K signalling pathway and the CpG-island methylator phenotype (CIMP) in primary colorectal tumours can predict liver metastases.MethodsFormalin-fixed paraffin-embedded material from primary colorectal tumours of three different groups were investigated: patients with CRC without metastases (M0, n=39), patients who were treated with hyperthermal intraperitoneal chemotherapy for CRC metastases confined to the peritoneum (PM, n=46) and those who had isolated hepatic perfusion for CRC metastases confined to the liver (LM, n=48).ResultsAll samples were analysed for DNA copy number changes, PIK3CA, KRAS, BRAF mutations, CIMP and microsatellite instability. The primary CRCs of the LM group had significantly higher frequency of amplified chromosome 20q (P=0.003), significantly fewer mutations in the PI(3)K signalling pathway (P=0.003) and fewer CIMP high tumours (P=0.05). There was a strong inverse correlation between 20q and the PI(3)K pathway mutations.ConclusionThe development of CRC liver metastases is associated with amplification of chromosome 20q and not driven by mutations in the PI(3)K signalling pathway.

Published
2011

5. COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer

Author

Tomlinson, IPM, Dunlop, M, Campbell, H, Zanke, B, Gallinger, S, Hudson, T, Koessler, T, Pharoah, PD, Niittymäkix, I, Tuupanenx, S, Aaltonen, LA, Hemminki, K, Lindblom, A, Försti, A, Sieber, O, Lipton, L, van Wezel, T, Morreau, H, Wijnen, JT, Devilee, P, Matsuda, K, Nakamura, Y, Castellví-Bel, S, Ruiz-Ponte, C, Castells, A, Carracedo, A, Ho, JWC, Sham, P, Hofstra, RMW, Vodicka, P, Brenner, H, Hampe, J, Schafmayer, C, Tepel, J, Schreiber, S, Völzke, H, Lerch, MM, Schmidt, CA, Buch, S, Moreno, V, Villanueva, CM, Peterlongo, P, Radice, P, Echeverry, MM, Velez, A, Carvajal-Carmona, L, Scott, R, Penegar, S, Broderick, P, Tenesa, A, and Houlston, RS

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Digestive Diseases, Genetics, Colo-Rectal Cancer, Cancer, Prevention, Aetiology, 2.1 Biological and endogenous factors, Colorectal Neoplasms, Genetic Predisposition to Disease, Humans, Penetrance, Polymorphism, Genetic, Prognosis, Risk, Risk Factors, colorectal cancer, association, polymorphism, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

Published
2010

8. A clinically applicable molecular classification of oncocytic cell thyroid nodules.

Author

Koster, E.J. de, Corver, W.E., Geus-Oei, L.F. de, Oyen, W.J.G., Ruano, D., Schepers, A., Snel, M., Wezel, T. van, Vriens, D., Morreau, H., Koster, E.J. de, Corver, W.E., Geus-Oei, L.F. de, Oyen, W.J.G., Ruano, D., Schepers, A., Snel, M., Wezel, T. van, Vriens, D., and Morreau, H.

Abstract

Item does not contain fulltext, Whole chromosome instability with near-whole genome haploidization (GH) and subsequent endoreduplication is considered a main genomic driver in the tumorigenesis of oncocytic cell thyroid neoplasms (OCN). These copy number alterations (CNA) occur less frequently in oncocytic thyroid adenoma (OA) than in oncocytic carcinoma (OCA), suggesting a continuous process. The current study described the CNA patterns in a cohort of 30 benign and malignant OCN, observed using a next-generation sequencing (NGS) panel that assesses genome-wide loss of heterozygosity (LOH) and chromosomal imbalances using 1500 single-nucleotide polymorphisms (SNPs) across all autosomes and the X chromosome in DNA derived from cytological and histological samples. Observed CNA patterns were verified using multiparameter DNA flow cytometry with or without whole-genome SNP array analysis and lesser-allele intensity-ratio (LAIR) analysis. On CNA-LOH analysis using the NGS panel, GH-type CNA were observed in 4 of 11 (36%) OA and in 14 of 16 OCA (88%). Endoreduplication was suspected in 8 of 16 (50%) OCA, all with more extensive GH-type CNA (P < 0.001). Reciprocal chromosomal imbalance type CNA, characterized by (imbalanced) chromosomal copy number gains and associated with benign disease, were observed in 6 of 11 (55%) OA and one equivocal case of OCA. CNA patterns were different between the histopathological subgroups (P < 0.001). By applying the structured interpretation and considerations provided by the current study, CNA-LOH analysis using an NGS panel that is feasible for daily practice may be of great added value to the widespread application of molecular diagnostics in the diagnosis and risk stratification of OCN.

Published
2023

10. Surveillance for pancreatic cancer in high-risk individuals leads to improved outcomes: a propensity score-matched analysis

Author

Klatte, D.C.F., primary, Boekestijn, B., additional, Onnekink, Anke M., additional, Dekker, F.W., additional, van der Geest, L.G., additional, Wasser, M.N.J.M., additional, Feshtali, S.Shahbazi, additional, Mieog, J.S.D., additional, Luelmo, S.A.C., additional, Morreau, H., additional, Potjer, T.P., additional, Inderson, A., additional, Boonstra, J.J., additional, Vasen, H.F.A., additional, van Hooft, J.E., additional, Bonsing, B.A., additional, and van Leerdam, M.E., additional

Published
2023
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11. Cost-effectiveness of pancreas surveillance

Author

Ibrahim, I.S., Vasen, H.F.A., Wasser, M.N.J.M., Feshtali, S., Bonsing, B.A., Morreau, H., Inderson, A., Cappel, W.H.D.T.N., and Hout, W.B. van den

Subjects
Oncology, high-risk, Gastroenterology, surveillance, PDAC, CDKN2A-p16-Leiden mutation carriers, cost-effectiveness, survival
Abstract

Background: CDKN2A-p16-Leiden mutation carriers have a high lifetime risk of developing pancreatic ductal adenocarcinoma (PDAC), with very poor survival. Surveillance may improve prognosis. Objective: To assess the cost-effectiveness of surveillance, as compared to no surveillance. Methods: In 2000, a surveillance program was initiated at Leiden University Medical Center with annual MRI and optional endoscopic ultrasound. Data were collected on the resection rate of screen-detected tumors and on survival. The Kaplan-Meier method and a parametric cure model were used to analyze and compare survival. Based on the surveillance and survival data from the screening program, a state-transition model was constructed to estimate lifelong outcomes. Results: A total of 347 mutation carriers participated in the surveillance program. PDAC was detected in 31 patients (8.9%) and the tumor could be resected in 22 patients (71.0%). Long-term cure among patients with resected PDAC was estimated at 47.1% (p < 0.001). The surveillance program was estimated to reduce mortality from PDAC by 12.1% and increase average life expectancy by 2.10 years. Lifelong costs increased by euro13,900 per patient, with a cost-utility ratio of euro14,000 per quality-adjusted life year gained. For annual surveillance to have an acceptable cost-effectiveness in other settings, lifetime PDAC risk needs to be 10% or higher. Conclusion: The tumor could be resected in most patients with a screen-detected PDAC. These patients had considerably better survival and as a result annual surveillance was found to be cost-effective.

Published
2023

15. Mismatch repair deficiency and MUTYH variants in small intestine-neuroendocrine tumors

Author

Helderman, N.C., Elsayed, F.A., Wezel, T. van, Terlouw, D., Langers, A.M.J., Egmond, D. van, Kilinc, G., Hristova, H., Sarasqueta, A.F., Morreau, H., Nielsen, M., Suerink, M., and Pathology

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, MUTYH, Brain Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA Mismatch Repair, Pathology and Forensic Medicine, DNA Glycosylases, Neuroendocrine Tumors, Lynch syndrome, Neoplastic Syndromes, Hereditary, Intestine, Small, Humans, Small intestine-neuroendocrine tumors, Colorectal Neoplasms, MutL Protein Homolog 1, Cancer genetics, Mismatch repair deficiency, Germ-Line Mutation, Mismatch Repair Endonuclease PMS2
Abstract

& nbsp;Small intestine-neuroendocrine tumors (SI-NETs) are one of the most common tumors of the small bowel. Despite an increasing incidence, the exact mechanisms driving underlying pathology remain to be determined. Interestingly, recent studies linked the development of (SI-)NETs to both Lynch syndrome (LS) and MUTYH variants. If confirmed, these associations would have important consequences for treatment. In this study we therefore investigated the prevalence of mismatch repair (MMR) deficiency and MUTYH variants in 64 primary resected SI-NETs. Immunohistochemistry was used to assess the expression of the MMR genes, and competitive allele-specific PCR (KASPar) targeting two hotspot MUTYH variants [p.(Tyr179Cys), p.(Gly396Asp)] was performed to determine their prevalence in SI-NETs. Strikingly, all 64 SI-NETs stained positive for MSH6 and PMS2, indicating & nbsp;MMR proficiency. In addition, no MUTYH hotspot variant was found in any of the 64 SI-NETs. As such, these results do not support an association between SI-NET development and LS or MUTYH variants. In order to gain insight into SI-NET pathogenesis and optimally manage patients, future research should therefore focus on other candidate genes. (C) 2022 Published by Elsevier Inc

Published
2022

17. 1750P Molecular genotyping in refractory thyroid cancers: Results of a European survey

Author

Fouchardiere, C. de la, primary, Fugazzola, L., additional, Taylor, J., additional, Appetecchia, M., additional, Besic, N., additional, Bongiovanni, A., additional, Buffet, C., additional, Costante, G., additional, Gay, S., additional, Grande, E., additional, Kapiteijn, E., additional, Krajewska, J., additional, Kroiss, M., additional, Morreau, H., additional, Netea-Maier, R., additional, Peeters, R., additional, Soares, P., additional, Sykiotis, G., additional, Blay, J-Y., additional, and Locati, L.D., additional

Published
2021
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18. IGF2 is a potential factor in RAI-refractory differentiated thyroid cancer

Author

Crezee, T., Tesselaar, M.H., Jaeger, M., Rabold, K., Corver, Willem, Morreau, H., Engen-van Grunsven, A.C.H. van, Smit, J.W.A., Netea-Maier, R.T., Plantinga, T.S., Crezee, T., Tesselaar, M.H., Jaeger, M., Rabold, K., Corver, Willem, Morreau, H., Engen-van Grunsven, A.C.H. van, Smit, J.W.A., Netea-Maier, R.T., and Plantinga, T.S.

Abstract

Item does not contain fulltext

Published
2021

21. Duodenal carcinoma in MUTYH-associated polyposis

Author

Nielsen, M., Poley, J.W., Verhoef, S., Puijenbroek, M. van, Weiss, M.M., Burger, G.T., Dommering, C.J., Vasen, H.F.A., Kuipers, E.J., Wagner, A., Morreau, H., and Hes, F.J.

Subjects
Small intestine cancer -- Case studies, Small intestine cancer -- Genetic aspects, Small intestine cancer -- Diagnosis, Gene mutations -- Analysis, Health
Published
2006

23. Mutational Analyses of EGFR and Downstream Pathways in Adrenocortical Carcinoma: Correlation with Mitotane Response and Survival

Author

Hermsen, IGC, primary, Haak, HR, additional, de Krijger, R, additional, Kerkhofs, TMA, additional, Feelders, RA, additional, de Herder, W, additional, Wilmink, JW, additional, Smit, JWA, additional, Gelderblom, AJ, additional, Miranda, NFCC, additional, v Eijck, R, additional, Wezel, T, additional, and Morreau, H, additional

Published
2011
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24. The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) – Results of an international collaborative study

Author

Müller, Wolfram, Burgart, Lawrence J., Krause-Paulus, Ruth, Thibodeau, Stephen N., Almeida, M., Edmonston, T. Brocker, Boland, C. R., Sutter, C., Jass, J. R., Lindblom, A., Lubinski, J., MacDermot, K., Sanders, D. S. A., Morreau, H., Müller, A., Oliani, C., Orntoft, T., De Leon, M. Ponz, Rosty, C., Rodriguez-Bigas, M., Rüschoff, J., Ruszkiewicz, A., Sabourin, J., Salovaara, R., and Möslein, Gabriela

Published
2001
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28. High detection rate of adenomas in familial colorectal cancer

Author

van der Meulen-de Jong, A E, Morreau, H, Becx, M C J M, Crobach, L F S J, Haastert, M van, Hove, W R ten, Kleibeuker, J H, Meijssen, M A C, Nagengast, F M, Rijk, M C M, Salemans, J M J I, Stronkhorst, A, Tuynman, H A R E, Vecht, J, Verhulst, M L, de Vos tot Nederveen Cappel, W H, Walinga, H, Weinhardt, O K, Westerveld, B D, Witte, A M C, Wolters, H J, and Vasen, H F A

Published
2011
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29. 594P The Drug Rediscovery Protocol (DRUP): Results of the first 500 treated patients

Author

Hoes, L.R., primary, van der Wijngaart, H., additional, van Berge Henegouwen, J.M., additional, Zeverijn, L.J., additional, van der Velden, D.L., additional, Roepman, P., additional, de Leng, W., additional, Jansen, A.M.L., additional, van Werkhoven, E., additional, Huitema, A., additional, Smit, E.F., additional, Van Herpen, C., additional, Labots, M., additional, Hoeben, A., additional, Morreau, H., additional, Lolkema, M.P., additional, Cuppen, E., additional, Gelderblom, H., additional, Verheul, H.M.W., additional, and Voest, E.E., additional

Published
2020
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35. Transanal minimally invasive surgery (TAMIS) versus endoscopic submucosal dissection (ESD) for resection of non-pedunculated rectal lesions (TRIASSIC study): Study protocol of a European multicenter randomised controlled trial

Author

Dekkers, N. (Nik), Boonstra, J.J. (Jurjen), Moons, L.M.G. (Leon), Hompes, R. (Roel), Bastiaansen, D. (Dennis), Tuynman, J.B., Koch, A.D. (Arjun), Weusten, B.L. (Bas), Pronk, A. (Apollo), Neijenhuis, P.A. (Peter), Westerterp, M. (Marinke), Hout, W.B. (Wilbert) van den, Langers, A.M. (Alexandra), Van Der Kraan, J. (Jolein), Alkhalaf, A. (Alaa), Lai, J.Y.L. (Jonathan Y. L.), Borg, F. (Frank) ter, Fabry, H. (Hans), Halet, E. (Eric), Schwartz, M.P. (Matthijs), Nagengast, W.B. (Wouter B.), Straathof, J.W.A., Ten Hove, R.W.R. (Rogier W. R.), Oterdoom, L.H. (Leendert H.), Hoff, C. (Christiaan), Belt, E.J.T. (Eric), Zimmerman, D.D.E. (David), Hadithi, M. (Muhammed), Morreau, H. (Hans), De Cuba, E.M.V., Leijtens, J.W.A. (Jeroen), Vasen, H. (Hans), Leerdam, M.E. (Monique) van, Graaf, E.J.R. (Eelco) de, Doornebosch, P. (Pascal), Hardwick, J.C. (James), Dekkers, N. (Nik), Boonstra, J.J. (Jurjen), Moons, L.M.G. (Leon), Hompes, R. (Roel), Bastiaansen, D. (Dennis), Tuynman, J.B., Koch, A.D. (Arjun), Weusten, B.L. (Bas), Pronk, A. (Apollo), Neijenhuis, P.A. (Peter), Westerterp, M. (Marinke), Hout, W.B. (Wilbert) van den, Langers, A.M. (Alexandra), Van Der Kraan, J. (Jolein), Alkhalaf, A. (Alaa), Lai, J.Y.L. (Jonathan Y. L.), Borg, F. (Frank) ter, Fabry, H. (Hans), Halet, E. (Eric), Schwartz, M.P. (Matthijs), Nagengast, W.B. (Wouter B.), Straathof, J.W.A., Ten Hove, R.W.R. (Rogier W. R.), Oterdoom, L.H. (Leendert H.), Hoff, C. (Christiaan), Belt, E.J.T. (Eric), Zimmerman, D.D.E. (David), Hadithi, M. (Muhammed), Morreau, H. (Hans), De Cuba, E.M.V., Leijtens, J.W.A. (Jeroen), Vasen, H. (Hans), Leerdam, M.E. (Monique) van, Graaf, E.J.R. (Eelco) de, Doornebosch, P. (Pascal), and Hardwick, J.C. (James)

Abstract

Background: In the recent years two innovative approaches have become available for minimally invasive en bloc resections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. Methods: Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. Discussion: This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for the en bloc resection of large non-pedunculated rectal lesions. This is important as the detection rate of the

Published
2020
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36. Transanal minimally invasive surgery (TAMIS) versus endoscopic submucosal dissection (ESD) for resection of non-pedunculated rectal lesions (TRIASSIC study): study protocol of a European multicenter randomised controlled trial

Author

Dekkers, N, Boonstra, JG, Moons, LM, Hompes, R, Bastiaansen, BAJ, Tuynman, JB, Koch, Arjun, Weusten, B, Pronk, A, Neijenhuis, PA, Westerterp, M, van den Hout, WB, Langers, AM, Kraan, J, Alkhalaf, A, Lai, JYL, ter Borg, F, Fabry, H, Halet, E, Schwartz, MP, Nagengast, WB, Straathof, JW, ten Hove, RWR, Oterdoom, LH, Hoff, C, Belt, EJT, Zimmerman, DD, Hadithi, M, Morreau, H, de Cuba, E M V, Leijtens, JWA, Vasen, HF, Leerdam, ME, Graaf, E, Doornebosch, PG, Hardwick, JCH, Dekkers, N, Boonstra, JG, Moons, LM, Hompes, R, Bastiaansen, BAJ, Tuynman, JB, Koch, Arjun, Weusten, B, Pronk, A, Neijenhuis, PA, Westerterp, M, van den Hout, WB, Langers, AM, Kraan, J, Alkhalaf, A, Lai, JYL, ter Borg, F, Fabry, H, Halet, E, Schwartz, MP, Nagengast, WB, Straathof, JW, ten Hove, RWR, Oterdoom, LH, Hoff, C, Belt, EJT, Zimmerman, DD, Hadithi, M, Morreau, H, de Cuba, E M V, Leijtens, JWA, Vasen, HF, Leerdam, ME, Graaf, E, Doornebosch, PG, and Hardwick, JCH

Published
2020

38. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP)

Author

Nielsen, M, Franken, P F, Reinards, T H C M, Weiss, M M, Wagner, A, van der Klift, H, Kloosterman, S, Houwing-Duistermaat, J J, Aalfs, C M, Ausems, M G E M, Bröcker-Vriends, A H J T, Garcia, E B Gomez, Hoogerbrugge, N, Menko, F H, Sijmons, R H, Verhoef, S, Kuipers, E J, Morreau, H, Breuning, M H, Tops, C M J, Wijnen, J T, Vasen, H F A, Fodde, R, and Hes, F J

Published
2005

43. Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations

Author

Crobach, S., Ruano, D., Eijk, R. van, Schrumpf, M., Fleuren, G., Wezel, T. van, Morreau, H., and PALGA Grp

Subjects
0301 basic medicine, Neuroblastoma RAS viral oncogene homolog, Colorectal cancer, Ovary, Bioinformatics, medicine.disease_cause, Pathology and Forensic Medicine, molecular diagnostics, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, gene panel, medicine, cancer, PTEN, metastases, neoplasms, biology, high‐throughput sequencing, high-throughput sequencing, Cancer, Original Articles, medicine.disease, Molecular diagnostics, digestive system diseases, 030104 developmental biology, medicine.anatomical_structure, colon cancer, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Original Article, KRAS
Abstract

The mutational profiles of primary colorectal cancers (CRCs) and corresponding ovarian metastases were compared. Using a custom‐made next generation sequencing panel, 115 cancer‐driving genes were analyzed in a cohort of 26 primary CRCs and 30 matching ovarian metastases (four with bilateral metastases). To obtain a complete overview of the mutational profile, low thresholds were used in bioinformatics analysis to prevent low frequency passenger mutations from being filtered out. A subset of variants was validated using Sanger and/or hydrolysis probe assays. The mutational landscape of CRC that metastasized to the ovary was not strikingly different from CRC in consecutive series. When comparing primary CRCs and their matching ovarian metastases, there was considerable overlap in the mutations of early affected genes. A subset of mutations demonstrated less overlap, presumably being passenger mutations. In particular, primary CRCs showed a substantially high number of passenger mutations. We also compared the primary CRCs and matching metastases for stratifying variants of six genes (KRAS, NRAS, BRAF, FBXW7, PTEN and PIK3CA) that select for established (EGFR directed) or future targeted therapies. In a total of 31 variants 12 were not found in either of the two locations. Tumours thus differed in the number of discordant variants between the primary tumours and matching metastases. Half of these discordant variants were definitive class 4/5 pathogenic variants. However, in terms of temporal heterogeneity, no clear relationship was observed between the number of discordant variants and the time interval between primary CRCs and the detection of ovarian metastases. This suggests that dormant metastases may be present from the early days of the primary tumours.

Published
2016
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50. Targetable gene fusions identified in radioactive iodine refractory advanced thyroid carcinoma

Author

Tuin, K., Garcia, M., Corver, W.E., Khalifa, M.N., Neto, D. Ruano, Corssmit, E.P.M., Hes, F.J., Links, T.P., Smit, J.W.A., Plantinga, T.S., Kapiteijn, E., Wezel, T. van, Morreau, H., Tuin, K., Garcia, M., Corver, W.E., Khalifa, M.N., Neto, D. Ruano, Corssmit, E.P.M., Hes, F.J., Links, T.P., Smit, J.W.A., Plantinga, T.S., Kapiteijn, E., Wezel, T. van, and Morreau, H.

Abstract

Contains fulltext : 202947.pdf (publisher's version ) (Closed access), Objective Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas. Design Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hurthle cell- and 14 anaplastic thyroid carcinoma). Methods Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants. Results Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET (PTC1), PRKAR1A/RET (PTC2) and ETV6/NTRK3 , and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hurthle cell carcinomas are rare (2/35). Conclusion Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants and can be effectively identified in formalin-fixed tissue. These gene fusions might provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

Published
2019

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