Eugène T P Verwiel
Radboud University Nijmegen
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Featured researches published by Eugène T P Verwiel.
Nature Genetics | 2015
Robbert D.A. Weren; Marjolijn J. L. Ligtenberg; C. Marleen Kets; Richarda M. de Voer; Eugène T P Verwiel; Liesbeth Spruijt; Wendy A. G. van Zelst-Stams; Marjolijn C.J. Jongmans; Christian Gilissen; Jayne Y. Hehir-Kwa; Alexander Hoischen; Jay Shendure; Evan A. Boyle; Eveline J. Kamping; Iris D. Nagtegaal; Bastiaan Tops; Fokko M. Nagengast; Ad Geurts van Kessel; J. Han van Krieken; Roland P. Kuiper; Nicoline Hoogerbrugge
The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.
Nature Genetics | 2012
David A. Koolen; Jamie M. Kramer; Kornelia Neveling; Willy M. Nillesen; Heather L. Moore-Barton; Frances Elmslie; Annick Toutain; Jeanne Amiel; Valérie Malan; Anne Chun Hui Tsai; Sau Wai Cheung; Christian Gilissen; Eugène T P Verwiel; Sarah Martens; Ton Feuth; Ernie M.H.F. Bongers; Petra de Vries; H. Scheffer; Lisenka E.L.M. Vissers; Arjan P.M. de Brouwer; Han G. Brunner; Joris A. Veltman; Annette Schenck; Helger G. Yntema; Bert B.A. de Vries
We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes.
Nature Communications | 2013
Sanne P. Smeekens; Aylwin Ng; Vinod Kumar; Melissa D. Johnson; Theo S. Plantinga; Cleo C. van Diemen; Peer Arts; Eugène T P Verwiel; Mark S. Gresnigt; Karin Fransen; Suzanne van Sommeren; Marije Oosting; Shih-Chin Cheng; Leo A. B. Joosten; Alexander Hoischen; Bart Jan Kullberg; William K. Scott; John R. Perfect; Jos W. M. van der Meer; Cisca Wijmenga; Mihai G. Netea; Ramnik J. Xavier
Candida albicans is the most common human fungal pathogen causing mucosal and systemic infections. However, human antifungal immunity remains poorly defined. Here, by integrating transcriptional analysis and functional genomics, we identified Candida-specific host defense mechanisms in humans. Candida induced significant expression of genes from the type I interferon (IFN) pathway in human peripheral blood mononuclear cells. This unexpectedly prominent role of type I IFN pathway in anti-Candida host defense was supported by additional evidence. Polymorphisms in type I IFN genes modulated Candida-induced cytokine production and were correlated with susceptibility to systemic candidiasis. In in-vitro experiments, type I IFNs skewed Candida-induced inflammation from a Th17-response toward a Th1-response. Patients with chronic mucocutaneaous candidiasis displayed defective expression of genes in the type I IFN pathway. These findings indicate that the type I IFN pathway is a main signature of Candida-induced inflammation and plays a crucial role in anti-Candida host defense in humans.
International Journal of Cancer | 2011
Ramprasath Venkatachalam; Eugène T P Verwiel; Eveline J. Kamping; Eveline Hoenselaar; Heike Görgens; Hans K. Schackert; J. Han van Krieken; Marjolijn J. L. Ligtenberg; Nicoline Hoogerbrugge; Ad Geurts van Kessel; Roland P. Kuiper
In the majority of colorectal cancers (CRCs) under clinical suspicion for a hereditary cause, the disease‐causing genetic factors are still to be discovered. To identify such genetic factors we stringently selected a discovery cohort of 41 CRC index patients with microsatellite‐stable tumors. All patients were below 40 years of age at diagnosis and/or exhibited an overt family history. We employed genome‐wide copy number profiling using high‐resolution SNP arrays on germline DNA, which resulted in the identification of novel copy number variants (CNVs) in six patients (15%) encompassing, among others, the cadherin gene CDH18, the bone morphogenetic protein antagonist family gene GREM1, and the breakpoint cluster region gene BCR. In addition, two genomic deletions were encountered encompassing two microRNA genes, hsa‐mir‐491/KIAA1797 and hsa‐mir‐646/AK309218. None of these CNVs has previously been reported in relation to CRC predisposition in humans, nor were they encountered in large control cohorts (>1,600 unaffected individuals). Since several of these newly identified candidate genes may be functionally linked to CRC development, our results illustrate the potential of this approach for the identification of novel candidate genes involved in CRC predisposition.
American Journal of Human Genetics | 2012
Marjolijn C.J. Jongmans; Eugène T P Verwiel; Yvonne F. Heijdra; Tom Vulliamy; Eveline J. Kamping; Jayne Y. Hehir-Kwa; Ernie M.H.F. Bongers; Rolph Pfundt; Liesbeth van Emst; Frank N. van Leeuwen; Koen L.I. van Gassen; Ad Geurts van Kessel; Inderjeet Dokal; Nicoline Hoogerbrugge; Marjolijn J. L. Ligtenberg; Roland P. Kuiper
Revertant mosaicism is an infrequently observed phenomenon caused by spontaneous correction of a pathogenic allele. We have observed such reversions caused by mitotic recombination of mutant TERC (telomerase RNA component) alleles in six patients from four families affected by dyskeratosis congenita (DC). DC is a multisystem disorder characterized by mucocutaneous abnormalities, dystrophic nails, bone-marrow failure, lung fibrosis, liver cirrhosis, and cancer. We identified a 4 nt deletion in TERC in a family with an autosomal-dominant form of DC. In two affected brothers without bone-marrow failure, sequence analysis revealed pronounced overrepresentation of the wild-type allele in blood cells, whereas no such skewing was observed in the other tissues tested. These observations suggest that this mosaic pattern might have resulted from somatic reversion of the mutated allele to the normal allele in blood-forming cells. SNP-microarray analysis on blood DNA from the two brothers indeed showed independent events of acquired segmental isodisomy of chromosome 3q, including TERC, indicating that the reversions must have resulted from mitotic recombination events. Subsequently, after developing a highly sensitive method of detecting mosaic homozygosity, we have found four additional cases with a mosaic-reversion pattern in blood cells; these four cases are part of a cohort of 17 individuals with germline TERC mutations. This shows that revertant mosaicism is a recurrent event in DC. This finding has important implications for improving diagnostic testing and understanding the variable phenotype of DC.
BMC Cancer | 2012
Leonie J.M. Mekenkamp; Jolien Tol; Jeroen R. Dijkstra; Inge de Krijger; M Elisa Vink-Börger; Shannon van Vliet; Steven Teerenstra; Eveline J. Kamping; Eugène T P Verwiel; Miriam Koopman; Gerrit A. Meijer; J. Han van Krieken; Roland P. Kuiper; Cornelis J. A. Punt; Iris D. Nagtegaal
BackgroundKRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab.MethodsFormalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17) or poor (n = 17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR.ResultsCopy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model.ConclusionsOur results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.
Gastroenterology | 2013
Richarda M. de Voer; Ad Geurts van Kessel; Robbert D.A. Weren; Marjolijn J. L. Ligtenberg; Dominique Smeets; Lei Fu; Lilian Vreede; Eveline J. Kamping; Eugène T P Verwiel; Marc–Manuel Hahn; Maayke Ariaans; Liesbeth Spruijt; Ton van Essen; Gunnar Houge; Hans K. Schackert; Jian Q. Sheng; Hanka Venselaar; Conny M.A. van Ravenswaaij–Arts; J. Han van Krieken; Nicoline Hoogerbrugge; Roland P. Kuiper
The spindle assembly checkpoint controls proper chromosome segregation during mitosis and prevents aneuploidy-an important feature of cancer cells. We performed genome-wide and targeted copy number and mutation analyses of germline DNA from 208 patients with familial or early-onset (40 years of age or younger) colorectal cancer; we identified haploinsufficiency or heterozygous mutations in the spindle assembly checkpoint genes BUB1 and BUB3 in 2.9% of them. Besides colorectal cancer, these patients had variegated aneuploidies in multiple tissues and variable dysmorphic features. These results indicate that mutations in BUB1 and BUB3 cause mosaic variegated aneuploidy and increase the risk of colorectal cancer at a young age.
European Journal of Medical Genetics | 2013
Anneke T. Vulto-van Silfhout; Conny Van Ravenswaaij; Jayne Y. Hehir-Kwa; Eugène T P Verwiel; Rita J.M. Dirks; Steven Van Vooren; Albert Schinzel; Bert B.A. de Vries; Nicole de Leeuw
The European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA, www.ecaruca.net) is an online database initiated in 2003 that collects and provides detailed, curated clinical and molecular information on rare unbalanced chromosome aberrations. ECARUCA now contains over 4800 cases with a total of more than 6600 genetic aberrations and has over 3000 account holders worldwide. Recently, the ECARUCA web site was renewed, including the presentation of interesting case reports in collaboration with the European Journal of Medical Genetics. This article gives an overview of the current status and future plans of the online ECARUCA database.
Scientific Reports | 2015
Richarda M. de Voer; Marc-Manuel Hahn; Arjen R. Mensenkamp; Alexander Hoischen; Christian Gilissen; Arjen Henkes; Liesbeth Spruijt; Wendy A. G. van Zelst-Stams; C. Marleen Kets; Eugène T P Verwiel; Iris D. Nagtegaal; Hans K. Schackert; Ad Geurts van Kessel; Nicoline Hoogerbrugge; Marjolijn J. L. Ligtenberg; Roland P. Kuiper
Bloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (≤50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P = 0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.
Cancer Genetics and Cytogenetics | 2009
Roland P. Kuiper; Lilian Vreede; Ramprasath Venkatachalam; Chris Ricketts; Eveline J. Kamping; Eugène T P Verwiel; Lutgarde Govaerts; Maria Debiec-Rychter; Evelyne Lerut; Femke van Erp; Nicoline Hoogerbrugge; Lianne van Kempen; Eric F.P.M. Schoenmakers; Anita Bonne; Eamonn R. Maher; Ad Geurts van Kessel
FBXW7 (alias CDC4) is a p53-dependent tumor suppressor gene that exhibits mutations or deletions in a variety of human tumors. Mutation or deletion of the FBXW7 gene has been associated with an increase in chromosomal instability and cell cycle progression. In addition, the FBXW7 protein has been found to act as a component of the ubiquitin proteasome system and to degrade several oncogenic proteins that function in cellular growth regulatory pathways. By using a rapid breakpoint cloning procedure in a case of renal cell cancer (RCC), we found that the FBXW7 gene was disrupted by a constitutional t(3;4)(q21;q31). Subsequent analysis of the tumor tissue revealed the presence of several anomalies, including loss of the derivative chromosome 3. Upon screening of a cohort of 29 independent primary RCCs, we identified one novel pathogenic mutation, suggesting that the FBXW7 gene may also play a role in the development of sporadic RCCs. In addition, we screened a cohort of 48 unrelated familial RCC cases with unknown etiology. Except for several known or benign sequence variants such as single nucleotide polymorphisms (SNPs), no additional pathogenic variants were found. Previous mouse models have suggested that the FBXW7 gene may play a role in the predisposition to tumor development. Here we report that disruption of this gene may predispose to the development of human RCC.