Winand N M Dinjens

Publications (74)440.4 Total impact

• Article: SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors.

  Lindsey Oudijk, José Gaal, Esther Korpershoek, Francien H van Nederveen, Lorna Kelly, Gaia Schiavon, Jaap Verweij, Ron H J Mathijssen, Michael A den Bakker, Rogier A Oldenburg, Rosa L E van Loon, Maureen J O'Sullivan, Ronald R de Krijger, Winand N M Dinjens
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  ABSTRACT: Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-α. However, a small subset of GISTs lacks such mutations and is termed 'wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C>T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.Modern Pathology advance online publication, 23 November 2012; doi:10.1038/modpathol.2012.186.
  Modern Pathology 11/2012; · 4.79 Impact Factor
• Article: Defects in the DNA mismatch repair system do not contribute to the development of childhood Wilms tumors.

  Heidi Segers, Marry M van den Heuvel-Eibrink, Ronald R de Krijger, Rob Pieters, Anja Wagner, Winand N M Dinjens
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  ABSTRACT: Abstract Background Wilms tumor is the most common childhood renal malignancy. Most Wilms tumors occur sporadic, whereas a genetic predisposition is described in 9%-19% of the Wilms tumor patients. Beside constitutional aberrations, also somatic aberrations in multiple genetic loci such as WT1, WT2 or locus 11p15.5, CTNNB1, WTX, TP53, FBXW7 and MYCN have been linked to Wilms tumorigenesis. In sporadic Wilms tumors, however, the driving somatic genetic aberrations need to be further unraveled. Therefore, it is necessary to obtain more insight into other underlying mechanisms. Little is known about the role of defects in the DNA mismatch repair system in the etiology of Wilms tumors. Materials and methods To detect mismatch repair deficiency in a full cohort of Wilms tumor patients, we combined immunohistochemistry for the expression of mismatch repair proteins and microsatellite instability (MSI) analysis by a fluorescent multiplex PCR-based assay. Results Of the 121 Wilms tumor patients treated between 1987 and 2010 in our institution, 100 samples from 97 patients were available for analysis. Nuclear staining for MLH1, MSH2, MSH6 and PMS2 proteins was present in all 100 Wilms tumor samples. No pattern of MSI was found in any of the investigated 100 Wilms tumor samples. Conclusion The matching results of normal expression of the mismatch repair proteins detected by immunohistochemistry and the absence of MSI by DNA analysis in 100 Wilms tumor samples, lead us to conclude that defects in the DNA mismatch repair system do not play a significant role in the development of Wilms tumors.
  Pediatric and Developmental Pathology 11/2012; · 0.99 Impact Factor
• Source

  Available from: Mathilde C M Kouwenhoven

  Article: Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: Long-Term Follow-Up of EORTC Brain Tumor Group Study 26951.

  Martin J van den Bent, Alba A Brandes, Martin J B Taphoorn, Johan M Kros, Mathilde C M Kouwenhoven, Jean-Yves Delattre, Hans J J A Bernsen, Marc Frenay, Cees C Tijssen, Wolfgang Grisold, László Sipos, Roelien H Enting, Pim J French, Winand N M Dinjens, Charles J Vecht, Anouk Allgeier, Denis Lacombe, Thierry Gorlia, Khê Hoang-Xuan
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  ABSTRACT: PURPOSEAnaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT). PATIENTS AND METHODS Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis.ResultsA total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. CONCLUSION The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.
  Journal of Clinical Oncology 10/2012; · 18.37 Impact Factor
• Article: Identification of Familial Adenomatous Polyposis carriers among children with desmoid tumours.

  Anna A Kattentidt Mouravieva, Ina R R Geurts-Giele, Ronald R de Krijger, Max M van Noesel, Cees P van de Ven, Ans M W van den Ouweland, Joan N R Kromosoeto, Winand N M Dinjens, Hendrikus J Dubbink, Ron Smits, Anja Wagner
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  ABSTRACT: Desmoid tumours are rare mesenchymal tumours with unpredictable progression and high recurrence risk. They can occur sporadically or in association with Familial Adenomatous Polyposis (FAP), which is caused by germline APC mutations. The Wnt/β-catenin pathway has a central role in the pathogenesis of desmoid tumours. These tumours can occur due to either a somatic CTNNB1 or APC mutation but can also be the first manifestation of FAP. Because germline APC analysis is not routinely performed in children with desmoid tumours, the diagnosis FAP may escape detection. The aim of this study is to form guidelines for the identification of possible APC germline mutation carriers among children with desmoid tumours, based on CTNNB1 mutation analysis and immunohistochemical analysis (IHC) for β-catenin. We performed IHC of β-catenin and mutation analysis of CTNNB1 and APC in 18 paediatric desmoid tumours, diagnosed between 1990 and 2009 in the Erasmus MC, Rotterdam. In 11 tumours, IHC showed an abnormal nuclear β-catenin accumulation. In this group a CTNNB1 mutation was detected in seven tumours. In two tumours with an abnormal nuclear β-catenin accumulation and no CTNNB1 mutation, an APC mutation was identified, which appeared to be a germline mutation. Aberrant staining of β-catenin in paediatric desmoids helps to identify children at risk for FAP. We recommend to screen paediatric desmoid tumours for nuclear localisation of β-catenin and consequently for CTNNB1 mutations. For patients with nuclear β-catenin expression and no CTNNB1 mutations, APC mutation analysis should be offered after genetic counselling.
  European journal of cancer (Oxford, England: 1990) 02/2012; 48(12):1867-74. · 4.12 Impact Factor
• Article: Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤ 70 years.

  Celine H M Leenen, Margot G F van Lier, Helena C van Doorn, Monique E van Leerdam, Sjarlot G Kooi, Judith de Waard, Robert F Hoedemaeker, Ans M W van den Ouweland, Sanne M Hulspas, Hendrikus J Dubbink, Ernst J Kuipers, Anja Wagner, Winand N M Dinjens, Ewout W Steyerberg
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  ABSTRACT: Lynch syndrome (LS) is a hereditary syndrome that predisposes to multiple malignancies including endometrial cancer (EC). We aimed to evaluate a diagnostic strategy for LS based on routine analysis of microsatellite instability (MSI) and immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in tumour tissue of all newly diagnosed EC patients ≤ 70 years. Consecutive EC patients ≤ 70 years were included prospectively in eight Dutch centres. EC specimens were analysed for MSI, IHC of four MMR proteins, MMR gene methylation status and BRAF-mutations. tumours were classified as; 1) likely to be caused by LS, 2) sporadic MSI-H, or 3) microsatellite stable (MSS). Tumour specimens of 179 patients (median age 61 years, IQR 57-66) were analysed. In our study 92% of included patients were over 50 years of age. Eleven EC patients were found likely to have LS (6%; 95% CI 3-11%), including 1 patient suspected of an MLH1, 2 of an MSH2, 6 of an MSH6 and 2 of a PMS2 gene defect. Germline mutation analyses revealed 7 MMR gene germline mutations. Ten patients likely to have LS (92%) were older than 50 years. In addition, 31 sporadic MSI-H tumours with MLH1 promoter hypermethylation (17%; 95% CI 13-24%) were identified. Molecular screening for LS in patients with EC diagnosed ≤ 70 years, leads to identification of a profile likely to have LS in 6% of cases. New screening guidelines for LS are needed, including recommendations for EC patients older than 50 years of age.
  Gynecologic Oncology 02/2012; 125(2):414-20. · 3.89 Impact Factor
• Source

  Available from: Dominik T. Schneider

  Article: Prevalence of c-KIT mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian dysgerminomas.

  Remko Hersmus, Hans Stoop, Gert Jan van de Geijn, Ronak Eini, Katharina Biermann, J Wolter Oosterhuis, Catharina Dhooge, Dominik T Schneider, Isabelle C Meijssen, Winand N M Dinjens, Hendrikus Jan Dubbink, Stenvert L S Drop, Leendert H J Looijenga
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  ABSTRACT: Activating c-KIT mutations (exons 11 and 17) are found in 10-40% of testicular seminomas, the majority being missense point mutations (codon 816). Malignant ovarian dysgerminomas represent ~3% of all ovarian cancers in Western countries, resembling testicular seminomas, regarding chromosomal aberrations and c-KIT mutations. DSD patients with specific Y-sequences have an increased risk for Type II Germ Cell Tumor/Cancer, with gonadoblastoma as precursor progressing to dysgerminoma. Here we present analysis of c-KIT exon 8, 9, 11, 13 and 17, and PDGFRA exon 12, 14 and 18 by conventional sequencing together with mutational analysis of c-KIT codon 816 by a sensitive and specific LightCycler melting curve analysis, confirmed by sequencing. The results are combined with data on TSPY and OCT3/4 expression in a series of 16 DSD patients presenting with gonadoblastoma and dysgerminoma and 15 patients presenting pure ovarian dysgerminomas without DSD. c-KIT codon 816 mutations were detected in five out of the total of 31 cases (all found in pure ovarian dysgerminomas). A synonymous SNP (rs 5578615) was detected in two patients, one DSD patient (with bilateral disease) and one patient with dysgerminoma. Next to these, three codon N822K mutations were detected in the group of 15 pure ovarian dysgerminomas. In total activating c-KIT mutations were found in 53% of ovarian dysgerminomas without DSD. In the group of 16 DSD cases a N505I and D820E mutation was found in a single tumor of a patient with gonadoblastoma and dysgerminoma. No PDGFRA mutations were found. Positive OCT3/4 staining was present in all gonadoblastomas and dysgerminomas investigated, TSPY expression was only seen in the gonadoblastoma/dysgerminoma lesions of the 16 DSD patients. This data supports the existence of two distinct but parallel pathways in the development of dysgerminoma, in which mutational status of c-KIT might parallel the presence of TSPY.
  PLoS ONE 01/2012; 7(8):e43952. · 4.09 Impact Factor
• Article: Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome.

  Margot G F van Lier, Celine H M Leenen, Anja Wagner, Dewkoemar Ramsoekh, Hendrikus J Dubbink, Ans M W van den Ouweland, Pieter J Westenend, Eelco J R de Graaf, Leonieke M M Wolters, Wietske W Vrijland, Ernst J Kuipers, Monique E van Leerdam, Ewout W Steyerberg, Winand N M Dinjens
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  ABSTRACT: Although early detection of Lynch syndrome (LS) is important, a considerable proportion of patients with LS remains unrecognized. We aimed to study the yield of LS detection by routine molecular analyses in colorectal cancer (CRC) patients until 70 years of age. We prospectively included consecutive CRC patients ≤70 years. Tumour specimens were analysed for microsatellite instability (MSI), immunohistochemical mismatch-repair protein expression and MLH1-promoter methylation. Tumours were classified as either: (a) likely caused by LS; (b) sporadic microsatellite-unstable (MSI-H); or (c) microsatellite-stable (MSS). Predictors of LS were determined by multivariable logistic regression. A total of 1117 CRC patients (57% males, median age 61 years) were included. Fifty patients (4.5%, 95% CI 3.4-5.9) were likely to have LS, and 71 had a sporadic MSI-H tumour (6.4%, 95% CI 5.1-8.0). Thirty-five patients likely to have LS (70%) were aged > 50 years. A molecular profile compatible with LS was detected in 10% (15/144) of patients aged ≤50, in 4% (15/377) of those aged 51-60 and in 3% (20/596) of patients > 61 years. Compared to MSS cases, patients likely to have LS were significantly younger (OR 3.9, 95% CI 1.7-8.7) and more often had right-sided CRCs (OR 14, 95% CI 6.0-34). In conclusion, molecular screening for LS in CRC patients ≤70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age criterion (≤50 years) routinely used for LS assessment. Routine use of MSI testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients.
  The Journal of Pathology 11/2011; 226(5):764-74. · 6.32 Impact Factor
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  Available from: Kirsten Timms

  Article: Mapping of homozygous deletions in verified esophageal adenocarcinoma cell lines and xenografts.

  Jurjen J Boonstra, Ronald van Marion, Hannie J C W Douben, Jerry S Lanchbury, Kirsten M Timms, Victor Abkevich, Hugo W Tilanus, Annelies de Klein, Winand N M Dinjens
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  ABSTRACT: Human esophageal adenocarcinoma (EAC) cell lines and xenografts are powerful tools in the search for genetic alterations because these models are composed of pure human cancer cell populations without admixture of normal human cells. In particular detection of homozygous deletions (HDs) is easier using these pure populations of cancer cells. Identification of HDs could potentially lead to the subsequent identification of new tumor suppressor genes (TSGs) involved in esophageal adenocarcinogenesis. Genome wide single nucleotide polymorphism (SNP) arrays were used to identify HDs in 10 verified EAC cell lines and nine EAC xenografts. In total, 61 HDs (range 1-6 per sample) were detected and confirmed by polymerase chain reaction. Besides HDs observed in common fragile genomic regions (n = 26), and gene deserts (n = 8), 27 HDs were located in gene-containing regions. HDs were noted for known TSGs, including CDKN2A, SMAD4 and CDH3/CDH1. Twenty-two new chromosomal regions were detected harboring potentially new TSGs involved in EAC carcinogenesis. Two of these regions of homozygous loss, encompassing the ITGAV and RUNX1 gene, were detected in multiple samples indicating a potential role in the carcinogenesis of EAC. To exclude culturing artifacts, these last two deletions were confirmed by fluorescent in situ hybridization in the primary tumors of which the involved cell lines and xenografts were derived. In summary, in this report we describe the identification of HDs in a series of verified EAC cell lines and xenografts. The deletions documented here are a step forward identifying the key genes involved in EAC development.
  Genes Chromosomes and Cancer 11/2011; 51(3):272-82. · 3.31 Impact Factor
• Article: SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas.

  Esther Korpershoek, Judith Favier, José Gaal, Nelly Burnichon, Bram van Gessel, Lindsey Oudijk, Cécile Badoual, Noémie Gadessaud, Annabelle Venisse, Jean-Pierre Bayley, Marieke F van Dooren, Wouter W de Herder, Frédérique Tissier, Pierre-François Plouin, Francien H van Nederveen, Winand N M Dinjens, Anne-Paule Gimenez-Roqueplo, Ronald R de Krijger
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  ABSTRACT: Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Results: Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations. Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.
  The Journal of clinical endocrinology and metabolism 07/2011; 96(9):E1472-6. · 6.50 Impact Factor
• Article: PTEN in colorectal cancer: a report on two Cowden syndrome patients.

  R Kersseboom, H J Dubbink, W E Corver, A J P van Tilburg, J W Poley, M E van Leerdam, P N Atmodimedjo, I M B H van de Laar, J M Collée, W N M Dinjens, H Morreau, A Wagner
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  ABSTRACT: Heterozygous germline PTEN mutations cause Cowden syndrome. The risk of colorectal cancer in Cowden patients, however, remains a matter of debate. We describe two patients presenting with colorectal cancer at a young age (28 and 39 years) and dysmorphisms fitting the Cowden spectrum. Heterozygous germline mutations in PTEN were found in both patients. Moreover, analysis of the resected colorectal cancer specimens revealed loss of heterozygosity at the PTEN locus with retention of the mutated alleles, and greatly reduced or absent PTEN expression. Histologically and molecularly, the tumours showed resemblance with sporadic colorectal cancers, although they had prominent fibrotic stroma. Our data indicate that PTEN loss was involved in carcinogenesis in the two patients, supporting that colorectal cancer is part of the Cowden syndrome-spectrum. This is in line with data on sporadic colorectal cancer, mice studies and emerging epidemiological data on Cowden syndrome. Although the exact role of germline PTEN mutations in the carcinogenesis of colorectal cancer remains unclear, we think that Cowden syndrome should be in the differential diagnosis of colorectal cancer certainly in view of the possible prognostic and therapeutic consequences. Prospective follow-up and surveillance of PTEN mutation carriers from the age of 25 to 30 years in a study setting should clarify this issue.
  Clinical Genetics 02/2011; 81(6):555-62. · 3.13 Impact Factor
• Source

  Available from: Mathilde C M Kouwenhoven

  Article: MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation.

  Floris H Groenendijk, Walter Taal, Hendrikus J Dubbink, Cathleen R Haarloo, Mathilde C Kouwenhoven, Martin J van den Bent, Johan M Kros, Winand N M Dinjens
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  ABSTRACT: Hypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB). In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations. For 27 patients biopsy samples both of primary tumors and their recurrences were available. For the other 24 patients histology of either the low-grade lesion or the high-grade recurrence was available. It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time. No correlation was found between MGMT methylation status and the presence of TP53 mutations. In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations. These results argue against the putative TP53 G:C>A:T transition mutations suggested to occur preferentially in MGMT hypermethylated tumors.
  Journal of Neuro-Oncology 02/2011; 101(3):405-17. · 3.21 Impact Factor
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  Available from: Mathilde C M Kouwenhoven

  Article: First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response.

  Walter Taal, Hendrikus J Dubbink, Chris B L Zonnenberg, Bernard A Zonnenberg, Tjeerd J Postma, Johanna M M Gijtenbeek, Willem Boogerd, Floris H Groenendijk, Johan M Kros, Mathilde C M Kouwenhoven, Ronald van Marion, Irene van Heuvel, Bronno van der Holt, Jacoline E C Bromberg, Peter A E Sillevis Smitt, Winand N M Dinjens, Martin J van den Bent
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  ABSTRACT: Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1-5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.
  Neuro-Oncology 02/2011; 13(2):235-41. · 5.72 Impact Factor
• Article: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.

  Katherine A Janeway, Su Young Kim, Maya Lodish, Vânia Nosé, Pierre Rustin, José Gaal, Patricia L M Dahia, Bernadette Liegl, Evan R Ball, Margarita Raygada, [......], Lorna Kelly, Jason L Hornick, Maureen O'Sullivan, Ronald R de Krijger, Winand N M Dinjens, George D Demetri, Cristina R Antonescu, Jonathan A Fletcher, Lee Helman, Constantine A Stratakis
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  ABSTRACT: Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1-associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.
  Proceedings of the National Academy of Sciences 01/2011; 108(1):314-8. · 9.68 Impact Factor
• Article: Lymphatic micrometastases in patients with early esophageal adenocarcinoma.

  Brechtje A Grotenhuis, Mark van Heijl, Bas P L Wijnhoven, Mark I van Berge Henegouwen, Katharina Biermann, Fiebo J W ten Kate, Olivier R C Busch, Winand N M Dinjens, Hugo W Tilanus, J Jan B van Lanschot
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  ABSTRACT: Both endoscopic and surgical treatments are recommended for m3- or sm1-adenocarcinomas of the esophagus, depending on patients' lymph nodal status. Lymphatic dissemination is related to tumor infiltration depth, but varying incidences have been reported in m3- and sm1-adenocarcinomas. The study aim was to investigate whether the presence of occult tumor cells in lymph nodes could explain this variation. Sixty-three node-negative (N0) patients with early esophageal adenocarcinoma (m2/m3/sm1-tumors) were included. Multilevel-sectioning of lymph nodes was performed; sections were stained by means of immunohistochemistry with cytokeratin marker CAM5.2. Two pathologists searched for micrometastases (0.2-2.0  mm) and isolated tumor cells (ITCs, <0.2  mm). Positive CAM5.2 staining in lymph nodes was not seen in any of the 18 m2-patients. In 2/25 m3-tumors (8.0%) an ITC was found, but no micrometastases. Tumor cells were identified in 4/20 sm1-tumors (20.0%): three micrometastases and one ITC. Median follow-up was 121 months. Two m3-patients (3.2%) died due to disease recurrence, including one patient in whom an ITC was detected. Lymphatic migration of tumor cells was found in node-negative m3- and sm1-adenocarcinomas of the esophagus (8.0% and 20.0%, respectively). However, the clinical relevance of these occult tumor cells should become apparent from large series of endoscopically treated patients.
  Journal of Surgical Oncology 12/2010; 102(7):863-7. · 2.10 Impact Factor
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  Available from: PubMed Central

  Article: Functional polymorphisms associated with disease-free survival in resected carcinoma of the esophagus.

  Jurjen J Boonstra, Ronald van Marion, Hugo W Tilanus, Winand N M Dinjens
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  ABSTRACT: The aim of this study was to determine whether clinical outcome after surgical resection of esophageal adenocarcinoma (EAC) or esophageal squamous cell carcinoma (ESCC) could be predicted by functional polymorphisms in different proto-oncogenes and tumor suppressor genes. Six single nucleotide polymorphisms (SNPs) in the AURKA (rs2273535), ERBB2 (rs1136201), MDM2 (rs2279744), CDH1 (rs5030625), CDKN2A (rs11515), and TP73 (rs2273953) genes were genotyped in a consecutive cohort of 346 esophageal cancer patients, who had underwent surgical resection with curative intent. Associations with disease-free survival (DFS) were analyzed with Kaplan-Meier curves and Cox regression, adjusting for potential confounders. Univariate analysis showed no significant associations between the tested polymorphisms and DFS in patients with EAC or ESCC. However, in a multivariate analysis, patients with EAC carrying the heterozygous MDM2 (rs2279744) T/G genotype had significantly improved DFS compared with patients carrying the wild-type genotype (adjusted hazard ratio (AHR), 0.63; 95% confidence interval (CI) [0.45-0.88]). Patients with EAC harboring the homozygous CDH1 (rs5030625) GA/GA genotype had a significantly reduced survival as compared with patients carrying the wild-type genotype AHR 4.0, 95% CI [1.4-11]. In a large cohort of esophageal cancer patients, the MDM2 T/G and CDH1 GA/GA genotype confer risk of death in patients with EAC. These data suggest that inter-individual differences in germ-line DNA have an impact on DFS in patients with EAC.
  Journal of Gastrointestinal Surgery 10/2010; 15(1):48-56. · 2.83 Impact Factor
• Article: Intra-tumoral molecular heterogeneity in benign and malignant pheochromocytomas and extra-adrenal sympathetic paragangliomas.

  Esther Korpershoek, Claudia K Stobbe, Francien H van Nederveen, Ronald R de Krijger, Winand N M Dinjens
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  ABSTRACT: Pheochromocytomas (PCCs) and extra-adrenal sympathetic paragangliomas (sPGLs) are catecholamine-producing tumors occurring in the context of hereditary tumor syndromes, with known germline mutations, and as sporadic tumors. The pathogenesis of sporadic PCC and sPGL is poorly understood, and little is known about intra-tumoral heterogeneity with respect to molecular aberrations. Since knowledge on intra-tumoral heterogeneity is important for understanding the pathogenesis of these tumors, we investigated 12 benign and 8 malignant PCCs and sPGLs for loss of heterozygosity (LOH) on DNA extracted from different regions of each tumor and from metastases. LOH markers were selected on chromosomal regions frequently deleted in PCC, including 1p, 3q, 3p, and 11p. Benign tumors were found to have less intra-tumoral heterogeneity (overall 8%) than malignant tumors (overall 23%), with the highest frequencies for chromosome 1p36 in the benign tumors (17%) and 1p13 and 3q24 in malignant tumors (both 38%). In addition, differences in LOH patterns were detected between paired primary malignant tumors, and their metastases and different LOH patterns were observed in bilateral PCC of a multiple endocrine neoplasia type 2 patient. We demonstrate that malignant PCC and sPGL have more intra-tumoral molecular heterogeneity than benign tumors, which suggests that benign and malignant PCC and sPGL have a different pathogenesis.
  Endocrine Related Cancer 09/2010; 17(3):653-62. · 4.36 Impact Factor
• Article: Mutation of SDHB is a cause of hypoxia-related high-altitude paraganglioma.

  Nidia Y Cerecer-Gil, Luis E Figuera, Francisco J Llamas, Mauricio Lara, José G Escamilla, Ruben Ramos, Gerardo Estrada, A Karim Hussain, José Gaal, Esther Korpershoek, Ronald R de Krijger, Winand N M Dinjens, Peter Devilee, Jean Pierre Bayley
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  ABSTRACT: Paragangliomas of the head and neck are neuroendocrine tumors and are associated with germ line mutations of the tricarboxylic acid cycle-related genes SDHB, SDHC, SDHD, and SDHAF2. Hypoxia is important in most solid tumors, and was directly implicated in tumorigenesis over 40 years ago when it was shown that dwelling at high altitudes increases the incidence of carotid body hyperplasia and paragangliomas. Although recent research has now elucidated several pathways of hypoxia in paragangliomas, nothing is currently known of the genetics or of gene-environment interactions in high-altitude paraganglioma. We postulated that SDH mutations might play a role in these tumors. Patients from a Mexican family, originating and resident in Guadalajara, were tested for mutations of SDHD, and subsequently, for mutations of SDHB followed by immunohistochemical confirmation of SDHB loss. Two patients, born and resident at altitudes of between 1,560 and 2,240 m, were found to have head and neck paragangliomas, including a remarkably aggressive recurrent tumor. Mutation analysis identified a pathogenic missense mutation in exon 7 of SDHB, c.689G>A, p.Arg230His, and loss of the SDHB protein was confirmed by immunohistochemistry. This is the first report of a SDH gene mutation in paraganglioma at high altitude. A rapidly recurrent head and neck paraganglioma is a very rare finding in an SDH mutation carrier, suggesting a gene-environment interaction. Neither patient showed evidence of sympathetic paraganglioma.
  Clinical Cancer Research 08/2010; 16(16):4148-54. · 7.74 Impact Factor
• Chapter: The Pathogenesis of Barrett’s Metaplasia and the Progression to Esophageal Adenocarcinoma

  Brechtje A. Grotenhuis, J. Jan B. van Lanschot, Winand N. M. Dinjens, Bas P. L. Wijnhoven
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  ABSTRACT: The most important risk factor for the development of Barrett’s esophagus is the reflux of both gastric and duodenal contents into the esophagus. The reason why Barrett’s metaplasia develops only in a minority of patients suffering from gastroesophageal reflux disease remains unknown.The exact mechanism behind the transition of normal squamous epithelium into specialized columnar epithelium is also unclear. It is likely that stem cells are involved in this metaplastic change, as they are the only permanent residents of the epithelium. Several tumorigenic steps that lead to the underlying genetic instability, which is indispensable in the progression from columnar metaplasia to esophageal adenocarcinoma have been des­c­rib­ed. This review outlines the process of pathogenesis of Barrett’s metaplasia and its pro­gression to esophageal adenocarcinoma.
  08/2010: pages 39-63;
• Article: Barrett's oesophageal adenocarcinoma encompasses tumour-initiating cells that do not express common cancer stem cell markers.

  Brechtje A Grotenhuis, Winand N M Dinjens, Bas P L Wijnhoven, Petra Sonneveld, Andrea Sacchetti, Patrick F Franken, Herman van Dekken, Hugo W Tilanus, J Jan B van Lanschot, Riccardo Fodde
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  ABSTRACT: Accumulating evidence has suggested that tumours have a hierarchical organization in which only the cancer stem cells (CSCs) have tumour-initiating properties. Several surface antigens have been employed to isolate CSCs from various malignancies, although not from oesophageal adenocarcinoma (EA). We tested whether Barrett's oesophagus (BE) and EA might serve as a model for the CSC concept. In vivo assays were performed by transplantation of serially diluted bulk EA cells into NOD-SCID mice to establish the presence and frequency of tumour-initiating cells. These were found to be present as ca. 1 in 64 000 cells. The transplanted tumours fully recapitulated the primary lesions. Subsequently, a panel of previously established CSC markers was employed for immunohistochemistry. CD24, CD29 and CD44 showed heterogeneous staining in EA. Nuclear beta-catenin accumulation increased during progression from metaplasia to dysplasia and was often observed in the basal compartment with CD24 and CD29 staining. However, the overall staining patterns were not such to clearly point out specific candidate markers. Accordingly, all markers were employed to sort the corresponding subpopulations of cancer cells and transplant them at low multiplicities in NOD-SCID mice. No increased tumour-initiating capacity of sorted EA cells was observed upon transplantation. These results indicate that tumour-initiating cells are present in EA, thus reflecting a hierarchical organization. However, antibodies directed against novel surface antigens are needed to detect subpopulations enriched for CSCs in EA by transplantation assays.
  The Journal of Pathology 08/2010; 221(4):379-89. · 6.32 Impact Factor
• Article: On the advent of MSI testing of all colorectal cancers and a substantial part of other Lynch syndrome-related neoplasms.

  Winand N M Dinjens, Monique E van Leerdam, Anja Wagner
  Expert Review of Molecular Diagnostics 05/2010; 10(4):381-4. · 4.86 Impact Factor