Godelieve A.M. Tytgat
Boston Children's Hospital
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Featured researches published by Godelieve A.M. Tytgat.
Nature Genetics | 2015
Thomas F. Eleveld; Derek A. Oldridge; Virginie Bernard; Jan Koster; Leo Colmet Daage; Sharon J. Diskin; Linda Schild; Nadia Bessoltane Bentahar; Angela Bellini; Mathieu Chicard; Eve Lapouble; Valérie Combaret; Patricia Legoix-Né; Jean Michon; Trevor J. Pugh; Lori S. Hart; JulieAnn Rader; Edward F. Attiyeh; Jun S. Wei; Shile Zhang; Arlene Naranjo; Julie M. Gastier-Foster; Michael D. Hogarty; Shahab Asgharzadeh; Malcolm A. Smith; Jaime M. Guidry Auvil; Thomas B. K. Watkins; Danny A. Zwijnenburg; Marli E. Ebus; Peter van Sluis
The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.
Cancer Cell | 2015
Jenny Wegert; Naveed Ishaque; Romina Vardapour; Christina Geörg; Zuguang Gu; Matthias Bieg; Barbara Ziegler; Sabrina Bausenwein; Nasenien Nourkami; Nicole Ludwig; Andreas Keller; Clemens Grimm; Susanne Kneitz; Richard D. Williams; Tas Chagtai; Kathy Pritchard-Jones; Peter van Sluis; Richard Volckmann; Jan Koster; Rogier Versteeg; T Acha; Maureen O’Sullivan; Peter Bode; Felix Niggli; Godelieve A.M. Tytgat; Harm van Tinteren; Marry M. van den Heuvel-Eibrink; Eckart Meese; Christian Vokuhl; Ivo Leuschner
Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.
Nature Genetics | 2015
Linda J. Valentijn; Jan Koster; Danny A. Zwijnenburg; Nancy E. Hasselt; Peter van Sluis; Richard Volckmann; Max M. van Noesel; Rani E. George; Godelieve A.M. Tytgat; Jan J. Molenaar; Rogier Versteeg
Whole-genome sequencing detected structural rearrangements of TERT in 17 of 75 high-stage neuroblastomas, with five cases resulting from chromothripsis. Rearrangements were associated with increased TERT expression and targeted regions immediately up- and downstream of TERT, positioning a super-enhancer close to the breakpoints in seven cases. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non-overlapping groups of high-stage neuroblastoma, each associated with very poor prognosis.
Journal of Clinical Oncology | 2008
Janine Stutterheim; Annemieke Gerritsen; Lily Zappeij-Kannegieter; Ilona Kleijn; Rob Dee; Lotty Hooft; Max M. van Noesel; Marc Bierings; Frank Berthold; Rogier Versteeg; Huib N. Caron; C. Ellen van der Schoot; Godelieve A.M. Tytgat
PURPOSE Polymerase chain reaction (PCR)-based detection of minimal residual disease (MRD) in neuroblastoma can be used to monitor therapy response and to evaluate stem cell harvests. Commonly used PCR markers, tyrosine hydroxylase (TH) and GD2 synthase, have expression in normal tissues, thus limiting MRD detection. To identify a more specific MRD marker, we tested PHOX2B. PATIENTS AND METHODS To determine PHOX2B, TH, and GD2 synthase expression in normal tissues, it was measured by real-time quantitative PCR in samples of normal bone marrow (BM; n = 51), peripheral blood (PB; n = 37), and peripheral-blood stem cells (PBSCs; n = 24). Then, 289 samples of 101 Dutch patients and 47 samples of 43 German patients were tested for PHOX2B and TH; these samples included 52 tumor, 214 BM, 32 BM, and 38 PBSC harvests. Of the 214 BM samples, 167 were compared with cytology, and 47 BM samples were compared with immunocytology (IC). RESULTS In contrast to TH and GD2 synthase, PHOX2B was not expressed in any of the normal samples. In patient samples, PHOX2B was detected in 32% cytology-negative and in 14% IC-negative samples and in 94% of cytology-positive and in 90% of IC-positive BM samples. Overall, PHOX2B was positive in 43% compared with 31% for TH. In 24% of all samples, TH expression was inconclusive, which is similar to expression found in normal tissues. In 42% of these samples, PHOX2B expression was positive. CONCLUSION PHOX2B is superior to TH and GD2 synthase in specificity and sensitivity for MRD detection of neuroblastoma by using real-time quantitative PCR. We propose to include PHOX2B in additional prospective MRD studies in neuroblastoma alongside TH and other MRD markers.
Cellular and Molecular Life Sciences | 2010
Roos Cuperus; René Leen; Godelieve A.M. Tytgat; Huib N. Caron; André B.P. van Kuilenburg
Fenretinide induces apoptosis in neuroblastoma by induction of reactive oxygen species (ROS). In this study, we investigated the role of mitochondria in fenretinide-induced cytotoxicity and ROS production in six neuroblastoma cell lines. ROS induction by fenretinide was of mitochondrial origin, demonstrated by detection of superoxide with MitoSOX, the scavenging effect of the mitochondrial antioxidant MitoQ and reduced ROS production in cells without a functional mitochondrial respiratory chain (Rho zero cells). In digitonin-permeabilized cells, a fenretinide concentration-dependent decrease in ATP synthesis and substrate oxidation was observed, reflecting inhibition of the mitochondrial respiratory chain. However, inhibition of the mitochondrial respiratory chain was not required for ROS production. Co-incubation of fenretinide with inhibitors of different complexes of the respiratory chain suggested that fenretinide-induced ROS production occurred via complex II. The cytotoxicity of fenretinide was exerted through the generation of mitochondrial ROS and, at higher concentrations, also through inhibition of the mitochondrial respiratory chain.
Journal of Clinical Oncology | 2016
Tasnim Chagtai; Christina Zill; Linda Dainese; Jenny Wegert; Suvi Savola; Sergey Popov; William Mifsud; Gordan Vujanic; Nj Sebire; Yves Le Bouc; Peter F. Ambros; Leo Kager; Maureen J. O'Sullivan; Annick Blaise; Christophe Bergeron; Linda Holmquist Mengelbier; David Gisselsson; Marcel Kool; Godelieve A.M. Tytgat; Marry M. van den Heuvel-Eibrink; Norbert Graf; Harm van Tinteren; Aurore Coulomb; Manfred Gessler; Richard D. Williams; Kathy Pritchard-Jones
Purpose Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. Materials and Methods WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. Results One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. Conclusion Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.
European Journal of Cancer | 2011
Janine Stutterheim; Lily Zappeij-Kannegieter; Rogier Versteeg; H.N. Caron; C.E. van der Schoot; Godelieve A.M. Tytgat
BACKGROUND Quantitative real-time (q)PCR for detection of minimal residual disease (MRD) in children with neuroblastoma (NB) can evaluate molecular bone marrow (BM) response to therapy, but the prognostic value of tumour kinetics in the BM during induction treatment remains to be established. The purpose of this study was to analyse at which time points MRD detection by sequential molecular assessment of BM was prognostic for overall survival (OS). METHODS In this single centre study, qPCR was performed with five NB-specific markers: PHOX2B, TH, DDC, GAP43 and CHRNA3, on 106 retrospectively analysed BM samples of 53 patients >1 year with stage 4 neuroblastoma. The prognostic impact of MRD at diagnosis (n = 39), at 3 months after diagnosis (n = 38) and after completing induction chemotherapy (n = 29) was assessed using univariate and bivariate Cox regression analyses. RESULTS There was no correlation between tumour load at diagnosis and outcome (p = 0.93). Molecular BM remission was observed in 11/38 (29%) of patients at 3 months after diagnosis and associated with favourable outcome (5-y-OS 62 ± 15.0% versus 19 ± 8%; p = 0.009). After completion of induction chemotherapy, BM of 41% (12/29) of the patients was still MRD positive, which was associated with poor outcome (5-y-OS 0% versus 52 ± 12%; p<0.001). For both time points, the prognostic value of molecular response remained significant in bivariate analysis. CONCLUSIONS MRD detection measured by a panel of NB specific-PCR targets could identify fast responders, who clear their BM early during treatment. Fast molecular response was a prognostic factor, associated with better outcome. Our data indicate that MRD analysis during induction therapy should be included in prospective MRD studies.
Pediatric Blood & Cancer | 2013
Sarah C. Clement; B. L. F. van Eck-Smit; A.S.P. van Trotsenburg; Leontien Kremer; Godelieve A.M. Tytgat; H.M. van Santen
Thyroid dysfunction has been reported in up to 52% of patients 1.4 years after treatment with 131I‐Metaiodobenzylguanidine (MIBG) in children with neuroblastoma (NBL), despite the use of potassium‐iodide (KI). Our aim was to investigate if the incidence and severity of thyroid damage increases in time.
Nature Genetics | 2017
Tim van Groningen; Jan Koster; Linda J. Valentijn; Danny A. Zwijnenburg; Nurdan Akogul; Nancy E. Hasselt; Marloes Broekmans; Franciska Haneveld; Natalia E. Nowakowska; Johannes Bras; Carel J. M. van Noesel; Aldo Jongejan; Antoine H. C. van Kampen; Linda Koster; Frank Baas; Lianne van Dijk-Kerkhoven; Margriet Huizer-Smit; Maria C Lecca; Alvin Chan; Arjan Lakeman; Piet Molenaar; Richard Volckmann; Ellen M. Westerhout; Mohamed Hamdi; Peter van Sluis; Marli E. Ebus; Jan J. Molenaar; Godelieve A.M. Tytgat; Bart A. Westerman; Johan van Nes
Neuroblastoma and other pediatric tumors show a paucity of gene mutations, which has sparked an interest in their epigenetic regulation. Several tumor types include phenotypically divergent cells, resembling cells from different lineage development stages. It has been proposed that super-enhancer-associated transcription factor (TF) networks underlie lineage identity, but the role of these enhancers in intratumoral heterogeneity is unknown. Here we show that most neuroblastomas include two types of tumor cells with divergent gene expression profiles. Undifferentiated mesenchymal cells and committed adrenergic cells can interconvert and resemble cells from different lineage differentiation stages. ChIP–seq analysis of isogenic pairs of mesenchymal and adrenergic cells identified a distinct super-enhancer landscape and super-enhancer-associated TF network for each cell type. Expression of the mesenchymal TF PRRX1 could reprogram the super-enhancer and mRNA landscapes of adrenergic cells toward a mesenchymal state. Mesenchymal cells were more chemoresistant in vitro and were enriched in post-therapy and relapse tumors. Two super-enhancer-associated TF networks, which probably mediate lineage control in normal development, thus dominate epigenetic control of neuroblastoma and shape intratumoral heterogeneity.
Thyroid | 2012
Hanneke M. van Santen; Godelieve A.M. Tytgat; Marianne D. van de Wetering; Berthe L. F. van Eck-Smit; Saskia M.J. Hopman; Alida F. W. van der Steeg; Els J.M. Nieveen van Dijkum; A. S. Paul van Trotsenburg
BACKGROUND It is well known that the thyroid gland is sensitive to the damaging effects of irradiation (X-radiation or (131)I¯). For this reason, during exposure to (131)I- metaiodobenzylguanidine (MIBG) in children with neuroblastoma (NBL), the thyroid gland is protected against radiation damage by the administration of either potassium iodide (KI) or a combination of KI, thyroxine, and methimazole. Although hypothyroidism and benign thyroid nodules are frequently encountered during follow-up of these children, differentiated thyroid carcinoma (DTC) has never been reported after treatment with (131)I-MIBG in children who have not been given external beam irradiation. Here, we describe the first two cases of DTC after (131)I-MIBG-therapy. PATIENT FINDINGS A 6-year-old boy, treated with (131)I-MIBG for NBL at the age of 4 months, and a 13-year-old girl, treated at the age of 9 months, were both diagnosed with DTC at 5 and 12 years after (131)I-MIBG treatment, respectively. Both children received thyroid protection during exposure to (131)I-MIBG. In each child DTC was discovered in nonpalpable nodules by thyroid ultrasound. SUMMARY The first two pediatric patients with DTC after treatment with (131)I-MIBG are reported. CONCLUSIONS Both these cases of DTC after (131)I-MIBG for childhood NBL underline the importance of adequate thyroid protection against radiation exposure during treatment for NBL. Children who have been treated with (131)I-MIBG should be given life-long follow-up, not only with regard to thyroid function, but also with surveillance for the development of thyroid nodules and thyroid cancer.