TY  - JOUR
AU  - Eissing, M.L.L.G.
AU  - Ripken, L.S.
AU  - Schreibelt, G.
AU  - Westdorp, H.
AU  - Ligtenberg, M.J.
AU  - Netea-Maier, R.T.
AU  - Netea, M.G.
AU  - Vries, I.J.M. de
AU  - Hoogerbrugge, N.
PY  - 2018
UR  - https://hdl.handle.net/2066/200303
AB  - Carriers of a pathogenic germline mutations in the PTEN gene, a well-known tumor suppressor gene, are at increased risk of multiple benign and malignant tumors, e.g. breast, thyroid, endometrial and colon cancer. This is called PTEN Hamartomous Tumor Syndrome (PHTS). PHTS patients may also have an increased risk of immunological dysregulation, such as autoimmunity and immune deficiencies. The effects of PTEN on the immune system have been studied in murine knockout models demonstrating that loss of PTEN function leads to dysregulation of the immune response. This results in susceptibility to autoimmunity, impaired B cell class switching with subsequent hypogammaglobulinemia. Additionally, a decreased ability of dendritic cells to prime CD8(+) T cells was observed, leading to impaired tumor eradication. Immune dysfunction in PHTS patients has not yet been extensively studied but might be a manageable contributing factor to the increased cancer risk in PHTS.
TI  - PTEN Hamartoma Tumor Syndrome and Immune Dysregulation
EP  - 367
SN  - 1936-5233
IS  - iss. 2
SP  - 361
JF  - Translational Oncology
VL  - vol. 12
DO  - https://doi.org/10.1016/j.tranon.2018.11.003
L1  - https://repository.ubn.ru.nl/bitstream/handle/2066/200303/200303.pdf?sequence=1
ER  - 
TY  - JOUR
AU  - Plantinga, T.S.
AU  - Arts, P.
AU  - Knarren, G.H.
AU  - Mulder, A.H.
AU  - Wakelkamp, I.M.
AU  - Hermus, A.R.M.M.
AU  - Joosten, L.A.
AU  - Netea, M.G.
AU  - Gilissen, C.F.
AU  - Veltman, J.A.
AU  - Hoischen, A.
AU  - Smit, J.W.A.
AU  - Netea-Maier, R.T.
PY  - 2017
UR  - https://hdl.handle.net/2066/179606
TI  - Rare NOX3 Variants Confer Susceptibility to Agranulocytosis During Thyrostatic Treatment of Graves' Disease
EP  - 1024
SN  - 0009-9236
IS  - iss. 6
SP  - 1017
JF  - Clinical Pharmacology and Therapeutics
VL  - vol. 102
DO  - https://doi.org/10.1002/cpt.733
ER  - 
TY  - JOUR
AU  - Ham, J.C.
AU  - Tops, B.B.J.
AU  - Driessen, C.M.L.
AU  - Raaij, A.W. van
AU  - Slootweg, P.J.
AU  - Melchers, W.J.G.
AU  - Ligtenberg, M.J.L.
AU  - Herpen, C.M.L. van
PY  - 2017
UR  - https://hdl.handle.net/2066/174696
AB  - OBJECTIVES: The aim of this study was to assess the feasibility of testing actionable mutations in small amounts of formalin-fixed paraffin-embedded material in multiple genes of the receptor tyrosine kinase pathway and to determine the frequency of these mutations in human papillomavirus (HPV)-positive and HPV-negative oropharyngeal cancer (OPC). DESIGN: A retrospective pilot study was performed. SETTING: In OPC, no predictive markers for response to epidermal growth factor receptor inhibition are known. Therefore, identifying predictive biomarkers is of utmost importance, but is often hampered by the small amount of tumour material available. PARTICIPANTS: We included the archival material of 45 OPC, all treated with concomitant chemoradiotherapy between 2003 and 2010. MAIN OUTCOME MEASURES: Besides the HPV status, we assessed mutations using a gene panel that targets 16 genes in the receptor tyrosine kinase pathway and six other genes. The polymerase chain reaction required only 10 ng DNA. RESULTS: In total, 42 of the 45 biopsies have been successfully analysed. In total 20 of 42 samples were HPV-positive and 22 of 42 were HPV-negative. In the receptor tyrosine kinase pathway, mutations in PIK3CA were most frequently identified. A TP53 mutation was identified in one HPV-positive sample and in 13 HPV-negative samples. Additionally, three mutations in three different genes were found. CONCLUSIONS: We evaluated an assay to identify mutations in the receptor tyrosine kinase pathway. As only small amounts of formalin-fixed paraffin-embedded material are sufficient for reliable analysis, this test opens up new possibilities for personalised medicine.
TI  - Using a semi-conductor sequencing-based panel for genotyping of HPV-positive and HPV-negative oropharyngeal cancer: a retrospective pilot study
EP  - 686
SN  - 0307-7772
IS  - iss. 3
SP  - 681
JF  - Clinical Otolaryngology
VL  - vol. 42
DO  - https://doi.org/10.1111/coa.12800
ER  - 
TY  - JOUR
AU  - Becker, K.L.
AU  - Arts, P.
AU  - Jaeger, M.
AU  - Plantinga, T.S.
AU  - Gilissen, C.F.
AU  - Laarhoven, A. van
AU  - Ingen, J. van
AU  - Veltman, J.A.
AU  - Joosten, L.A.B.
AU  - Hoischen, A.
AU  - Netea, M.G.
AU  - Iseman, M.D.
AU  - Chan, E.D.
AU  - Veerdonk, F.L. van de
PY  - 2017
UR  - https://hdl.handle.net/2066/169740
TI  - MST1R mutation as a genetic cause of Lady Windermere syndrome
SN  - 0903-1936
IS  - iss. 1
JF  - European Respiratory Journal
VL  - vol. 49
DO  - https://doi.org/10.1183/13993003.01478-2016
ER  - 
TY  - JOUR
AU  - Neveling, K.
AU  - Mensenkamp, A.R.
AU  - Derks, R
AU  - Kwint, M.P.
AU  - Ouchene, H.
AU  - Steehouwer, M.
AU  - Lier, L.A. van
AU  - Bosgoed, E.A.J.
AU  - Rikken, A.
AU  - Tychon, M.W.J.
AU  - Zafeiropoulou, D.
AU  - Castelein, S.
AU  - Hehir-Kwa, J.Y.
AU  - Thung, G.W.
AU  - Hofste, T.
AU  - Lelieveld, S.H.
AU  - Bertens, S.M.
AU  - Adan, I.B.
AU  - Eijkelenboom, A.
AU  - Tops, B.B.J.
AU  - Yntema, H.G.
AU  - Stokowy, T.
AU  - Knappskog, P.M.
AU  - Hoberg-Vetti, H.
AU  - Steen, V.M.
AU  - Boyle, E.
AU  - Martin, B.
AU  - Ligtenberg, M.J.L.
AU  - Shendure, J.
AU  - Nelen, M.R.
AU  - Hoischen, A.
PY  - 2017
UR  - https://hdl.handle.net/2066/169902
AB  - BACKGROUND: Despite advances in next generation DNA sequencing (NGS), NGS-based single gene tests for diagnostic purposes require improvements in terms of completeness, quality, speed, and cost. Single-molecule molecular inversion probes (smMIPs) are a technology with unrealized potential in the area of clinical genetic testing. In this proof-of-concept study, we selected 2 frequently requested gene tests, those for the breast cancer genes BRCA1 and BRCA2, and developed an automated work flow based on smMIPs. METHODS: The BRCA1 and BRCA2 smMIPs were validated using 166 human genomic DNA samples with known variant status. A generic automated work flow was built to perform smMIP-based enrichment and sequencing for BRCA1, BRCA2, and the checkpoint kinase 2 (CHEK2) c.1100del variant. RESULTS: Pathogenic and benign variants were analyzed in a subset of 152 previously BRCA-genotyped samples, yielding an analytical sensitivity and specificity of 100%. Following automation, blind analysis of 65 in-house samples and 267 Norwegian samples correctly identified all true-positive variants (>3000), with no false positives. Consequent to process optimization, turnaround times were reduced by 60% to currently 10-15 days. Copy number variants were detected with an analytical sensitivity of 100% and an analytical specificity of 88%. CONCLUSIONS: smMIP-based genetic testing enables automated and reliable analysis of the coding sequences of BRCA1 and BRCA2. The use of single-molecule tags, double-tiled targeted enrichment, and capturing and sequencing in duplo, in combination with automated library preparation and data analysis, results in a robust process and reduces routine turnaround times. Furthermore, smMIP-based copy number variation analysis could make independent copy number variation tools like multiplex ligation-dependent probes amplification dispensable.
TI  - BRCA Testing by Single-Molecule Molecular Inversion Probes
EP  - 512
SN  - 0009-9147
IS  - iss. 2
SP  - 503
JF  - Clinical Chemistry
VL  - vol. 63
DO  - https://doi.org/10.1373/clinchem.2016.263897
ER  - 
TY  - JOUR
AU  - Weren, R.D.A.
AU  - Mensenkamp, A.R.
AU  - Simons, M.
AU  - Eijkelenboom, A.
AU  - Sie, A.S.
AU  - Ouchene, H.
AU  - Asseldonk, M. van
AU  - Gomez-Garcia, E.B.
AU  - Blok, M.J.
AU  - Hullu, J.A. de
AU  - Nelen, M.R.
AU  - Hoischen, A.
AU  - Bulten, J.
AU  - Tops, B.B.J.
AU  - Hoogerbrugge, N.
AU  - Ligtenberg, M.J.L.
PY  - 2017
UR  - https://hdl.handle.net/2066/170272
TI  - Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas.
EP  - 235
SN  - 1059-7794
IS  - iss. 2
SP  - 226
JF  - Human Mutation
VL  - vol. 38
DO  - https://doi.org/10.1002/humu.23137
L1  - https://repository.ubn.ru.nl/bitstream/handle/2066/170272/170272.pdf?sequence=1
ER  - 
TY  - JOUR
AU  - Zhang, J.
AU  - Wang, W.
AU  - Voer, R.M. de
AU  - Hehir-Kwa, J.Y.
AU  - Kamping, E.J.
AU  - Weren, R.D.A.
AU  - Nelen, M.
AU  - Hoischen, A.
AU  - Ligtenberg, M.J.L.
AU  - Hoogerbrugge, N.
AU  - Yang, X
AU  - Yang, Z
AU  - Fan, X.
AU  - Wang, L.
AU  - Liu, H.
AU  - Wang, J
AU  - Kuiper, R.P.
AU  - Geurts van Kessel, A.H.M.
PY  - 2017
UR  - https://hdl.handle.net/2066/169654
TI  - A molecular inversion probe-based next-generation sequencing panel to detect germline mutations in Chinese early-onset colorectal cancer patients.
EP  - 24547
SN  - 1949-2553
SP  - 24533
JF  - Oncotarget
VL  - vol. 8
DO  - https://doi.org/10.18632/oncotarget.15593
L1  - https://repository.ubn.ru.nl/bitstream/handle/2066/169654/169654.pdf?sequence=1
ER  - 
TY  - JOUR
AU  - Vogelaar, I.P.
AU  - Post, R.S. van der
AU  - Krieken, J.H. van
AU  - Spruijt, L.
AU  - Zelst-Stams, W.A.G. van
AU  - Kets, C.M.
AU  - Lubinski, J.
AU  - Jakubowska, A.
AU  - Teodorczyk, U.
AU  - Aalfs, C.M.
AU  - Hest, L.P. van
AU  - Pinheiro, H.
AU  - Oliveira, C. de
AU  - Jhangiani, S.N.
AU  - Muzny, D.M.
AU  - Gibbs, R.A.
AU  - Lupski, J.R.
AU  - Ligt, J. de
AU  - Vissers, L.E.L.M.
AU  - Hoischen, A.
AU  - Gilissen, C.
AU  - Vorst, J.M. van de
AU  - Goeman, J.J.
AU  - Schackert, H.K.
AU  - Ranzani, G.N.
AU  - Molinaro, V.
AU  - Garcia, E.B.
AU  - Hes, F.J.
AU  - Holinski-Feder, E.
AU  - Genuardi, M.
AU  - Ausems, M.
AU  - Sijmons, R.H.
AU  - Wagner, A.
AU  - Kolk, L.E. van der
AU  - Bjornevoll, I.
AU  - Hoberg-Vetti, H.
AU  - Geurts van Kessel, A.H.M.
AU  - Kuiper, R.P.
AU  - Ligtenberg, M.J.L.
AU  - Hoogerbrugge, N.
PY  - 2017
UR  - https://hdl.handle.net/2066/182216
AB  - Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
TI  - Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing
EP  - 1252
SN  - 1018-4813
IS  - iss. 11
SP  - 1246
JF  - European Journal of Human Genetics
VL  - vol. 25
DO  - https://doi.org/10.1038/ejhg.2017.138
L1  - https://repository.ubn.ru.nl/bitstream/handle/2066/182216/182216.pdf?sequence=1
ER  - 
TY  - JOUR
AU  - Vogelaar, I.P.
AU  - Ligtenberg, M.J.
AU  - Post, R.S. van der
AU  - Voer, R.M. de
AU  - Kets, C.M.
AU  - Jansen, T.J.
AU  - Jacobs, L.
AU  - Schreibelt, G.
AU  - Vries, I.J. de
AU  - Netea, M.G.
AU  - Hoogerbrugge, N.
PY  - 2016
UR  - https://hdl.handle.net/2066/171354
AB  - Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk.
TI  - Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect
EP  - 296
SN  - 1389-9600
IS  - iss. 2
SP  - 289
JF  - Familial Cancer
VL  - vol. 15
DO  - https://doi.org/10.1007/s10689-015-9859-z
L1  - https://repository.ubn.ru.nl/bitstream/handle/2066/171354/171354.pdf?sequence=1
ER  - 
TY  - JOUR
AU  - Schuurs-Hoeijmakers, J.H.M.
AU  - Geraghty, M.T.
AU  - Kamsteeg, E.J.
AU  - Ben-Salem, S.
AU  - Bot, S.T. de
AU  - Nijhof, B.
AU  - van de, V., II
AU  - Graaf, M. van der
AU  - Nobau, A.C.
AU  - Otte-Holler, I.
AU  - Vermeer, S.
AU  - Smith, A.C.
AU  - Humphreys, P.
AU  - Schwartzentruber, J.
AU  - Consortium, F.C.
AU  - Ali, B.R.
AU  - Al-Yahyaee, S.A.
AU  - Tariq, S.
AU  - Pramathan, T.
AU  - Bayoumi, R.
AU  - Kremer, H.P.H.
AU  - Warrenburg, B.P.C. van de
AU  - van den Akker, W.M.
AU  - Gilissen, C.F.H.A.
AU  - Veltman, J.A.
AU  - Janssen, I.M.
AU  - Vulto-van Silfhout, A.T.
AU  - van der Velde-Visser, S.
AU  - Lefeber, D.J.
AU  - Diekstra, A.
AU  - Erasmus, C.E.
AU  - Willemsen, M.A.A.P.
AU  - Peart-Vissers, L.E.L.M.
AU  - Lammens, M.M.Y.
AU  - Bokhoven, J.H.L.M. van
AU  - Brunner, H.G.
AU  - Wevers, R.A.
AU  - Schenck, A.
AU  - Al-Gazali, L.
AU  - Vries, L.B.A. de
AU  - Brouwer, A.P.M. de
PY  - 2012
UR  - https://hdl.handle.net/2066/108770
AB  - We report on four families affected by a clinical presentation of complex hereditary spastic paraplegia (HSP) due to recessive mutations in DDHD2, encoding one of the three mammalian intracellular phospholipases A(1) (iPLA(1)). The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging. An essential role for DDHD2 in the human CNS, and perhaps more specifically in synaptic functioning, is supported by a reduced number of active zones at synaptic terminals in Ddhd-knockdown Drosophila models. All identified mutations affect the protein's DDHD domain, which is vital for its phospholipase activity. In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance spectroscopy, which provides an applicable diagnostic biomarker that can distinguish the DDHD2 phenotype from other complex HSP phenotypes. We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease.
TI  - Mutations in DDHD2, Encoding an Intracellular Phospholipase A(1), Cause a Recessive Form of Complex Hereditary Spastic Paraplegia
EP  - 1081
SN  - 0002-9297
IS  - iss. 6
SP  - 1073
JF  - American Journal of Human Genetics
VL  - vol. 91
DO  - https://doi.org/10.1016/j.ajhg.2012.10.017
ER  -