Angela van Tilborg - Academia.edu (original) (raw)

Papers by Angela van Tilborg

Research paper thumbnail of Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glio... more Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

Research paper thumbnail of Data from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

A recent systematic sequence analysis of well-annotated human protein coding genes or consensus c... more A recent systematic sequence analysis of well-annotated human protein coding genes or consensus coding sequences led to the identification of 189 genes displaying somatic mutations in breast and colorectal cancers. Based on their mutation prevalence, a subset of these genes was identified as cancer candidate (CAN) genes as they could be potentially involved in cancer. We evaluated the mutational profiles of 19 CAN genes in the highly aggressive tumors: glioblastoma, melanoma, and pancreatic carcinoma. Among other changes, we found novel somatic mutations in EPHA3, MLL3, TECTA, FBXW7, and OBSCN, affecting amino acids not previously found to be mutated in human cancers. Interestingly, we also found a germline nucleotide variant of OBSCN that was previously reported as a somatic mutation. Our results identify specific genetic lesions in glioblastoma, melanoma, and pancreatic cancers and indicate that CAN genes and their mutational profiles are tumor specific. Some of the mutated genes, such as the tyrosine kinase EPHA3, are clearly amenable to pharmacologic intervention and could represent novel therapeutic targets for these incurable cancers. We also speculate that similar to other oncogenes and tumor suppressor genes, mutations affecting OBSCN could be involved in cancer predisposition. [Cancer Res 2007;67(8):3545–50]

Research paper thumbnail of Data from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

A recent systematic sequence analysis of well-annotated human protein coding genes or consensus c... more A recent systematic sequence analysis of well-annotated human protein coding genes or consensus coding sequences led to the identification of 189 genes displaying somatic mutations in breast and colorectal cancers. Based on their mutation prevalence, a subset of these genes was identified as cancer candidate (CAN) genes as they could be potentially involved in cancer. We evaluated the mutational profiles of 19 CAN genes in the highly aggressive tumors: glioblastoma, melanoma, and pancreatic carcinoma. Among other changes, we found novel somatic mutations in EPHA3, MLL3, TECTA, FBXW7, and OBSCN, affecting amino acids not previously found to be mutated in human cancers. Interestingly, we also found a germline nucleotide variant of OBSCN that was previously reported as a somatic mutation. Our results identify specific genetic lesions in glioblastoma, melanoma, and pancreatic cancers and indicate that CAN genes and their mutational profiles are tumor specific. Some of the mutated genes,...

Research paper thumbnail of Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glio... more Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

Research paper thumbnail of Characteristics of 109 GBM tumor samples

<p>Characteristics of 109 GBM tumor samples.</p

Research paper thumbnail of 1 A 3-plex methylation assay combined with the FGFR 3 mutation assay sensitively detects recurrent bladder cancer in voided urine Running title : Urine biomarkers for recurrent bladder cancer detection

Raju Kandimalla, Roy Masius, Willemien Beukers, Chris H. Bangma, Torben F. Orntoft, Lars Dyrskjot... more Raju Kandimalla, Roy Masius, Willemien Beukers, Chris H. Bangma, Torben F. Orntoft, Lars Dyrskjot, Nikki van Leeuwen, Hester Lingsma, Angela A. G. van Tilborg, Ellen C. Zwarthoff Department of Pathology, Erasmus MC, Rotterdam, The Netherlands Department of Urology, Erasmus MC, Rotterdam, The Netherlands Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark Department of Public Health, Erasmus MC, Rotterdam, The Netherlands

Research paper thumbnail of Polymorphisms in MMP-14 and MMP-2 genes and ovarian cancer survival

Research paper thumbnail of Immunohistochemical Profiles of Endometrioid Endometrial Carcinomas With and Without Metastatic Disease

Applied Immunohistochemistry & Molecular Morphology, 2016

A minority of endometrial carcinomas present at an advanced stage with a poor prognosis, and shou... more A minority of endometrial carcinomas present at an advanced stage with a poor prognosis, and should be identified to individualize treatment. Immunohistochemical markers have been studied, but most have not been directly linked to metastasis. This study analyzes the immunohistochemical profile of endometrioid endometrial carcinomas (EECs) with and without metastases, and corresponding metastases. Tissue microarray slides from stage I EECs, stage III-IV EECs, and corresponding metastases were stained and scored for expression of β-catenin, E-cadherin, ER, PR, PTEN, p16, MLH1, PMS2, L1CAM, p53, p21, and MIB1. Scores were compared between primary stage I and III-IV EECs, stage III-IV EECs, and the corresponding metastases, and between intra-abdominal and distant metastases. Primary tumors with distant metastases had a significantly lower ER expression than those without metastases or with intra-abdominal metastases. Distant metastases had a significantly lower PR expression than the co...

Research paper thumbnail of The chromosome 9q genes TGFBRI, TSCI, and ZNF189 are rarely mutated in bladder cancer

Journal of Pathology, 2001

Research paper thumbnail of A 3-Plex Methylation Assay Combined with the FGFR3 Mutation Assay Sensitively Detects Recurrent Bladder Cancer in Voided Urine

Clinical Cancer Research, 2013

Purpose: DNA methylation is associated with bladder cancer and these modifications could serve as... more Purpose: DNA methylation is associated with bladder cancer and these modifications could serve as useful biomarkers. FGFR3 mutations are present in 60% to 70% of non–muscle invasive bladder cancer (NMIBC). Low-grade bladder cancer recurs in more than 50% of patients. The aim of this study is to determine the sensitivity and specificity of a urine assay for the diagnosis of recurrences in patients with a previous primary NMIBC G1/G2 by using cystoscopy as the reference standard. Experimental Design: We selected eight CpG islands (CGI) methylated in bladder cancer from our earlier genome-wide study. Sensitivity of the CGIs for recurrences detection was investigated on a test set of 101 preTUR urines. Specificity was determined on 70 urines from healthy males aged more than 50 years. A 3-plex assay for the best combination was developed and validated on an independent set of 95 preTUR, recurrence free, and nonmalignant urines (n = 130). Results: The 3-plex assay identified recurrent bl...

Research paper thumbnail of In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma

Cancer Cell, 2010

Kinases execute pivotal cellular functions and are therefore widely investigated as potential tar... more Kinases execute pivotal cellular functions and are therefore widely investigated as potential targets in anticancer treatment. Here we analyze the kinase gene expression profiles of various tumor types and reveal the wee1 kinase to be overexpressed in glioblastomas. We demonstrate that WEE1 is a major regulator of the G 2 checkpoint in glioblastoma cells. Inhibition of WEE1 by siRNA or small molecular compound in cells exposed to DNA damaging agents results in abrogation of the G 2 arrest, premature termination of DNA repair, and cell death. Importantly, we show that the small-molecule inhibitor of WEE1 sensitizes glioblastoma to ionizing radiation in vivo. Our results suggest that inhibition of WEE1 kinase holds potential as a therapeutic approach in treatment of glioblastoma.

Research paper thumbnail of The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone

Neuro-Oncology, 2014

Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered ca... more Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered cancer genes of which only O(6)-methylguanine-methyltransferase (MGMT) methylation is used thus far as a predictive marker in a clinical setting. We investigated the prognostic significance of genetic and epigenetic alterations in glioblastoma patients. We screened 98 human glioblastoma samples for genetic and epigenetic alterations in 10 genes and chromosomal loci by PCR and multiplex ligation-dependent probe amplification (MLPA). We tested the association between these genetic and epigenetic alterations and glioblastoma patient survival. Subsequently, we developed a 2-gene survival predictor. Multivariate analyses revealed that mutations in isocitrate dehydrogenase 1 (IDH1), promoter methylation of MGMT, irradiation dosage, and Karnofsky Performance Status (KFS) were independent prognostic factors. A 2-gene predictor for glioblastoma survival was generated. Based on the genetic and epigenetic status of IDH1 and MGMT, glioblastoma patients were stratified into 3 clinically different genotypes: glioblastoma patients with IDH1mt/MGMTmet had the longest survival, followed by patients with IDH1mt/MGMTunmet or IDH1wt/MGMTmet, and patients with IDH1wt/MGMTunmet had the shortest survival. This 2-gene predictor was an independent prognostic factor and performed significantly better in predicting survival than either IDH1 mutations or MGMT methylation alone. The predictor was validated in 3 external datasets. The combination of IDH1 mutations and MGMT methylation outperforms either IDH1 mutations or MGMT methylation alone in predicting survival of glioblastoma patients. This information will help to increase our understanding of glioblastoma biology, and it may be helpful for baseline comparisons in future clinical trials.

Research paper thumbnail of Absence of AKT1 Mutations in Glioblastoma

PLoS ONE, 2009

Background: Oncogenic activation of the PI3K signalling pathway plays a pivotal role in the devel... more Background: Oncogenic activation of the PI3K signalling pathway plays a pivotal role in the development of glioblastoma multiforme (GBM). A central node in PI3K downstream signalling is controlled by the serine-threonine kinase AKT1. A somatic mutation affecting residue E17 of the AKT1 gene has recently been identified in breast and colon cancer. The E17K change results in constitutive AKT1 activation, induces leukaemia in mice, and accordingly, may be therapeutically exploited to target the PI3K pathway. Assessing whether AKT1 is activated by somatic mutations in GBM is relevant to establish its role in this aggressive disease.

Research paper thumbnail of Mutational profiling of kinases in glioblastoma

BMC Cancer, 2014

Background: Glioblastoma is a highly malignant brain tumor for which no cure is available. To ide... more Background: Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma. Methods: Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before. Among those we selected 34 kinase genes for mutation analysis. We also included IDH1, IDH2, PTEN, TP53 and NRAS, genes that are known to be mutated at considerable frequencies in glioblastoma. In total, 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high-grade glioma (HGG) cell lines were sequenced. Results: Our mutation analysis led to the identification of 148 non-synonymous somatic mutations, of which 25 have not been reported before in glioblastoma. Somatic mutations were found in TP53, PTEN, IDH1, PIK3CA, EGFR, BRAF, EPHA3, NRAS, TGFBR2, FLT3 and RPS6KC1. Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K-AKT pathway.

Research paper thumbnail of Prognostic significance of highly sulfated chondroitin sulfates in ovarian cancer defined by the single chain antibody GD3A11

Gynecologic oncology, Jan 28, 2015

The extracellular matrix (ECM) of ovarian cancer may provide a number of potential biomarkers. Ch... more The extracellular matrix (ECM) of ovarian cancer may provide a number of potential biomarkers. Chondroitin sulfate (CS), a class of sulfated polysaccharides, is abundantly present in the ECM of ovarian cancer. Structural alterations of CS chains (i.e. sulfation pattern) have been demonstrated to play a role in cancer development and progression. In this study we investigate the potential of highly sulfated CS as a biomarker in ovarian cancer using the single chain antibody GD3A11 selected by the phage display technology. The specificity of the antibody was determined by an indirect ELISA. GD3A11 epitope expression was assessed by immunohistochemistry in healthy organs, benign and malignant ovarian tumors (N=359) and correlated to clinical parameters. The CHST15 gene, responsible for the biosynthesis of highly sulfated CS was evaluated for mutation and methylation status. The GD3A11 epitope was minimally expressed in normal organs. Intense expression was observed in the ECM of differ...

Research paper thumbnail of Chromosomal instability in meningiomas. J Neuropathol Exp Neurol

Journal of Neuropathology and Experimental Neurology

ABSTRACT

Research paper thumbnail of Lentiviral delivery of shRNA in glioblastoma multiforme spheroids

Research paper thumbnail of Value of immunohistochemical WT-1 detection in widespread serous carcinomas

International Journal of Gynecological Cancer

Research paper thumbnail of Chondroitin sulfates as a novel class of biomarkers to aid clinical decision making in ovarian cancer

International Journal of Gynecological Cancer

Research paper thumbnail of Mutational profiling of high-grade gliomas reveals inactivating mutations in IDH1

Neuro-Oncology

High-grade gliomas (HGGs) are malignant brain tumors for which no cure is available. To identify ... more High-grade gliomas (HGGs) are malignant brain tumors for which no cure is available. To identify new therapeutic targets we performed an extensive mutation analysis. We sequenced 39 genes in 113 HGG (including 109 glioblastoma) tumor samples and 16 HGG cell lines. We analyzed 200 exons belonging to 35 kinases, isocitrate dehydrogenase 1 (IDH1), NRAS, PTEN, and TP53 genes. At least one somatic mutation was found in 90 out of 129 HGG samples (70%). Most mutations were observed in genes belonging to the PI3K-AKT pathway; in more than 45% of HGGs we detected a mutational activation of the pathway, indicating that the PI3K-AKT axis represents a relevant therapeutic target for HGG. In addition, five different types of somatic mutations affecting the IDH1-R132 residue were detected in 20% (23 of 113) of HGG tumor samples. IDH1 mutations were predominantly observed in secondary glioblastoma (11 of 94 vs. 11 of 15, p-value=0.0000016). It has been established that IDH1 mutations occur early i...

Research paper thumbnail of Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glio... more Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

Research paper thumbnail of Data from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

A recent systematic sequence analysis of well-annotated human protein coding genes or consensus c... more A recent systematic sequence analysis of well-annotated human protein coding genes or consensus coding sequences led to the identification of 189 genes displaying somatic mutations in breast and colorectal cancers. Based on their mutation prevalence, a subset of these genes was identified as cancer candidate (CAN) genes as they could be potentially involved in cancer. We evaluated the mutational profiles of 19 CAN genes in the highly aggressive tumors: glioblastoma, melanoma, and pancreatic carcinoma. Among other changes, we found novel somatic mutations in EPHA3, MLL3, TECTA, FBXW7, and OBSCN, affecting amino acids not previously found to be mutated in human cancers. Interestingly, we also found a germline nucleotide variant of OBSCN that was previously reported as a somatic mutation. Our results identify specific genetic lesions in glioblastoma, melanoma, and pancreatic cancers and indicate that CAN genes and their mutational profiles are tumor specific. Some of the mutated genes, such as the tyrosine kinase EPHA3, are clearly amenable to pharmacologic intervention and could represent novel therapeutic targets for these incurable cancers. We also speculate that similar to other oncogenes and tumor suppressor genes, mutations affecting OBSCN could be involved in cancer predisposition. [Cancer Res 2007;67(8):3545–50]

Research paper thumbnail of Data from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

A recent systematic sequence analysis of well-annotated human protein coding genes or consensus c... more A recent systematic sequence analysis of well-annotated human protein coding genes or consensus coding sequences led to the identification of 189 genes displaying somatic mutations in breast and colorectal cancers. Based on their mutation prevalence, a subset of these genes was identified as cancer candidate (CAN) genes as they could be potentially involved in cancer. We evaluated the mutational profiles of 19 CAN genes in the highly aggressive tumors: glioblastoma, melanoma, and pancreatic carcinoma. Among other changes, we found novel somatic mutations in EPHA3, MLL3, TECTA, FBXW7, and OBSCN, affecting amino acids not previously found to be mutated in human cancers. Interestingly, we also found a germline nucleotide variant of OBSCN that was previously reported as a somatic mutation. Our results identify specific genetic lesions in glioblastoma, melanoma, and pancreatic cancers and indicate that CAN genes and their mutational profiles are tumor specific. Some of the mutated genes,...

Research paper thumbnail of Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glio... more Supplementary Table 1 from Novel Somatic and Germline Mutations in Cancer Candidate Genes in Glioblastoma, Melanoma, and Pancreatic Carcinoma

Research paper thumbnail of Characteristics of 109 GBM tumor samples

<p>Characteristics of 109 GBM tumor samples.</p

Research paper thumbnail of 1 A 3-plex methylation assay combined with the FGFR 3 mutation assay sensitively detects recurrent bladder cancer in voided urine Running title : Urine biomarkers for recurrent bladder cancer detection

Raju Kandimalla, Roy Masius, Willemien Beukers, Chris H. Bangma, Torben F. Orntoft, Lars Dyrskjot... more Raju Kandimalla, Roy Masius, Willemien Beukers, Chris H. Bangma, Torben F. Orntoft, Lars Dyrskjot, Nikki van Leeuwen, Hester Lingsma, Angela A. G. van Tilborg, Ellen C. Zwarthoff Department of Pathology, Erasmus MC, Rotterdam, The Netherlands Department of Urology, Erasmus MC, Rotterdam, The Netherlands Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark Department of Public Health, Erasmus MC, Rotterdam, The Netherlands

Research paper thumbnail of Polymorphisms in MMP-14 and MMP-2 genes and ovarian cancer survival

Research paper thumbnail of Immunohistochemical Profiles of Endometrioid Endometrial Carcinomas With and Without Metastatic Disease

Applied Immunohistochemistry & Molecular Morphology, 2016

A minority of endometrial carcinomas present at an advanced stage with a poor prognosis, and shou... more A minority of endometrial carcinomas present at an advanced stage with a poor prognosis, and should be identified to individualize treatment. Immunohistochemical markers have been studied, but most have not been directly linked to metastasis. This study analyzes the immunohistochemical profile of endometrioid endometrial carcinomas (EECs) with and without metastases, and corresponding metastases. Tissue microarray slides from stage I EECs, stage III-IV EECs, and corresponding metastases were stained and scored for expression of β-catenin, E-cadherin, ER, PR, PTEN, p16, MLH1, PMS2, L1CAM, p53, p21, and MIB1. Scores were compared between primary stage I and III-IV EECs, stage III-IV EECs, and the corresponding metastases, and between intra-abdominal and distant metastases. Primary tumors with distant metastases had a significantly lower ER expression than those without metastases or with intra-abdominal metastases. Distant metastases had a significantly lower PR expression than the co...

Research paper thumbnail of The chromosome 9q genes TGFBRI, TSCI, and ZNF189 are rarely mutated in bladder cancer

Journal of Pathology, 2001

Research paper thumbnail of A 3-Plex Methylation Assay Combined with the FGFR3 Mutation Assay Sensitively Detects Recurrent Bladder Cancer in Voided Urine

Clinical Cancer Research, 2013

Purpose: DNA methylation is associated with bladder cancer and these modifications could serve as... more Purpose: DNA methylation is associated with bladder cancer and these modifications could serve as useful biomarkers. FGFR3 mutations are present in 60% to 70% of non–muscle invasive bladder cancer (NMIBC). Low-grade bladder cancer recurs in more than 50% of patients. The aim of this study is to determine the sensitivity and specificity of a urine assay for the diagnosis of recurrences in patients with a previous primary NMIBC G1/G2 by using cystoscopy as the reference standard. Experimental Design: We selected eight CpG islands (CGI) methylated in bladder cancer from our earlier genome-wide study. Sensitivity of the CGIs for recurrences detection was investigated on a test set of 101 preTUR urines. Specificity was determined on 70 urines from healthy males aged more than 50 years. A 3-plex assay for the best combination was developed and validated on an independent set of 95 preTUR, recurrence free, and nonmalignant urines (n = 130). Results: The 3-plex assay identified recurrent bl...

Research paper thumbnail of In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma

Cancer Cell, 2010

Kinases execute pivotal cellular functions and are therefore widely investigated as potential tar... more Kinases execute pivotal cellular functions and are therefore widely investigated as potential targets in anticancer treatment. Here we analyze the kinase gene expression profiles of various tumor types and reveal the wee1 kinase to be overexpressed in glioblastomas. We demonstrate that WEE1 is a major regulator of the G 2 checkpoint in glioblastoma cells. Inhibition of WEE1 by siRNA or small molecular compound in cells exposed to DNA damaging agents results in abrogation of the G 2 arrest, premature termination of DNA repair, and cell death. Importantly, we show that the small-molecule inhibitor of WEE1 sensitizes glioblastoma to ionizing radiation in vivo. Our results suggest that inhibition of WEE1 kinase holds potential as a therapeutic approach in treatment of glioblastoma.

Research paper thumbnail of The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone

Neuro-Oncology, 2014

Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered ca... more Genetic and epigenetic profiling of glioblastomas has provided a comprehensive list of altered cancer genes of which only O(6)-methylguanine-methyltransferase (MGMT) methylation is used thus far as a predictive marker in a clinical setting. We investigated the prognostic significance of genetic and epigenetic alterations in glioblastoma patients. We screened 98 human glioblastoma samples for genetic and epigenetic alterations in 10 genes and chromosomal loci by PCR and multiplex ligation-dependent probe amplification (MLPA). We tested the association between these genetic and epigenetic alterations and glioblastoma patient survival. Subsequently, we developed a 2-gene survival predictor. Multivariate analyses revealed that mutations in isocitrate dehydrogenase 1 (IDH1), promoter methylation of MGMT, irradiation dosage, and Karnofsky Performance Status (KFS) were independent prognostic factors. A 2-gene predictor for glioblastoma survival was generated. Based on the genetic and epigenetic status of IDH1 and MGMT, glioblastoma patients were stratified into 3 clinically different genotypes: glioblastoma patients with IDH1mt/MGMTmet had the longest survival, followed by patients with IDH1mt/MGMTunmet or IDH1wt/MGMTmet, and patients with IDH1wt/MGMTunmet had the shortest survival. This 2-gene predictor was an independent prognostic factor and performed significantly better in predicting survival than either IDH1 mutations or MGMT methylation alone. The predictor was validated in 3 external datasets. The combination of IDH1 mutations and MGMT methylation outperforms either IDH1 mutations or MGMT methylation alone in predicting survival of glioblastoma patients. This information will help to increase our understanding of glioblastoma biology, and it may be helpful for baseline comparisons in future clinical trials.

Research paper thumbnail of Absence of AKT1 Mutations in Glioblastoma

PLoS ONE, 2009

Background: Oncogenic activation of the PI3K signalling pathway plays a pivotal role in the devel... more Background: Oncogenic activation of the PI3K signalling pathway plays a pivotal role in the development of glioblastoma multiforme (GBM). A central node in PI3K downstream signalling is controlled by the serine-threonine kinase AKT1. A somatic mutation affecting residue E17 of the AKT1 gene has recently been identified in breast and colon cancer. The E17K change results in constitutive AKT1 activation, induces leukaemia in mice, and accordingly, may be therapeutically exploited to target the PI3K pathway. Assessing whether AKT1 is activated by somatic mutations in GBM is relevant to establish its role in this aggressive disease.

Research paper thumbnail of Mutational profiling of kinases in glioblastoma

BMC Cancer, 2014

Background: Glioblastoma is a highly malignant brain tumor for which no cure is available. To ide... more Background: Glioblastoma is a highly malignant brain tumor for which no cure is available. To identify new therapeutic targets, we performed a mutation analysis of kinase genes in glioblastoma. Methods: Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before. Among those we selected 34 kinase genes for mutation analysis. We also included IDH1, IDH2, PTEN, TP53 and NRAS, genes that are known to be mutated at considerable frequencies in glioblastoma. In total, 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high-grade glioma (HGG) cell lines were sequenced. Results: Our mutation analysis led to the identification of 148 non-synonymous somatic mutations, of which 25 have not been reported before in glioblastoma. Somatic mutations were found in TP53, PTEN, IDH1, PIK3CA, EGFR, BRAF, EPHA3, NRAS, TGFBR2, FLT3 and RPS6KC1. Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K-AKT pathway.

Research paper thumbnail of Prognostic significance of highly sulfated chondroitin sulfates in ovarian cancer defined by the single chain antibody GD3A11

Gynecologic oncology, Jan 28, 2015

The extracellular matrix (ECM) of ovarian cancer may provide a number of potential biomarkers. Ch... more The extracellular matrix (ECM) of ovarian cancer may provide a number of potential biomarkers. Chondroitin sulfate (CS), a class of sulfated polysaccharides, is abundantly present in the ECM of ovarian cancer. Structural alterations of CS chains (i.e. sulfation pattern) have been demonstrated to play a role in cancer development and progression. In this study we investigate the potential of highly sulfated CS as a biomarker in ovarian cancer using the single chain antibody GD3A11 selected by the phage display technology. The specificity of the antibody was determined by an indirect ELISA. GD3A11 epitope expression was assessed by immunohistochemistry in healthy organs, benign and malignant ovarian tumors (N=359) and correlated to clinical parameters. The CHST15 gene, responsible for the biosynthesis of highly sulfated CS was evaluated for mutation and methylation status. The GD3A11 epitope was minimally expressed in normal organs. Intense expression was observed in the ECM of differ...

Research paper thumbnail of Chromosomal instability in meningiomas. J Neuropathol Exp Neurol

Journal of Neuropathology and Experimental Neurology

ABSTRACT

Research paper thumbnail of Lentiviral delivery of shRNA in glioblastoma multiforme spheroids

Research paper thumbnail of Value of immunohistochemical WT-1 detection in widespread serous carcinomas

International Journal of Gynecological Cancer

Research paper thumbnail of Chondroitin sulfates as a novel class of biomarkers to aid clinical decision making in ovarian cancer

International Journal of Gynecological Cancer

Research paper thumbnail of Mutational profiling of high-grade gliomas reveals inactivating mutations in IDH1

Neuro-Oncology

High-grade gliomas (HGGs) are malignant brain tumors for which no cure is available. To identify ... more High-grade gliomas (HGGs) are malignant brain tumors for which no cure is available. To identify new therapeutic targets we performed an extensive mutation analysis. We sequenced 39 genes in 113 HGG (including 109 glioblastoma) tumor samples and 16 HGG cell lines. We analyzed 200 exons belonging to 35 kinases, isocitrate dehydrogenase 1 (IDH1), NRAS, PTEN, and TP53 genes. At least one somatic mutation was found in 90 out of 129 HGG samples (70%). Most mutations were observed in genes belonging to the PI3K-AKT pathway; in more than 45% of HGGs we detected a mutational activation of the pathway, indicating that the PI3K-AKT axis represents a relevant therapeutic target for HGG. In addition, five different types of somatic mutations affecting the IDH1-R132 residue were detected in 20% (23 of 113) of HGG tumor samples. IDH1 mutations were predominantly observed in secondary glioblastoma (11 of 94 vs. 11 of 15, p-value=0.0000016). It has been established that IDH1 mutations occur early i...