Anke van den Berg - Academia.edu (original) (raw)

Papers by Anke van den Berg

Blood Cancer Journal, Mar 7, 2022

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Despite the proven eff... more Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Despite the proven efficacy of combined immunochemotherapy (R-CHOP) in the majority of patients,~40% of DLBCL patients do not respond or will relapse and consequently have a very poor prognosis. The development of targeted therapies has not improved patient survival, underscoring the need for new treatment approaches. Using an unbiased genome-wide CD20 guilt-by-association approach in more than 1800 DLBCL patients, we previously identified the estrogen receptor beta (ERβ) as a new target in DLBCL. Here, we demonstrate that ERβ is expressed at significantly higher levels in DLBCL compared to normal B cells, and ERβ plays a role in the protection against apoptosis in DLBCL. Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduces cell viability in all tested DLBCL cell lines. Tamoxifen-induced cell death was significantly decreased in an ERβ knockout cell line. The activity of tamoxifen was confirmed in a xenograft human lymphoma model, as tumor growth decreased, and survival significantly improved. Finally, tamoxifen-treated breast cancer (BC) patients showed a significantly reduced risk of 38% for DLBCL compared to BC patients who did not receive tamoxifen. Our findings provide a rationale to investigate tamoxifen, a hormonal drug with a good safety profile, in DLBCL patients.

Frontiers in Endocrinology

IntroductionTransformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) is on... more IntroductionTransformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) is one of the mechanisms responsible for acquired EGFR-TKIs resistance. Although it rarely happens this event determines a rapid disease deterioration and needs specific treatment.Patient and methodWe report a case of 75-year-old LUAD female with a p.L858R mutation in Epidermal Growth Factor Receptor (EGFR) who presented with SCLC transformation after responding to first line osimertinib treatment for only 6 months. To understand the underlying molecular mechanism, we retrospectively sequenced the first (LUAD) and the second (SCLC) biopsy using a 56 multi-gene panel. Immunohistochemistry (IHC) staining and Fluorescence In Situ Hybridization (FISH) was applied to confirm the genetic aberrations identified.ResultsEGFR p.E709A and p.L858R, Tumor Protein p53 (TP53) p.A159D and Retinoblastoma 1 (RB1) c.365-1G>A were detected in both the diagnostic LUAD and transformed SCLC samples. A high copy ...

Leukemia

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesti... more Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genomewide significant loci (P < 5 × 10 −8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10 −9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10 −8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

International Journal of Molecular Sciences

Cytochrome P450 enzymes (CYP450s) exert mighty catalytic actions in cellular metabolism and detox... more Cytochrome P450 enzymes (CYP450s) exert mighty catalytic actions in cellular metabolism and detoxication, which play pivotal roles in cell fate determination. Preliminary data shows differential expression levels of CYP27C1, one of the “orphan P450s” in human lung cancer cell lines. Here, we study the functions of CYP27C1 in lung cancer progression and drug endurance, and explore its potential to be a diagnostic and therapeutic target for lung cancer management. Quantitative real-time PCR and immunoblot assays were conducted to estimate the transcription and protein expression level of CYP27C1 in human lung cancer cell lines, which was relatively higher in A549 and H1975 cells, but was lower in H460 cells. Stable CYP27C1-knockdown A549 and H1975 cell lines were established, in which these cells showed enhancement in cell proliferation, colony formation, and migration. In addition, aberrant IGF-1R/Akt/p53 signal transduction was also detected in stable CYP27C1-knockdown human lung ca...

Cancers

The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory... more The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We noticed that 4EBP1 gains are genetically linked to gains in neighboring genes, including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition, and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and the inositol pathwa...

Molecules, 2021

Bacillus thuringiensis (Bt) is a bacterium capable of producing Cry toxins, which are recognized ... more Bacillus thuringiensis (Bt) is a bacterium capable of producing Cry toxins, which are recognized for their bio-controlling actions against insects. However, a few Bt strains encode proteins lacking insecticidal activity but showing cytotoxic activity against different cancer cell lines and low or no cytotoxicity toward normal human cells. A subset of Cry anticancer proteins, termed parasporins (PSs), has recently arisen as a potential alternative for cancer treatment. However, the molecular receptors that allow the binding of PSs to cells and their cytotoxic mechanisms of action have not been well established. Nonetheless, their selective cytotoxic activity against different types of cancer cell lines places PSs as a promising alternative treatment modality. In this review, we provide an overview of the classification, structures, mechanisms of action, and insights obtained from genetic modification approaches for PS proteins.

Cancers, 2021

Several human leukocyte antigen (HLA) alleles are strongly associated with susceptibility to clas... more Several human leukocyte antigen (HLA) alleles are strongly associated with susceptibility to classic Hodgkin lymphoma (cHL), also in subgroups stratified for presence of the Epstein–Barr virus (EBV). We tested the hypothesis that the pressure on cHL tumour cells to lose HLA expression is associated with HLA susceptibility alleles. A meta-analysis was carried out to identify consistent protective and risk HLA alleles in a combined cohort of 839 cHL patients from the Netherlands and the United Kingdom. Tumour cell HLA expression was studied in 338 cHL cases from these two cohorts and correlated to the presence of specific susceptibility HLA alleles. Carriers of the HLA-DRB1*07 protective allele frequently lost HLA class II expression in cHL overall. Patients carrying the HLA-DRB1*15/16 (DR2) risk allele retained HLA class II expression in EBV− cHL and patients with the HLA-B*37 risk allele retained HLA class I expression more frequently than non-carriers in EBV+ cHL. The other suscept...

The Lancet Haematology, 2020

Therapeutic Advances in Hematology, 2020

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, characterized by hi... more Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, characterized by high levels of genomic instability and the activation of DNA damage repair pathways. We previously found high expression of the cell cycle regulator WEE1 in DLBCL cell lines. Here, we investigated the combination of the WEE1 inhibitor, AZD1775, with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and radiation therapy (RT), with the aim of improving first-line treatment. Methods: Cell viability experiments were performed to determine synergistic combinations. Levels of DNA damage were established using flow cytometry for γH2AX and protein analysis for DNA damage response proteins CHK1 and CHK2. Flow cytometry analysis for cell cycle and pH3 were performed to determine cell cycle distribution and premature mitotic entry. Results: Treatment with either RT or CHOP led to enhanced sensitivity to AZD1775 in several DLBCL cell lines. Treatment of cells with AZD1775 induced unsch...

International Journal of Molecular Sciences, 2019

Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large... more Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large B-cell lymphoma (DLBCL) strongly correlates with resistance to standard therapy with cyclophosphamide, vincristine, doxorubicin, prednisolone, and rituximab (R-CHOP). Although studies focus mainly on the contribution of BCL-2, here we also investigate the contribution of other anti-apoptotic proteins to CHOP-therapy resistance in DLBCL. Functional dynamic BCL-2 homology (BH)3 profiling was applied to DLBCL cell lines upon CHOP treatment or single CHOP compounds. Cell-specific anti-apoptotic dependencies were validated with corresponding BH3-mimetics. We found high expression of anti-apoptotic BCL-2, MCL-1, and BCL-XL in DLBCL cell lines and patients. CHOP treatment resulted in both enhanced and altered anti-apoptotic dependency. Enhanced sensitivity to different BH3-mimetics after CHOP treatment was confirmed in specific cell lines, indicating heterogeneity of CHOP-induced resistance in...

Cancer Treatment Reviews, 2019

Hodgkin lymphoma is a B cell derived malignancy characterized by a low number of tumor cells with... more Hodgkin lymphoma is a B cell derived malignancy characterized by a low number of tumor cells within an environment consisting of inflammatory cells. Recently, immune checkpoint blockade targeting the PD-1-PD-L1 axis has shown to be a great success in relapsed and refractory Hodgkin lymphoma patients. However, complete responses are scarce and median progression-free survival is limited to around 11-15 months. Efficiency of PD-1 blockade in HL might be dependent on CD4+ T cells, but also tumor associated macrophages (TAMs) and NK cells are implicated. The aim of this review is to highlight currently known prominent immune evasion strategies and discuss their possible contribution to primary or acquired resistance to immune checkpoint blockade in Hodgkin lymphoma. These include T cell dependent mechanisms such as shaping of the inflammatory infiltrate, lack of presentation of antigens and neoantigens and production of molecules involved in suppression of T cell functionality such as other immune checkpoints, indoleamine 2,3-dioxygenase and adenosine. Moreover, the role of NK cells and TAMs in efficient PD-1 blockade will be discussed. Targeting these mechanisms in parallel to PD-1 may potentially increase efficiency of PD-1 blockade therapy.

Annals of Oncology, 2019

Background The detection of driver aberrations such as EGFR and ALK, in tumour tissue or plasma h... more Background The detection of driver aberrations such as EGFR and ALK, in tumour tissue or plasma has become important for treating lung cancer patients. The aim of this study is to explore the feasibility of detecting therapy-guiding aberrations in RNA, isolated from platelet and plasma samples. Methods We applied a hybridization capture-based NGS approach on 10 platelet-derived RNA samples with 13 known variants. For validation, we applied RNA-based ddPCR focussing on T790M, L858R and E19del in EGFR, codon 12 and 13 of KRAS and the ALK-EML4/KIF5B fusions on both cell free plasma RNA and platelet RNA. Results For none of the platelet-derived RNA samples we detected the known variant with targeted RNA sequencing despite having sufficient unique reads (1.23x10^5 to 1.4x10^6). We next applied ddPCR to determine presence of mutated transcripts at a higher sensitivity (sensitivity of the assays reached down to 0.07%). No ALK fusion droplets were detected in platelet and plasma samples der...

Blood, 2011

Abstract 2626 In Hodgkin lymphoma (HL) a minority…

European Radiology, 2019

Objectives MYC gene rearrangements in diffuse large B cell lymphomas (DLBCLs) result in high prol... more Objectives MYC gene rearrangements in diffuse large B cell lymphomas (DLBCLs) result in high proliferation rates and are associated with a poor prognosis. Strong proliferation is associated with high metabolic demand and tumour necrosis. The aim of this study was to investigate differences in the presence of necrosis and semiquantitative 18 F-FDG PET metrics between DLBCL cases with or without a MYC rearrangement. The prognostic impact of necrosis and semiquantitative 18 F-FDG PET parameters was investigated in an explorative survival analysis. Methods Fluorescence in situ hybridisation analysis for MYC rearrangements, visual assesment, semiquantitative analysis of 18 F-FDG PET scans and patient survival analysis were performed in 61 DLBCL patients, treated at a single referral hospital between 2008 and 2015. Results Of 61 tumours, 21 (34%) had a MYC rearrangement (MYC +). MYC status was neither associated with the presence of necrosis on 18 F-FDG PET scans (necrosis PET ; p = 1.0) nor associated with the investigated semiquantitative parameters maximum standard uptake value (SUV max ; p = 0.43), single highest SUV max (p = 0.49), metabolic active tumour volume (MATV; p = 0.68) or total lesion glycolysis (TLG; p = 0.62). A multivariate patient survival analysis of the entire cohort showed necrosis PET as an independent prognostic marker for disease-specific survival (DSS) (HR = 13.9; 95% CI 3.0-65; p = 0.001). Conclusions MYC rearrangements in DLBCL have no influence on the visual parameter necrosis PET or the semi-quantiative parameters SUV max , MATV and TLG. Irrespective of MYC rearrangements, necrosis PET is an independent, adverse prognostic factor for DSS. Key Points • Retrospective analysis indicates that MYC rearrangement is not associated with necrosis on 18 F-FDG PET (necrosis PET) scans or semiquantitative 18 F-FDG PET parameters. • Necrosis PET is a potential independent adverse prognostic factor for disease-specific survival in patients with DLBCL and is not influenced by the presence of MYC rearrangements.

Critical reviews in oncology/hematology, 2017

Long noncoding (lnc)RNAs have emerged as essential mediators of cellular biology, differentiation... more Long noncoding (lnc)RNAs have emerged as essential mediators of cellular biology, differentiation and malignant transformation. LncRNAs have a broad range of possible functions at the transcriptional, posttranscriptional and protein level and their aberrant expression significantly contributes to the hallmarks of cancer cell biology. In addition, their high tissue- and cell-type specificity makes lncRNAs especially interesting as biomarkers, prognostic factors or specific therapeutic targets. Here, we review current knowledge on lncRNA expression changes during normal B-cell development, indicating essential functions in the differentiation process. In addition we address lncRNA deregulation in B-cell malignancies, the putative prognostic value of this as well as the molecular functions of multiple deregulated lncRNAs. Altogether, the discussed work indicates major roles for lncRNAs in normal and malignant B cells affecting oncogenic pathways as well as the response to common therap...

Current Aging Science, 2015

Age is the most important risk factor for the development of infectious diseases, cancer and chro... more Age is the most important risk factor for the development of infectious diseases, cancer and chronic inflammatory diseases including rheumatoid arthritis (RA). The very act of living causes damage to cells. A network of molecular, cellular and physiological maintenance and repair systems creates a buffering capacity against these damages. Aging leads to progressive shrinkage of the buffering capacity and increases vulnerability. In order to better understand the complex mammalian aging processes, nine hallmarks of aging and their interrelatedness were recently put forward. RA is a chronic autoimmune disease affecting the joints. Although RA may develop at a young age, the incidence of RA increases with age. It has been suggested that RA may develop as a consequence of premature aging (immunosenescence) of the immune system. Alternatively, premature aging may be the consequence of the inflammatory state in RA. In an effort to answer this chicken and egg conundrum, we here outline and discuss the nine hallmarks of aging, their contribution to the pre-aged phenotype and the effects of treatment on the reversibility of immunosenescence in RA.

Research Square (Research Square), Nov 15, 2022

Background: Lung adenocarcinoma (LUAD) is the most predominant histological subtype of lung cance... more Background: Lung adenocarcinoma (LUAD) is the most predominant histological subtype of lung cancer characterized by driver mutations detected in a substantial proportion of the cases. Tyrosine kinase inhibitors (TKIs) are standard care for the patients with these mutations. In this study, we evaluated the e ciency of an NGS-based 8-gene test in selecting TKIs-sensitive Chinese LUAD patients who are treatment-naïve. Material and methods: Targeted sequencing covering the hotspot regions of eight LUAD driver genes was performed across 853 treatment-naïve LUAD patients. Logistic regression analysis was used to determine the factors associated with presence of these mutations. Genetically modi ed LUAD PC9 cells were established to evaluated the sensitivity of selected EGFRcompound mutations to different EGFR-TKIs invivo. Results: A total of 574 single nucleotide variants, 270 InDels, 88 ampli cations, and 87 rearrangements were identi ed in this study, with EGFR and KRAS being the most frequently mutated genes. Females, mostly lifelong non-smokers, had signi cantly higher EGFRmutation rates than males and had a T>A conversion signature, for which the etiological factor is still unknown. Males, primarily smokers, more frequently had KRAS mutations and a smoking-associated signature of C>A conversions. Rare EGFR compound mutations identi ed in this study (Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873) conferred genetically modi ed PC9 cells, constantly and consistently, more sensitive to second-generation EGFR-TKI afatinib in-vivo. Conclusion: Over 70% of Chinese treatment-naïve LUAD patients are TKIs-targetable. Patients with rare EGFR compound mutations might conside second-generation EGFR-TKIs for treatment.

Virchows Archiv, Mar 19, 2019

Next-generation sequencing (NGS) panel analysis on DNA from formalin-fixed paraffin-embedded (FFP... more Next-generation sequencing (NGS) panel analysis on DNA from formalin-fixed paraffin-embedded (FFPE) tissue is increasingly used to also identify actionable copy number gains (gene amplifications) in addition to sequence variants. While guidelines for the reporting of sequence variants are available, guidance with respect to reporting copy number gains from gene-panel NGS data is limited. Here, we report on Dutch consensus recommendations obtained in the context of the national Predictive Analysis for THerapy (PATH) project, which aims to optimize and harmonize routine diagnostics in molecular pathology. We briefly discuss two common approaches to detect gene copy number gains from NGS data, i.e., the relative coverage and B-allele frequencies. In addition, we provide recommendations for reporting gene copy gains for clinical purposes. In addition to general QC metrics associated with NGS in routine diagnostics, it is recommended to include clinically relevant quantitative parameters of copy number gains in the clinical report, such as (i) relative coverage and estimated copy numbers in neoplastic cells, (ii) statistical scores to show significance (e.g., z-scores), and (iii) the sensitivity of the assay and restrictions of NGS-based detection of copy This article is part of the Topical Collection on Quality in Pathology Electronic supplementary material The online version of this article (

Journal of Thoracic Oncology, 2018

Figure 1. Medical imaging of the patient with adenocarcinoma in the left upper lobe of the lung a... more Figure 1. Medical imaging of the patient with adenocarcinoma in the left upper lobe of the lung and cervical metastasis. (A) Computed tomography (CT) scan showing multiple bone metastases before the start of BRAF/MEK inhibition. (B) Fludeoxyglucose F 18-positron emission tomography (FDG/PET) scan 6 months after start of treatment with evidence of therapy response. (C) Progressive disease (PD) was observed with FDG/PET-avid bone and cervical lymph nodes metastases 3 months after the intial partial response (PR). (D) Time line. In retrospect, a KRAS mutation was detected at a very low allelic frequency in a BRAF p. V600E-positive lymph node metastasis at first diagnosis. At therapy failure after an initial PR, the allelic frequencies of the BRAF and KRAS mutations were comparable. DOD, dead of disease.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 9, 2017

ALK rearrangement detection using fluorescence in situ hybridization (FISH) is the standard test ... more ALK rearrangement detection using fluorescence in situ hybridization (FISH) is the standard test to identify non-small cell lung carcinoma (NSCLC) patients eligible for treatment with ALK inhibitors. Recently ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of advanced NSCLC patients with ALK activation using both dichotomous immunohistochemical staining (IHC) and FISH. Design Stage IV NSCLC patients treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-Break-Apart FISH-Probe KIT) and IHC ( Ventana ALK-D5F3-CDx assay). Cohorts of ALK-FISH-positive advanced NSCLC patients from 4 other hospitals were used for validation. Results Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC-positive pat...