ORCID Profile
0000-0003-1249-4442
Current Organisation
Erasmus MC
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Publisher: American Association for Cancer Research (AACR)
Date: 31-10-2013
DOI: 10.1158/1078-0432.CCR-13-1337
Abstract: Purpose: Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1- lified tumors show licon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy in CCNE1- lified cancers and mechanisms of resistance. Experimental Design: We examined the effect of CDK2 suppression using RNA interference and small-molecule inhibitors in SK-OV-3, OVCAR-4, and OVCAR-3 ovarian cancer cell lines. To identify mechanisms of resistance, we derived multiple, independent resistant sublines of OVCAR-3 to CDK2 inhibitors. Resistant cells were extensively characterized by gene expression and copy number analysis, fluorescence-activated cell sorting profiling and conventional karyotyping. In addition, we explored the relationship between CCNE1 lification and polyploidy using data from primary tumors. Results: We validate CDK2 as a therapeutic target in CCNE1- lified cells by showing selective sensitivity to suppression, either by gene knockdown or using small-molecule inhibitors. In addition, we identified two resistance mechanisms, one involving upregulation of CDK2 and another novel mechanism involving selection of polyploid cells from the pretreatment tumor population. Our analysis of genomic data shows that polyploidy is a feature of cancer genomes with CCNE1 lification. Conclusions: These findings suggest that cyclinE1/CDK2 is an important therapeutic target in HGSC, but that resistance to CDK2 inhibitors may emerge due to upregulation of CDK2 target protein and through preexisting cellular polyploidy. Clin Cancer Res 19(21) 5960–71. ©2013 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2012
DOI: 10.1158/0008-5472.CAN-12-0203
Abstract: High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from in idual patients were analyzed along with 22 paired pretreatment and posttreatment s les. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients. Cancer Res 72(16) 4060–73. ©2012 AACR.
Publisher: SAGE Publications
Date: 03-10-2014
Abstract: Observations that migraine increases risk of cardiovascular disease and ischemic brain changes may suggest sustained vascular differences between migraineurs and controls. In a population-based setting, we compared cerebral blood flow between migraineurs in the attack-free period and controls. Between 2006 and 2008, 2642 participants, aged 45–65, from the Rotterdam Study completed a migraine questionnaire and had complete usable MRI data. Participants were classified into controls (N = 2033), probable migraine (N = 153), or migraine (N = 456). Using 2D phase contrast MRI, we performed a cross-sectional analysis of the effect of migraine on total cerebral blood flow (tCBF), parenchymal cerebral blood flow (pCBF), and blood flow in each intracranial arterial using linear regression. Additionally, we performed stratified analysis of subtypes of migraine. Compared with controls, migraineurs had higher pCBF (1.07 ml/min/100 ml, 95% CI 0.08 2.05). In particular, migraineurs had significantly higher blood flow in the basilar artery (4.70 ml/min, 95% CI 0.77 8.62). Migraineurs in the attack-free period have higher pCBF, particularly basilar artery flow, compared to controls, supporting the notion of sustained vascular differences between these groups outside of migraine attacks.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2023
DOI: 10.1161/STROKEAHA.122.040715
Abstract: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ] P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98] P =0.0041). The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
Publisher: Wiley
Date: 30-10-2020
DOI: 10.1002/ACN3.51228
Publisher: Oxford University Press (OUP)
Date: 20-06-2022
Abstract: Migraine is a highly common and debilitating disorder that often affects in iduals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = −0.11, P = 1 × 10−3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippoc al and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in in iduals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.
Publisher: Wiley
Date: 04-05-2018
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.NEUROBIOLAGING.2013.09.012
Abstract: In cerebral amyloid angiopathy patients, microbleeds often cluster, mostly occipital, and are associated with apolipoprotein E (APOE) genotype. Microbleeds also frequently occur in the asymptomatic, general population. In this population, we investigated spatial distribution of microbleeds and whether this is influenced by APOE genotype. In 292 persons with microbleeds, we labeled microbleeds on baseline and follow-up magnetic resonance images. We calculated distance between incident and prevalent microbleeds within and between persons and performed lobar segmentation on the magnetic resonance images. Subsequently, we investigated proximity and lobar distribution in strata of APOE genotype. Microbleeds occurred closer within persons than between persons (-42.2 mm, 95% confidence interval, -44.6 to -39.9 p < 0.001). Microbleeds within APOE ε2 and ε4 carriers occurred closer than those in persons with ε3ε3 genotype (-11.9 mm, 95% confidence interval, -24.4 to 0.6 p = 0.06). Persons with ε2 and ε4 alleles had a larger proportion of microbleeds in the occipital lobe than persons with ε3ε3 genotype. Similar to cerebral amyloid angiopathy patients, microbleeds in the general population cluster and the distribution is affected by APOE genotype.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2016
DOI: 10.1038/NG.3598
Publisher: SAGE Publications
Date: 08-07-2015
Abstract: The question remains whether reduced cerebral blood flow (CBF) leads to brain atrophy or vice versa. We studied the longitudinal relation between CBF and brain volume in a community-dwelling population. In the Rotterdam Study, 3011 participants (mean age 59.6 years (s.d. 8.0)) underwent repeat brain magnetic resonance imaging to quantify brain volume and CBF at two time points. Adjusted linear regression models were used to investigate the bidirectional relation between CBF and brain volume. We found that smaller brain volume at baseline was associated with a steeper decrease in CBF in the whole population (standardized change per s.d. increase of total brain volume (TBV) = 0.296 (95% confidence interval (CI) 0.200 0.393)). Only in persons aged ≥ 65 years, a lower CBF at baseline was associated with steeper decline of TBV (standardized change per s.d. increase of CBF = 0.003 (95% CI −0.004 0.010) in the whole population and 0.020 (95% CI 0.004 0.036) in those aged ≥65 years of age). Our results indicate that brain atrophy causes CBF to decrease over time, rather than vice versa. Only in persons aged years of age did we find lower CBF to also relate to brain atrophy.
Publisher: Wiley
Date: 23-03-2020
DOI: 10.1002/CAM4.3015
Publisher: Springer Science and Business Media LLC
Date: 06-07-2020
DOI: 10.1038/S41467-020-17002-0
Abstract: Blood pressure (BP) was inconsistently associated with migraine and the mechanisms of BP-lowering medications in migraine prophylaxis are unknown. Leveraging large-scale summary statistics for migraine ( N cases / N controls = 59,674/316,078) and BP ( N = 757,601), we find positive genetic correlations of migraine with diastolic BP (DBP, r g = 0.11, P = 3.56 × 10 −06 ) and systolic BP (SBP, r g = 0.06, P = 0.01), but not pulse pressure (PP, r g = −0.01, P = 0.75). Cross-trait meta-analysis reveals 14 shared loci ( P ≤ 5 × 10 −08 ), nine of which replicate ( P 0.05) in the UK Biobank. Five shared loci ( ITGB5 , SMG6 , ADRA2B , ANKDD1B , and KIAA0040 ) are reinforced in gene-level analysis and highlight potential mechanisms involving vascular development, endothelial function and calcium homeostasis. Mendelian randomization reveals stronger instrumental estimates of DBP (OR [95% CI] = 1.20 [1.15–1.25]/10 mmHg P = 5.57 × 10 −25 ) on migraine than SBP (1.05 [1.03–1.07]/10 mmHg P = 2.60 × 10 −07 ) and a corresponding opposite effect for PP (0.92 [0.88–0.95]/10 mmHg P = 3.65 × 10 −07 ). These findings support a critical role of DBP in migraine susceptibility and shared biology underlying BP and migraine.
Publisher: Wiley
Date: 27-01-2023
DOI: 10.1111/HEAD.14470
Abstract: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease. Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition. Linkage disequilibrium score regression and two‐s le bidirectional Mendelian randomization analyses were performed using summary statistics from cohort‐based genome‐wide association studies of migraine (59,674 cases 316,078 controls), IBD (25,042 cases 34,915 controls) and celiac disease (11,812 or 4533 cases 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed. Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99–1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99–1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96–1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79–1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00–1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92–0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02–1.29, p = 0.025). However, the results were not significant after multiple testing correction. We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes.
Publisher: Springer Science and Business Media LLC
Date: 11-07-2018
Publisher: Springer Science and Business Media LLC
Date: 23-02-2016
DOI: 10.1038/MP.2016.9
Publisher: Springer Science and Business Media LLC
Date: 28-09-2016
DOI: 10.1038/NG1016-1296C
Publisher: Springer Science and Business Media LLC
Date: 21-01-2022
DOI: 10.1038/S41430-022-01078-6
Abstract: This study was conducted to explore the causal associations of high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglyceride (TG) with the risk of upper gastrointestinal cancers (esophageal cancer [EC] and gastric cancer [GC]). A total of 5623 Chinese and 4133 Europeans afforded the in idual-level genotyping data, and 203,608 Japanese from Biobank Japan project and 393,926 Europeans from UK Biobank supported summary statistics of cancer genetic associations. Mendelian randomization (MR) analyses, including weighted genetic risk scores (wGRSs), inverse-variance weighted (IVW), weighted median and Egger-regression, were utilized to evaluate the causal effects of three blood lipids on upper gastrointestinal cancers risk. There was no significantly causal relationships between three blood lipids and EC or GC risk among Chinese or Europeans but a potential causal association between TG and GC risk among Japanese (IVW: odds ratio [OR] = 1.11, P = 0.034 P This trans-ancestry MR study suggested null significant causality between serum HDL, LDL or TG and the risk of upper gastrointestinal cancers among Chinese and Europeans, but provided evidence for a causal role of TG involved in GC etiology in Japanese (especially females), which would support a prevention guide for high-risk groups of GC. Further research with more comprehensive information is needed to explore the underlying mechanism.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2012
DOI: 10.1007/S10875-011-9644-1
Abstract: This retrospective study aimed to characterize the clinical hematological and immunological features of patients with thymic epithelial neoplasms. From a cohort of 512 patients with thymic epithelial neoplasms, 79 patients diagnosed with autoimmune/immunodeficiency conditions or signs and/or symptoms suggesting an autoimmune or immunodeficiency state were evaluated by standard immunological and hematological testing. Elevated percentages of CD2+, CD3+, and CD8+ lymphocytes were observed in 44 (57.1%), 33 (41.8%), and 32 (40.5%) patients. Low CD4+ and CD19+ percentages were observed in 25 (31.6%) and 36 (46.2%), respectively CD4+:CD8+ ratios were inverted in 18 (22.8%). IgG, IgA, and IgM levels were low in 12 (15.8%), 9 (11.7%) and 15 (19.7%) patients, respectively. Patients with immunodeficiency condition(s) were more likely to have high CD8+ percentages (p = 0.040), low CD19+ percentages (p = 0.025), and/or inverted CD4+/CD8+ ratios (p = 0.034). Patients with autoimmune condition(s) were more likely to have a high/normal CD4+ percentage (p = 0.038). High CD2+ percentages were associated with lower mean IgG and IgA levels (p = 0.030 and p = 0.017, respectively). High CD3+ and CD8+ percentages were associated with lower mean IgA levels (p = 0.046 and p = 0.013, respectively). Low CD19+ percentages were associated with lower mean IgG and IgA levels (p = 0.004 and p < 0.001, respectively). Signs/symptoms and history of autoimmune and immunodeficiency conditions among patients with thymic epithelial neoplasms are associated with high frequencies of abnormalities in immunoglobulin levels and lymphocyte immunophenotypes, suggesting a role for their assessment.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2019
DOI: 10.1158/1055-9965.EPI-18-1190
Abstract: Higher levels of circulating 25-hydroxyvitamin D [25(OH)D] are associated with longer survival in several cancers, but the results have differed across cancer sites. The association between serum 25(OH)D levels and overall survival (OS) time in esophageal adenocarcinoma remains unclear. We utilized serum s les from 476 patients with primary esophageal adenocarcinoma, recruited from Massachusetts General Hospital (Boston, MA) between 1999 and 2015. We used log-rank tests to test the difference in survival curves across quartiles of 25(OH)D levels and extended Cox modeling to estimate adjusted HRs. We tested for interactions between clinical stage or BMI on the association between 25(OH)D and OS. We additionally performed sensitivity analyses to determine whether race or timing of blood draw (relative to treatment) affected these results. We found no evidence that survival differed across quartiles of 25(OH)D (log rank P = 0.48). Adjusting for confounders, we found no evidence that the hazard of death among the highest quartile of 25(OH)D (quartile 1) differed from any other quartile [quartile 2 HR = 0.90, 95% confidence interval (CI), 0.67–1.23 quartile 3 HR = 1.03, 95% CI, 0.76–1.38 quartile 4 (lowest) HR = 0.98, 95% CI, 0.72–1.33]. Sensitivity analyses yielded consistent results when accounting for race or time between diagnosis and blood draw. Moreover, we did not find evidence of interaction between 25(OH)D and clinical stage or BMI on OS. Serum level of 25(OH)D near time of diagnosis was not associated with OS in patients with esophageal adenocarcinoma. Screening 25(OH)D levels among patients with esophageal adenocarcinoma at diagnosis is not clinically relevant to their cancer prognosis based on present evidence.
Publisher: Wiley
Date: 26-09-2019
DOI: 10.1111/HEAD.13651
Publisher: American Association for the Advancement of Science (AAAS)
Date: 22-06-2018
Abstract: Consistent classification of neuropsychiatric diseases is problematic because it can lead to misunderstanding of etiology. The Brainstorm Consortium examined multiple genome-wide association studies drawn from more than 200,000 patients for 25 brain-associated disorders and 17 phenotypes. Broadly, it appears that psychiatric and neurologic disorders share relatively little common genetic risk. However, different and independent pathways can result in similar clinical manifestations (e.g., psychosis, which occurs in both schizophrenia and Alzheimer's disease). Schizophrenia correlated with many psychiatric disorders, whereas the immunopathological affliction Crohn's disease did not, and posttraumatic stress syndrome was also largely independent of underlying traits. Essentially, the earlier the onset of a disorder, the more inheritable it appeared to be. Science , this issue p. eaap8757
Publisher: American Association for Cancer Research (AACR)
Date: 2022
DOI: 10.1158/1055-9965.EPI-21-0503
Abstract: Body mass index (BMI) change after a lung cancer diagnosis has been associated with non–small cell lung cancer (NSCLC) survival. This study aimed to quantify the association based on a large-scale observational study. Included in the study were 7,547 patients with NSCLC with prospectively collected BMI data from Massachusetts General Hospital and Brigham and Women's Hospital/Dana-Farber Cancer Institute. Cox proportional hazards regression with time-dependent covariates was used to estimate effect of time-varying postdiagnosis BMI change rate (% per month) on overall survival (OS), stratified by clinical subgroups. Spline analysis was conducted to quantify the nonlinear association. A Mendelian Randomization (MR) analysis with a total of 3,495 patients further validated the association. There was a J-shape association between postdiagnosis BMI change and OS among patients with NSCLC. Specifically, a moderate BMI decrease [0.5–2.0 HR = 2.45 95% confidence interval (CI), 2.25–2.67] and large BMI decrease (≥2.0 HR = 4.65 95% CI, 4.15–5.20) were strongly associated with worse OS, whereas moderate weight gain (0.5–2.0) reduced the risk for mortality (HR = 0.78 95% CI, 0.68–0.89) and large weight gain (≥2.0) slightly increased the risk of mortality without reaching statistical significance (HR = 1.10 95% CI, 0.86–1.42). MR analyses supported the potential causal roles of postdiagnosis BMI change in survival. This study indicates that BMI change after diagnosis was associated with mortality risk. Our findings, which reinforce the importance of postdiagnosis BMI surveillance, suggest that weight loss or large weight gain may be unwarranted.
Publisher: Walter de Gruyter GmbH
Date: 2014
DOI: 10.2478/S13380-014-0217-7
Abstract: Cerebral microbleeds are considered an imaging marker of cerebral small vessel disease. The location of microbleeds is thought to reflect the underlying pathology. Microbleeds in the deep and infratentorial region are thought to reflect hypertensive arteriopathy whereas lobar microbleeds are associated clinically with cerebral amyloid angiopathy (CAA). Aside from patient populations, microbleeds are frequently observed in seemingly asymptomatic populations. Moreover, many elderly, both in clinical and preclinical populations, have multiple coexisting pathologies in their brains, which complicates the interpretation of cerebral microbleeds, especially early in the clinical course. In this commentary, we discuss the influence of the strongest genetic risk factor for CAA, Apolipoprotein E (APOE), in the spatial distribution of microbleeds, and we additionally address issues in interpretation and implication of the location of microbleeds in clinical and asymptomatic populations.
Publisher: Springer Science and Business Media LLC
Date: 08-12-2020
DOI: 10.1038/S41467-020-19111-2
Abstract: White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older in iduals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk in iduals and for genetically-informed prioritization of drug targets for prevention trials.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2015
DOI: 10.1038/MP.2015.69
Location: United States of America
No related grants have been discovered for Elizabeth Loehrer.