Renee Xavier Menezes

Renee Xavier Menezes
Netherlands Cancer Institute · Biostatistics Unit

D.Phil. in Statistics, University of Oxford

About

173
Publications
13,807
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
5,067
Citations
Introduction
I am a biostatistician with a passion for developing methods that solve data-motivated problems. I strive to build realistic (parametric) models that avoid over-complexity. I mostly work with high-dimensional data, and my main research interest currently lies in methods for simultaneous analysis of many high-dimensional data sets.
Additional affiliations
February 2020 - present
Netherlands Cancer Institute
Position
  • Head of Department
August 2009 - January 2020
Amsterdam University Medical Center
Position
  • Professor (Assistant)
April 2002 - July 2009
Leiden University Medical Centre
Position
  • PostDoc Position

Publications

Publications (173)
Article
Full-text available
The progression of anchorage-dependent epithelial cells to anchorage-independent growth represents a critical hallmark of malignant transformation. Using an in vitro model of human papillomavirus (HPV)-induced transformation, we previously showed that acquisition of anchorage-independent growth is associated with marked (epi)genetic changes, includ...
Preprint
CRISPR screens provide large-scale assessment of cellular gene functions. Pooled libraries typically consist of several single guide RNAs (sgRNAs) per gene, for a large number of genes, which are transduced in such a way that every cell receives at most one sgRNA, resulting in the disruption of a single gene in that cell. This approach is often use...
Article
Full-text available
Background Coeliac disease (CD) has an estimated prevalence of ∼1% in Europe with a significant gap between undiagnosed and diagnosed CD. Active case finding may help to bridge this gap yet the diagnostic yield of such active case finding in general practice by serological testing is unknown. Objective The aim of this study was to determine (1) th...
Article
Full-text available
Comprehensive analysis of tumor infiltrating myeloid cells in the tumor microenvironment of penile squamous cell carcinoma (PSCC) is lacking. In this retrospective study, for the first time, PSCC resection specimens (N = 103) were annotated into the following compartments: intratumoral tumor (IT Tumor), intratumoral stroma (IT Stroma), peritumoral...
Article
Human papillomavirus (HPV) drives high-grade intraepithelial neoplasia and cancer; for unknown reasons, this occurs most often in the cervical transformation zone. Either mutation or HPV E6-driven inhibition of Notch1 can drive neoplastic development in stratified squamous epithelia. However, the contribution of Notch1 and its Delta-like ligands (D...
Article
Full-text available
Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown. Here we show that deleting FLCN activates TFE3, u...
Article
Full-text available
Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in combination with low doses of arsenic trioxide or chemotherapy leads to exceptionally high cure rates (>90%). ATRA forces APL cells into differentiation and cell death. Unfortunately, ATRA-based therapy has not been effective among any other acute myeloid leukemi...
Article
Full-text available
Oncolytic adenoviruses are being developed as new anti-cancer agents. Their efficacy can be improved by incorporating RNA interference (RNAi) molecules. RNAi molecules can be expressed in various precursor formats. The aim of this study was to determine the most effective format. To this end, we constructed three D24-type oncolytic adenoviruses, wi...
Preprint
Full-text available
In a recent paper in Nature Communications, Narayan et al ¹ described the development of an in silico method to predict synergy of drug combinations, validated in vivo using 5 different models for 5 different drug pairs. The published analysis of the in vivo experimental data used the Chou and Talalay Combination Index, which ignores important aspe...
Conference Paper
p>Standard induction chemotherapy, consisting of an anthracycline and cytarabine, has been the first-line therapeutic to treat acute myeloid leukemia (AML). Although this treatment induces complete remissions (CR) in the majority of patients, many face a relapse. Relapse is caused by the survival of chemotherapy-resistant leukemia cells (minimal re...
Article
Full-text available
Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a d...
Article
Full-text available
Fecal volatile organic compounds (VOC) reflect human and gut microbiota metabolic pathways and their interaction. VOC behold potential as non-invasive preclinical diagnostic biomarkers in various diseases, e.g., necrotizing enterocolitis and late onset sepsis. There is a need for standardization and assessment of the influence of clinical and envir...
Article
Full-text available
HPV-negative head and neck squamous cell carcinomas (HNSCCs) develop in precancerous changes in the mucosal lining of the upper-aerodigestive tract. These precancerous cells contain cancer-associated genomic changes and cause primary tumors and local relapses. Therapeutic strategies to eradicate these precancerous cells are very limited. Using func...
Article
Full-text available
Resistance to chemotherapy is widely recognized as one of the major factors limiting therapeutic efficacy and influences clinical outcomes in patients with cancer. Many studies on various tumor types have focused on combining standard-of-care chemotherapy with immunotherapy. However, for cervical cancer, the role of neoadjuvant chemotherapy (NACT)...
Article
Full-text available
This paper introduces the paired lasso: a generalisation of the lasso for paired covariate settings. Our aim is to predict a single response from two high-dimensional covariate sets. We assume a one-to-one correspondence between the covariate sets, with each covariate in one set forming a pair with a covariate in the other set. Paired covariates ar...
Article
Full-text available
Loss of function of BRCA1 associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy. A genetically engineered model was established expressing either functional or non-functional BAP1 and whole-genome siRNA...
Article
Introduction Fecal volatile organic compounds (VOCs) are gaseous metabolic products which are increasingly considered potential non-invasive biomarkers for the detection of various (gastrointestinal) diseases. The influence of lifestyle factors on fecal VOC patterns remains unexplored but is of importance prior to implementation of VOC analysis as...
Article
Full-text available
Novel therapeutic strategies for non-small-cell lung cancer (NSCLC) are urgently needed. RNA splicing, orchestrated by the spliceosome, is deregulated in many forms of cancer, including NSCLC. Here, we performed high-throughput screening with a small interfering RNA library targeting all annotated human spliceosome proteins to identify cancer-selec...
Data
Figure S1 Identification and quantification of tumor‐associated T lymphocytes in tonsil. A) Hematoxylin–eosin staining staning of tonsillar tumor specimen. Tumor area was delimited by the segmented line. B) Tails segmentation of tumor‐containing area. 50% of random tails were used for the analysis. C) Pre‐selected tails were segmented into ‘tumor’...
Data
Figure S2 Effect of HLA‐DP/DQ/DR expression and numbers of CD68 + CD163+ TAMs on survival. Cumulative incidence analysis was performed with HLA‐DP/DQ/DR expression and numbers of TAMs. Importantly, only patients with high HLA‐DP/DQ/DR expression and low number of TAMs showed significantly improved DFS and DSS.
Data
Figure S3 Impact of HPV status and treatment on disease free survival and disease progression. 2A) Effect of HPV status on the cumulative incidence or loco‐regional recurrence, metastasis (DFS) or disease‐specific death (DSS). 2B) Effect of different treatment regimens in the cumulative incidence or loco‐regional recurrence, metastasis (DFS) or dis...
Data
Table S1 List of all the antibodies used in this study.
Data
Table S2 Quantification of the number of myeloid cells and lymphocytes in tumor, tumor margins and stroma in view of HPV status. Quantification of the multiplex immunofluorescence staining scored in the tumor and in the surrounding stroma. Median represents the median of number of cells/mm2.
Article
Full-text available
Leukemic stem cells (LSCs) are thought to be the major cause of the recurrence of acute myeloid leukemia (AML) due to their potential for self-renewal. To identify therapeutic strategies targeting LSCs, while sparing healthy hematopoietic stem cells (HSCs), we performed gene expression profiling of LSCs, HSCs, and leukemic progenitors all residing...
Article
Full-text available
Background Human papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (OPSCC) is a highly immunogenic tumor and differences in tumor microenvironment might contribute to the improved survival of HPV‐positive OPSCC patient. Methods A comprehensive multivariate analysis with clinical and immune variables (human leukocyte antigen [HLA]...
Article
Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired transcriptional differentiation programs. Despite important advances in AML therapy, the five-year overall survival rate of AML patients remains a disappointing 30-40%. This poor prognosis is mainly caused by survival of chemotherapy resistant leukem...
Article
Objective In this study we aimed to pilot test the hypothesis that in women who are severely bothered by their menopausal complaints, improvement of menopausal symptoms is associated with an improvement in self-perceived work ability. Study design This retrospective cohort study assessed the work ability of first-time attendees (n = 31) of a menop...
Article
Full-text available
Background Dysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of...
Article
Full-text available
An important factor in quality control of non-invasive prenatal screening (NIPS) or testing (NIPT) is a sufficient percentage of fetal DNA to avoid false-negative results. Here we evaluate 14,379 shallow whole-genome sequenced diagnostic NIPS samples, as well as negative controls, for both technical and biological factors that can influence fetal f...
Data
Figure S1. Kidney function and PTH serum levels in male Wistar rats (end point). Comparison of urea (μmol/L) (A) and creatinine (mmol/L) (B) serum measurements in CKD animals at week 11 (n=7–8). P=0.0098 for diet in creatinine. PTH (pg/mL) serum analysis at week 11 (C) (pooled groups n=17–19) and (D) (not pooled groups n=4–5). P=0.003 for surgery,...
Article
Full-text available
Background: Reproducibility of hits from independent CRISPR or siRNA screens is poor. This is partly due to data normalization primarily addressing technical variability within independent screens, and not the technical differences between them. Results: We present "rscreenorm", a method that standardizes the functional data ranges between scree...
Preprint
Full-text available
Introduction: Loss of function of BRCA1 associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy. Methods: A genetically engineered model was established expressing either functional or non-functional BAP1...
Article
Integrative analysis of copy number and gene expression data can help in understanding the cis and trans effect of copy number aberrations on transcription levels of genes involved in a pathway. To analyse how these copy number mediated gene-gene interactions differ between groups of samples we propose a new method, named dNET. Our method uses ridg...
Article
Full-text available
Thrombin and other inflammatory mediators may induce vascular permeability through the disruption of adherens junctions between adjacent endothelial cells. If uncontrolled, hyperpermeability leads to an impaired barrier, fluid leakage and edema, which can contribute to multi-organ failure and death. RhoGTPases control cytoskeletal dynamics, adhesio...
Article
Only 30-40% of acute myeloid leukemia (AML) patients survive five years after diagnosis. This poor prognosis is mainly caused by treatment failure due to chemotherapy resistance and relapse. Leukemic stem cells (LSCs) are thought to be the major determinants of AML relapse due their potential for self-renewal and chemotherapy resistance. It has bee...
Preprint
Here we propose a test to detect effects of single nucleotide polymorphisms (SNPs) on a quantitative trait. Significant SNP-SNP interactions are more difficult to detect than significant SNPs, partly due to the massive amount of SNP-SNP combinations. We propose to move away from testing interaction terms, and move towards testing whether an individ...
Article
Genes work together in sets known as pathways to contribute to cellular processes, such as apoptosis and cell proliferation. Pathway activation, or inactivation, may be reflected in varying partial correlations between the levels of expression of the genes that constitute the pathway. Here we present a method to identify pathway activation status f...
Article
Objective: Hypertensive disorders during pregnancy increase cardiovascular risk later in life by 2 to 9-fold. Endothelial activation is one of the underlying mechanisms of cardiovascular risk. Therefore, we decided to investigate endothelial activation in primiparous women, 2.5 years after a hypertensive pregnancy disorder. Study design: Plasma...
Article
Full-text available
Endothelial barrier function is carefully controlled to protect tissues from edema and damage inflicted by extravasated leukocytes. RhoGTPases, in conjunction with myriad regulatory proteins, exert both positive and negative effects on the endothelial barrier integrity. Precise knowledge about the relevant mechanisms is currently fragmented and we...
Data
Table S1. Knockdown‐phenotype analysis of individual siRNAs targeting 14 candidate p53 pathway inhibitors in A549/PG13Luc cells.
Data
Table S3. Primary p53 reporter screen results. The table lists the normalized luminescence values and the calculated robust Z‐scores of the three screens done.
Data
Table S4. Results of deconvolution confirmation screens. The table lists the fold induction in luciferase expression measured in A549/PG13Luc cells upon transfection with four distinct siRNAs for each candidate target gene (2‐4 independent experiments per gene).
Data
Fig. S1. STRING network of known and predicted protein–protein interactions between putative inhibitors and enhancers of p53 identified in the genome‐wide p53 transcriptional activity siRNA screen. Fig. S2. Cell viability and p53 activity screen scores of putative enhancers of p53 activity in comparison with 299 irrelevant controls. Fig. S3. Gati...
Data
Table S2. Sequences and exon annealing positions of primers used in qRT‐PCR analysis of TP53, MDM2 and MDM4 splice variants.
Data
Table S5. p53 activity screen results (average robust Z‐scores) for canonical spliceosome pathway member proteins, with subgroup designation as defined in the KEGG pathway database, and splice factors with a previously reported role in mitosis.
Article
Full-text available
Reinstating wild-type tumor suppressor p53 activity could be a valuable option for the treatment of cancer. To contribute to development of new treatment options for non-small cell lung cancer (NSCLC), we performed genome-wide siRNA screens for determinants of p53 activity in NSCLC cells. We identified many genes not previously known to be involved...
Article
Patients with advanced stage head and neck squamous cell carcinoma (HNSCC) are often treated with cisplatin-containing chemoradiation protocols. Although cisplatin is an effective radiation sensitizer, it causes severe toxicity and not all patients benefit from the combination treatment. HNSCCs expectantly not responding to cisplatin may better be...
Article
BACKGROUND. Cell-free circulating nucleic acids, including 22-nt microRNAs (miRNAs), represent noninvasive biomarkers for treatment response monitoring of cancer patients. While the majority of plasma miRNA is bound to proteins, a smaller, less well-characterized pool is associated with extracellular vesicles (EVs). Here, we addressed whether EV-as...
Article
In high-dimensional omics studies where multiple molecular profiles are obtained for each set of patients, there is often interest in identifying complex multivariate associations, for example, copy number regulated expression levels in a certain pathway or in a genomic region. To detect such associations, we present a novel approach to test for as...
Article
Full-text available
In many cancer types, the expression and function of ~22 nucleotide-long microRNAs (miRNA) is deregulated. Mature miRNAs can be stably detected in extracellular vesicles (EVs) in biofluids, therefore they are considered to have great potential as biomarkers. In the present study, we investigated whether miRNAs have a distinct expression pattern in...
Article
Full-text available
Background Testing for association between RNA-Seq and other genomic data is challenging due to high variability of the former and high dimensionality of the latter. Results Using the negative binomial distribution and a random-effects model, we develop an omnibus test that overcomes both difficulties. It may be conceptualised as a test of overall...
Article
Full-text available
It has been shown that a random-effects framework can be used to test the association between a gene’s expression level and the number of DNA copies of a set of genes. This gene-set modelling framework was later applied to find associations between mRNA expression and microRNA expression, by defining the gene sets using target prediction informatio...
Article
Full-text available
Background: Studies disagree on the location of grey matter (GM) atrophy in the multiple sclerosis (MS) brain. Aim: To examine the consistency between FSL, FreeSurfer, SPM for GM atrophy measurement (for volumes, patient/control discrimination, and correlations with cognition). Materials and methods: 127 MS patients and 50 controls were includ...
Article
Despite the proven efficacy of proteasome inhibitors like bortezomib (BTZ) in multiple myeloma, mantle cell lymphoma, and in an experimental setting in pediatric acute leukemia, development of drug resistance remains a primary hindrance. To further understand the molecular basis underlying this chemoresistance phenomenon, various leukemia cell line...
Article
Full-text available
Warsaw breakage syndrome (WABS) is caused by defective DDX11, a DNA helicase that is essential for chromatid cohesion. Here, a paired genome-wide siRNA screen in patient-derived cell lines reveals that WABS cells do not tolerate partial depletion of individual APC/C subunits or the spindle checkpoint inhibitor p31 comet. A combination of reduced co...