Research team

Human molecular genetics

Expertise

I have a background in Biomedical sciences, obtained a PhD in genetics and an additional master (ManaMa) in statistical data-analysis. My main expertise is in the statistical data-analysis of research data, mainly (but not exclusively) data from life sciences.

Improving current cancer detection and treatment follow-up through the development of a next generation cancer assay. 01/02/2020 - 31/01/2022

Abstract

Each year, an estimated 8.2 million people die of cancer. With appropriate detection methods and treatment, many of these deaths would be avoidable. Due to the high incidence and mortality rates, early and accurate diagnosis is paramount for a quick and adequate treatment of patients. Until recently, no truly non-invasive diagnostic methods for the detection of cancer existed. An attractive novel method is the detection of abnormally expressed biological markers manifested during carcinogenesis in so called "liquid biopsies". Liquid biopsy is a technique in which non-solid biological tissues such as urine, stool or peripheral blood, are sampled and analysed for disease diagnosis. The analysis of Circulating tumor DNA (CtDNA) in cancer patients is not new and has been performed in the past. However, until now, a strong focus existed on the detection of tumor specific mutations, which has several limitations. The use of methylation markers instead of mutation markers has many advantages and is understudied. We have recently published GSDME as a highly sensitive and specific methylation biomarker for both breast and colorectal cancer. We wish to build upon these data and extend our search for suitable cancer detection biomarkers genome wide. One of the problems with liquid biopsy nucleic acid biomarkers is the limited sensitivity for early detection. Indeed, in early stages of carcinogenesis, many tumor types have low concentrations of CtDNA. Sensitivity can be increased by measuring a multitude of markers simultaneously. However, to date, no efficient techniques exist that allow multi-region methylation analysis in plasma. Therefore, in this project, we will design a novel technique, next generation high resolution methylation detection in plasma of cancer patients and develop a novel multi-region pan-cancer detection assay, based on genome wide methylation tumor data. We believe that this novel technology is able to increase sensitivity 100 - 1000 fold while reducing the cost more than a 100 fold compared to the standard technologies that are used nowadays. Finally, we will validate our novel technique and assay in clinical samples.

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Improving current cancer detection and treatment follow up through the development of next generation cancer assays. 01/01/2020 - 31/12/2023

Abstract

Each year, an estimated 8.2 million people die of cancer. With appropriate detection methods and treatment, many of these deaths would be avoidable. However, current methods for detection and analysis of treatment response still suffer from major disadvantages. An attractive novel method is the detection of abnormally expressed biological markers manifested during carcinogenesis in so called "liquid biopsies". Liquid biopsy is a technique in which non-solid biological tissues such as urine, stool or peripheral blood, are sampled and analysed for disease diagnosis. The analysis of CtDNA (DNA originating from the tumor and present in the blood) in cancer patients is not new and has been performed in the past. However, until now, a strong focus existed on the detection of tumor specific mutations, which has several limitations, such as limited sensitivity. The use of methylation markers instead of mutation markers has many advantages, such as a potentially much higher sensitivity, and is understudied. We have recently published GSDME as a highly sensitive and specific methylation biomarker for both breast and colorectal cancer. In addition, we have analyzed 12 additional frequent cancer types, and we have strong preliminary data that GSDME is about equally sensitive in each of these 14 tumor types analyzed. These data show that GSDME has strong potential as the first true pan-cancer biomarker. In part A of the project, we will focus on GSDME, and test it as a true biomarker in a clinical setting. Next to detection markers, there is also a need for better follow-up markers. Follow-up of cancer patients is currently performed based on clinical, radiologic and tumor marker evaluation, which has limitations. Better follow-up markers have the potential to detect resistance or disease progression earlier. We aim to expand further on these concepts and conduct a clinical trial where we will evaluate the use of GSDME methylation analysis in liquid biopsies as a tool to guide treatment in metastatic colorectal patients and to explore whether GSDME has potential as a follow up biomarker (WP2). Moreover, GSDME has an interesting physiological function. Recent papers have identified Gasdermins, including GSDME, as a completely new type of regulated cell death executioners (RCD). Recently, it was proven that the N-terminal part of GSDME induces RCD through pore-formation and this is a key antitumor mechanism that is inactivated in several tumor types. In a third work package of part A, we will further investigate these fundamental aspects of the GSDME gene and study its involvement in carcinogenesis. One of the problems with liquid biopsy nucleic acid biomarkers is the limited sensitivity for early detection. Indeed, in early stages of carcinogenesis, many tumor types have low concentrations of CtDNA. Sensitivity can be increased by measuring a multitude of markers simultaneously. However, to date, no efficient techniques exist that allow multi-region methylation analysis in plasma. Therefore, in part B of this project, we will design a novel technique that is able to do this. In a previous unpublished analysis, we have shown that the cancer methylome contains a multitude of differentially methylated makers, that hold the potential to be used as pan-cancer biomarkers, and we have developed a bioinformatics analysis pipeline to detect and rank these according to their discriminating power. Using these data, we will develop a novel multi-region pan-cancer detection assay using our novel technique. We believe that our technology is able to increase sensitivity 100 - 1000 fold while reducing the cost more than a 100 fold compared to the standard technologies that are currently used for CtDNA biomarkers. Finally, we will validate our novel pan-cancer detection assay in the clinical samples that were collected in part A.

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Analysis of monogenic forms of deafness using dense genome-wide SNP data. 01/02/2009 - 31/12/2010

Abstract

The aim of this project is the identification of new loci for hereditary nonsyndromic forms of hearing loss. A unique collection of 30 highly informative Iranian families, with a high degree of consanguinity, is available. After an initial screening for recurrent mutations, a genome wide search is carried out using the most advanced techniques for genotyping using DNA chips, after which the diseases locus is pinpointed using linkage analysis.

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Identification of genes responsible for complex forms of hearing impairment using statistical and genetic-epidemiological techniques. 01/12/2007 - 30/11/2010

Abstract

The objective of this project is to find genes involved in age-related hearing impairment, nloise-induced hearing loss and otosclerosis. In a genome-wide association study, affected and non-affected persons are genotyped for hundred thousends of genetic variants across the entire genome. These variants are tested for association with the affection status. Apart from classical statistical tests, we will apply new analysis methods that are only possible if whole genome data are available.

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Identification of genes responsible for complex forms of hearing impairment using statistical and genetic-epidemiological techniques. 01/10/2006 - 31/03/2008

Abstract

The general aim of this project is to elucidate the genetic risk factors for complex forms of hearing impairment (age-related hearing impairment, noise-induced hearing loss and otosclerosis). In particular, we will analyze the data from high-throughput genotyping of large sample sets using statistical and epidemiological methods. Single SNP association, gene-gene interaction and gene-environment interactions will be tested.

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Construction and characterization of a transgenic mouse with a knockout in Coch, responsible for hearing loss and vestibular dysfunction in man. 01/01/2004 - 31/12/2007

Abstract

Mutations in the human COCH gene lead to autosomal dominant progressive hearing loss paralleled by vestibular dysfunction. To get a better understanding of the function of COCH and the way COCH mutations lead to inner ear dysfunction, we want to construct and chararacterize a transgenic mouse with a knockout of COCH.

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Identification and characterization of genes involved in hearing loss and imbalance problems. 01/10/2001 - 30/09/2004

Abstract

The inner ear contains the organs for hearing (the cochlea) and balance (the vestibulum). The cochlea and the vestibulum are evolutionary related and their functioning is similar, but not yet fully understood. A better understanding of these organs can lead to better treatments for patients suffering from hearing impairment or imbalance problems. The aim of this study is to obtain a better understanding of the functioning of the inner ear by searching and characterizing genes involved in hearing impairment and vestibular dysfunction. Specific aims include: i) positional cloning of disease genes in families with hereditary hearing loss and vestibular dysfunction ii) construction and characterization of cDNA libraries for the cochlea and the vestibulum iii) characterization of genes involved in hearing and balance using histologic and biochemical techniques.

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Construction of a transgenic mouse with an inactivation of the Coch gene, responsible for hearing loss and balance problems. 01/10/1999 - 31/12/2000

Abstract

The inner ear is a highly specialized structure, harboring the organs for hearing (the cochlea and balance (the vestibulum). One of the ways to obtain a better understanding of their functioning, is by searching and characterizing genes involved in hearing and balance disorders. Recently, a few families with autosomal dominant progressive hearing loss accompanied by balance problems (DFNA9) were shown to have mutations in a newly identified gene. This gene was termed COCH. but its role is unclear. The aim of this project is to gain insicht into the role of COCH in the functioning of the inner ear, through the construction of a transgenic mouse with an inactivated Coch gene. The mouse will be constructed via embryonic stem (ES) cell technology. Hygromycin-resistent ES cells are screened for a homologous recombination between the Coch locus in the targeting vector and the Coch focus in the ES cell genome. In these latter cells, the native Coch gene is inactivated by the insertion of the hygromycin gene. Recombinant ES cells are injected into the bastocyst of a mouse embryo. The chimaeric offspring is screened for individuals that transmit the truncated Coch gene to their offspring.

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    Identification and characterization of genes involved in hearing loss and imbalance problems. 01/10/1998 - 30/09/2001

    Abstract

    The inner ear contains the organs for hearing (the cochlea) and balance (the vestibulum). The cochlea and the vestibulum are evolutionary related and their functioning is similar, but not yet fully understood. A better understanding of these organs can lead to better treatments for patients suffering from hearing impairment or imbalance problems. The aim of this study is to obtain a better understanding of the functioning of the inner ear by searching and characterizing genes involved in hearing impairment and vestibular dysfunction. Specific aims include: i) positional cloning of disease genes in families with hereditary hearing loss and vestibular dysfunction ii) construction and characterization of cDNA libraries for the cochlea and the vestibulum iii) characterization of genes involved in hearing and balance using histologic and biochemical techniques.

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      The role of the neuronal cell adhesion molecule L1CAM in syndromes with X-linked mental retardation. 01/01/1997 - 30/06/1997

      Abstract

      L1CAM is a glycoprotein involved in the embryonic development of the nervous system. Mutations in the gene encoding LlCAM gice rise to CRASH syndrome, an X-linked condition characterised by Corpus callosum agenesis, Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus. In this study, the role of LlCAM in CRASH syndrome is studied using three different approaches: i) L1CAM mutation analysis in CRASH patients, ii) expression studies of mutant L1CAM protein (in collaboration with V. Lemmon, Case Western Reserve University, Cleveland, Ohio, U.S.A.) and iii) study of a transgene mouse model carrying an L1CAM knock-out mutation.

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        The role of the neuronal cell adhesion molecule L1CAM in X-linked mental retardation. 01/01/1995 - 31/12/1996

        Abstract

        Mutations in L, a neural cell adhesion molecule lead to X-linked hydrocephalus and mental retardation. The effect of these mutations will be studied by in vitro expressions analysis in cel systems and in vivo analysis in transgenic animals.

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          The role of the neuronal cell adhesion molecule L1CAM in X-linked mental retardation. 01/10/1994 - 31/12/1994

          Abstract

          Mutations in L, a neural cell adhesion molecule lead to X-linked hydrocephalus and mental retardation. The effect of these mutations will be studied by in vitro expressions analysis in cel systems and in vivo analysis in transgenic animals.

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