Genome Instability and Cancer

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Human Genetics.

Aim and focus

Genome-caretaking mechanisms counteract the deleterious effects of DNA damage and are essential to prevent toxicity, mutations, genome instability, ageing and disease. Inborn defects in genes controlling genome stability underlie inherited cancer predisposition and neurodegeneration whereas somatic loss of genome stability drives sporadic cancer, and is associated with ageing. Tumours with defects in DNA damage repair mechanisms may be candidates for immunotherapy and other molecular therapeutics specifically targeting these defects.

The main aims of our research programme are:

  • To obtain mechanistic understanding of genome surveillance mechanisms.
  • To elucidate how such mechanisms act to prevent pathologies.
  • To improve diagnosis of pathologies caused by impaired genome surveillance mechanisms.
  • To identify biomarkers of susceptibility to DNA damage to improve personalised cancer therapy.
  • To exploit opportunities for prevention and personalized treatment of cancer, with a focus on hereditary and sporadic colorectal, breast and ovarian cancer and head/neck paragangliomas.
  • To unveil roles of DNA damage and antibody effector pathways in inflammation.
The programme encompasses basic as well as patient-oriented (translational) research and includes the use of various model systems (such as yeast, worms, mice and mammalian cell culture), and state-of-the-art technologies (e.g. next generation sequence technologies, genome- and proteome-wide screens). In addition, functional assays are being used and developed to assess pathogenicity of DNA variants in cancer-associated genes, and/or to predict outcomes of treatment.

Position in international context

Principal investigators play prominent roles in their respective research fields, as evidenced by publications in high-impact journals, invitations to present at international meetings, and their contribution to national and international consortia (Netherlands Toxicogenomics Center; Marie Curie Ageing Consortium; Breast Cancer Association Consortium; Evidence-based Network for the Interpretation of Germline Mutant Alleles; Colorectal Cancer Genetics Consortium and the Concerted Action Polyp Prevention Studies). Their work is funded by prestigious national and international grants (e.g. EU, ERC, KWF, NWO and NIH). Generated mouse models are used to investigate the role of genome instability in cancer development and ageing, to address the efficacy of therapeutic monoclonal antibodies, and to improve our understanding of immune responses and autoimmune diseases. Some of these are being used by many collaborators all over the world.

Content / highlights / achievements

  • Identification of novel DNA damage repair pathways, distinct DNA damage response networks, and new factors involved in maintenance of genome stability.
  • Identification of gene defects causing hereditary paraganglioma.
  • A patent for detecting deletion mutations in BRCA genes: "Diagnostic test kit for determining a predisposition for breast and ovarian cancer, materials and methods for such determination".
  • Development of assays to assess the pathogenicity of gene variants in breast and colon cancer predisposition.
  • Founding of a spin-off company (TOXYS) for the assessment of genotoxic properties of chemicals.
  • Generation of a collection of immune-compromised mouse strains to study antibody-dependent inflammation and immunotherapy.
  • An ERC Consolidator grant has been awarded to Van Attikum (2014).
  • Prestigious KWF and NWO grants have been awarded to S.M. Noordermeer (KWF personal fellowship; 2014), M.S. Luijsterburg (VIDI, 2016), J. Schimmel (VENI, 2016).
  • Devilee is coordinator of an Horizon-2020 program on breast cancer susceptibility and personal risk stratification (BRIDGES, 2015-2020).
  • Verbeek was coordinator of a EU-FP7 MCA Initial Training Network on tumour infiltrating myeloid cell compartment (TIMCC, 2012-2016).
  • Industrial collaborations with Interactive Biosoftware SAS, Bioprodict, OcellO, Vitroscan.

Future themes

  • To identify and characterize caretakers of genome stability through, amongst others, comprehensive screens in model organisms and mammalian cells. To understand the relative contributions of drivers of genome instability (DNA damage, DNA replication stress, DNA secondary structures, DNA transcription, chromatin alterations) to the development of cancer and ageing-related pathologies, and rare disorders.
  • To define the role of DNA variants in inherited susceptibility to breast and ovarian cancer, colorectal cancer, and paraganglioma. To develop assays and technologies to assess pathogenicity of such variants, and to enable personalized prevention, diagnosis and treatment.
  • Implementation and further development of the latest genome-editing tools (modified BAC transgenics, and CRISPR/Cas9) to generate (conditional) mouse models and mammalian knock-out/in cell lines, organoids and organs, and perform genome-wide screens.
  • To exploit the intrinsic genome instability in tumours by designing and improving ex vivo assays to enable personalized therapy.
  • To address human health risk through establishing biomarkers and subsequent identification of individuals with elevated risk for adverse clinical responses to radiotherapy or chemotherapy. 

Cohesion within LUMC

This research programme is tightly connected to many clinical activities of the LUMC and within the medical research profile 'Cancer Pathogenesis and Therapy', in particular genetic counselling of cancer families at the Department of Clinical Genetics and cancer gene testing at the Laboratory for Diagnostic Genome Analysis, in collaboration with the departments of Pathology, Dermatology and Surgery. The functional genomics parts of this programme are also connected to the profile "Bioscience: the science base of health" of the University of Leiden. Ongoing local collaborations exist with academic (Leiden Academic Centre for Drug Research - LACDR) and non-academic industrial partners on development of in vitro cell systems for mechanism-based prediction of toxicity, the generation of stress-responsive antibodies, and genetic screens in human cells. Fruitful collaboration with the departments of Immunohematology, Rheumatology and Nephrology resulted in joint national and international grants. Part of the research comprises the LUMC research profile 'Ageing'.