Oncology Oncology

EBV related cancers

For the VUMC EBV website 

Diagnostic and pathogenic markers 

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus (also: EveryBody's Virus) causing Infectious Mononucleosis (IM or Kissing Disease) and etiologically linked to an increasing number acute chronic and malignant disease syndromes (see below).  In past years we identified and validated various (anti-) viral pathogenic markers in patients with different EBV-linked diseases and developed new methods and guidelines for diagnosis and virus-targeted treatment. We have created (and patented) a unique series of (early) diagnostic markers (proteins, peptides, sequences) plus reagents and tools to identify these markers. These markers, reagents and methods are being implemented for screening and monitoring (organ or stem cell) transplant recipients at risk for EBV-driven B-cell malignancies (PTLD), HIV carriers with lymphadenopathy and patients with autoimmune diseases like RA, SLE, Parkinson and Multiple Sclerosis. 
In the field of oncology we identified specific EBV gene expression profiles/functions (markers) causally involved in different types of cancer.  We have provided molecular and immunological evidence supporting and explaining the pathogenic role of EBV in these diseases. We now focus on using these markers for (early) diagnosis and treatment in patients with various EBV-driven lymphomas (i.e. classic Hodgkin and B-cell non-Hodgkin lymphomas, Burkitt Lymphoma, NK-T-cell lymphoma, CLL) as well as carcinomas (i.e. nasopharyngeal carcinoma and gastric carcinoma). We participate in large worldwide studies on identification of aberrant EBV genomic sequences and expression profiles and their disease association(s).

Oncogenesis and treatment

EBV is classified by WHO-IARC as a class-I human carcinogen causally implicated in multiple lymphomas and carcinomas. During lifelong persistence EBV hides latently in memory B-cells and preferentially replicates in epithelial cells. EBV-driven malignant disease is closely linked to the viral latent state with viral products being actively expressed in all tumor cells and involved in hijacking and modifying normal host-cell functions, such as cell cycle control, differentiation, apoptosis-inhibition and immune evasion. Expression profiling of EBV latent (LMP-1,-2 and EBNA-1,-2, BARF1) and lytic genes (ZEBRA, TK, VCA p18), as well as virus-encoded miRNAs, revealed viral activity characteristic for different the EBV-driven malignancies. Because of the universal presence of EBV genomes in these cancers, the virus (products) can be a target for specific therapeutic intervention, either by virus-targeted chemo- or immunotherapy (i.e. cytolytic virus activation (CLVA) treatment or anti-LMP1/-LMP2 extracellular loop domain detection by vaccination and antibody or (CAR-) T-cells)).  Our serological and molecular evidence suggests a role for virus replication in early stages, which can be exploited for improved non-invasive diagnosis and mass-screening in liquid biopsy material (blood drops, serum, plasma, urine or saliva). Viral DNA load testing in blood/plasma or nasopharyngeal brushings proved useful for confirmation in diagnosis and monitoring. 
Our expertise is exploited in a worldwide network of collaborations.

Our aims are: 

  1. to further support the (early) diagnosis of EBV-driven cancers in international studies by EBV-specific peptide-based serology and viral DNA load measurement in large patient cohorts and implementing new methylation and viral miRNA markers. The viral load will be used for monitoring therapy responses in blood and tissue samples, as well as in non-invasive nasopharyngeal brush specimens.
  2. to further develop virus targeted chemo- and immunotherapies (CLVA and anti-LMP1,2 loop detection) and develop diagnostic assays for monitoring therapy-responses based upon lytic components (RNA and proteins) and cell free EBV-DNA and miRNA quantification
  3. characterization of a carcinoma specific oncogene BARF1, function and presences of the secreted protein in body fluids

Staff

Jaap Middeldorp PhD -  program leader

Sandra Verkuijlen - technician  
Zlata Novalic - PhD student
Octavia Ramayanti - PhD student