Assessment of Residual VHL Function in Tumors – Can it Predict the Patients’ Individual Course of Disease?

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Brief Title

Assessment of Residual VHL Function in Tumors - Can it Predict the Patients' Individual Course of Disease?

Official Title

Assessment of Residual VHL Function in Tumors - Can it Predict the Patients' Individual Course of Disease?

Brief Summary

      The investigators aim to analyze tumors from vHL patients who have different courses of
      disease and different types of VHL gene alterations to characterize which types of genetic
      alterations the tumors contain and how these alterations affect the tumor cells' behavior on
      a molecular level. The investigators will then compare these observations to vHL disease
      outcome in patients and families.

      It is already known that most vHL tumors develop when both copies of the VHL gene in a cell
      are inactivated. The first copy is inactivated in all the person's cells from birth ("first
      hit"), leaving just one functional copy. A tumor can develop from cells where the second copy
      is also inactivated ("second hit"). So far, only the molecular consequences of the first hit
      have been investigated. It is our hypothesis that both the first and second hits in
      combination have consequences for tumor development and clinical outcome. The investigators
      will include tumors from patients with different disease courses and different types of
      "first hits" and analyse the tumors' DNA in order to find correlations between the first and
      second hits and patients' and families' medical histories. The investigators hereby hope to
      give new insights into how vHL tumors grow and which genetic factors influence tumor
      development. These results will contribute to the current knowledge of vHL and help us get
      one step closer to be able to predict an individual's tumor risks and need for surveillance.
    

Detailed Description

      In vHL tumors from patients with different phenotypes and different genetic backgrounds, the
      investigators aim to assess both the nature of germline and somatic VHL mutations along with
      the total residual VHL protein (pVHL) activity in tumor cells and evaluate association to
      disease outcome in patients and families.

      vHL tumor development follows Knudson's "two-hit-mode": patients are born with a germline
      mutation in one copy of their VHL gene in all the cells of the body - "the first hit".
      Somatic mutation in the other copy of the VHL gene - "the second hit" - initiates tumor
      development. Pheno-genotype correlations are well known in vHL, but have so far been
      explained exclusively by the nature of the germline mutation (the first hit). It is the
      investigators' hypothesis that it is the total residual activity of the protein (pVHL)
      present in the tumor after both first and second hit, which decides each tumor's destiny.

      The investigators will apply Sanger sequencing, MLPA (and multiplex ligation dependent probe
      amplification), LOH (Loss of heterogeneity) analysis, methylation assays, FISH (Fluorescence
      In Situ Hybridization), and immunohistochemistry to characterize the germline and somatic
      mutations, determine presence of mRNA and pVHL, and assess residual VHL activity in each
      tumor. All these methods are already established in our laboratory.

      The results will give deeper insight to vHL tumorigenesis and pave the road to future
      individual prediction of each patient´s course of disease and need for surveillance.
    


Study Type

Observational


Primary Outcome

Residual pVHL activity measured by amount of VHL mRNA in tumor cells

Secondary Outcome

 Presence of VHL protein (pVHL) in tumor cells

Condition

Von Hippel-Lindaus Disease


Study Arms / Comparison Groups

 von Hippel-Lindau disease
Description:  Patients with von Hippel-Lindau disease who have had at least one vHL-related tumor removed

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

50

Start Date

September 2014

Completion Date

August 2017

Primary Completion Date

August 2016

Eligibility Criteria

        Inclusion Criteria:

          -  vHL diagnosed in patient

          -  Patient over 18 years of age

          -  Informed consent to participate can be obtained

          -  Patient has had at least one vHL-related tumor removed

          -  A reference DNA sample (from blood or normal tissue) and tumor tissue
             (paraffin-embedded or fresh frozen) can be obtained.

        Exclusion Criteria:

          -  Patients under the age of 18 years

          -  Patients who had not previously had a vHL-related tumor removed

          -  Patients whos previously removed tumor tissue cannot be obtained or is of such a
             quantity or quality that no exact histological analysis can be done and/or no DNA can
             be extracted
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Marie Luise Bisgaard, MD, , 

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT02207686

Organization ID

H-2-2010-012-A


Responsible Party

Sponsor-Investigator

Study Sponsor

Marie Luise Bisgaard, MD


Study Sponsor

Marie Luise Bisgaard, MD, Principal Investigator, Department of Cellular and Molecular Medicine, University of Copenhagen


Verification Date

November 2015