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

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ClinicalTrials.gov Identifier: NCT02207686
Recruitment Status : Unknown
Verified November 2015 by Marie Luise Bisgaard, MD, University of Copenhagen.
Recruitment status was:  Enrolling by invitation
First Posted : August 4, 2014
Last Update Posted : November 13, 2015
Sponsor:
Information provided by (Responsible Party):
Marie Luise Bisgaard, MD, University of Copenhagen

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.


Condition or disease
Von Hippel-Lindaus Disease

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.


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Study Type : Observational
Estimated Enrollment : 50 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Assessment of Residual VHL Function in Tumors - Can it Predict the Patients' Individual Course of Disease?
Study Start Date : September 2014
Estimated Primary Completion Date : August 2016
Estimated Study Completion Date : August 2017


Group/Cohort
von Hippel-Lindau disease
Patients with von Hippel-Lindau disease who have had at least one vHL-related tumor removed



Primary Outcome Measures :
  1. Residual pVHL activity measured by amount of VHL mRNA in tumor cells [ Time Frame: Two years ]
    We will correlate amount of VHL mRNA in tumor cells with the type of the patients' first hit (germline mutation) and the tumor's second hits (somatic mutations).


Secondary Outcome Measures :
  1. Presence of VHL protein (pVHL) in tumor cells [ Time Frame: Two years ]
    We will correlated the presence of pVHL in tumor cells with the nature of the patients' (germline mutation) and the tumor cells' second hits (somatic mutations).

  2. Type of second hit (somatic mutation) found in DNA from tumor cells [ Time Frame: One year ]
    We will correlate the type of germline mutation found in the patient's DNA from blood with the types of second hits (somatic mutations) found in the tumor's DNA.

  3. Patient's age at tumor diagnosis [ Time Frame: Two years ]
    For each tumor we will correlate the previous outcome measures to the patient's age at tumor diagnosis

  4. Patient's total tumor burden [ Time Frame: Two years ]
    For each tumor we will correlate the previous outcome measures to the patient's total tumor burden


Other Outcome Measures:
  1. Type of clinical vHL in the patient's family (e.g. type 1, type 2) [ Time Frame: Two years ]
    For each tumor we will correlate the previous outcome measures to the type of clinical vHL found in the patient's family.


Biospecimen Retention:   Samples With DNA
Whole blood Tumor tissue (Paraffin embedded and fresh frozen)


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
vHL patients over 18 years of age who have had at least one vHL-related tumor removed, and for whom a reference DNA sample (from blood or normal tissue) and tumor tissue (paraffin-embedded or fresh frozen) can be obtained.
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02207686


Locations
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Denmark
Department of Cellular and Molecular Medicine, University of Copenhagen
Copenhagen, Copenhagen N, Denmark, DK-2200
Sponsors and Collaborators
Marie Luise Bisgaard, MD
Investigators
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Principal Investigator: Marie Luise Bisgaard, MD Department of Cellular and Molecular Medicine, University of Copenhagen

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Responsible Party: Marie Luise Bisgaard, MD, Associate professor, University of Copenhagen
ClinicalTrials.gov Identifier: NCT02207686     History of Changes
Other Study ID Numbers: H-2-2010-012-A
First Posted: August 4, 2014    Key Record Dates
Last Update Posted: November 13, 2015
Last Verified: November 2015
Keywords provided by Marie Luise Bisgaard, MD, University of Copenhagen:
CNS hemangioblastoma
Renal Cell Carcinoma
VHL germline mutation
VHL somatic mutation
Tumor development
Additional relevant MeSH terms:
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Von Hippel-Lindau Disease
Neurocutaneous Syndromes
Nervous System Diseases
Angiomatosis
Vascular Diseases
Cardiovascular Diseases
Ciliopathies
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn