<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02207686</url>
  </required_header>
  <id_info>
    <org_study_id>H-2-2010-012-A</org_study_id>
    <nct_id>NCT02207686</nct_id>
  </id_info>
  <brief_title>Assessment of Residual VHL Function in Tumors - Can it Predict the Patients' Individual Course of Disease?</brief_title>
  <official_title>Assessment of Residual VHL Function in Tumors - Can it Predict the Patients' Individual Course of Disease?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Marie Luise Bisgaard, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Copenhagen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators aim to analyze tumors from vHL patients who have different courses of&#xD;
      disease and different types of VHL gene alterations to characterize which types of genetic&#xD;
      alterations the tumors contain and how these alterations affect the tumor cells' behavior on&#xD;
      a molecular level. The investigators will then compare these observations to vHL disease&#xD;
      outcome in patients and families.&#xD;
&#xD;
      It is already known that most vHL tumors develop when both copies of the VHL gene in a cell&#xD;
      are inactivated. The first copy is inactivated in all the person's cells from birth (&quot;first&#xD;
      hit&quot;), leaving just one functional copy. A tumor can develop from cells where the second copy&#xD;
      is also inactivated (&quot;second hit&quot;). So far, only the molecular consequences of the first hit&#xD;
      have been investigated. It is our hypothesis that both the first and second hits in&#xD;
      combination have consequences for tumor development and clinical outcome. The investigators&#xD;
      will include tumors from patients with different disease courses and different types of&#xD;
      &quot;first hits&quot; and analyse the tumors' DNA in order to find correlations between the first and&#xD;
      second hits and patients' and families' medical histories. The investigators hereby hope to&#xD;
      give new insights into how vHL tumors grow and which genetic factors influence tumor&#xD;
      development. These results will contribute to the current knowledge of vHL and help us get&#xD;
      one step closer to be able to predict an individual's tumor risks and need for surveillance.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In vHL tumors from patients with different phenotypes and different genetic backgrounds, the&#xD;
      investigators aim to assess both the nature of germline and somatic VHL mutations along with&#xD;
      the total residual VHL protein (pVHL) activity in tumor cells and evaluate association to&#xD;
      disease outcome in patients and families.&#xD;
&#xD;
      vHL tumor development follows Knudson's &quot;two-hit-mode&quot;: patients are born with a germline&#xD;
      mutation in one copy of their VHL gene in all the cells of the body - &quot;the first hit&quot;.&#xD;
      Somatic mutation in the other copy of the VHL gene - &quot;the second hit&quot; - initiates tumor&#xD;
      development. Pheno-genotype correlations are well known in vHL, but have so far been&#xD;
      explained exclusively by the nature of the germline mutation (the first hit). It is the&#xD;
      investigators' hypothesis that it is the total residual activity of the protein (pVHL)&#xD;
      present in the tumor after both first and second hit, which decides each tumor's destiny.&#xD;
&#xD;
      The investigators will apply Sanger sequencing, MLPA (and multiplex ligation dependent probe&#xD;
      amplification), LOH (Loss of heterogeneity) analysis, methylation assays, FISH (Fluorescence&#xD;
      In Situ Hybridization), and immunohistochemistry to characterize the germline and somatic&#xD;
      mutations, determine presence of mRNA and pVHL, and assess residual VHL activity in each&#xD;
      tumor. All these methods are already established in our laboratory.&#xD;
&#xD;
      The results will give deeper insight to vHL tumorigenesis and pave the road to future&#xD;
      individual prediction of each patient´s course of disease and need for surveillance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Enrolling by invitation</last_known_status>
  <start_date>September 2014</start_date>
  <completion_date type="Anticipated">August 2017</completion_date>
  <primary_completion_date type="Anticipated">August 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Residual pVHL activity measured by amount of VHL mRNA in tumor cells</measure>
    <time_frame>Two years</time_frame>
    <description>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).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Presence of VHL protein (pVHL) in tumor cells</measure>
    <time_frame>Two years</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Type of second hit (somatic mutation) found in DNA from tumor cells</measure>
    <time_frame>One year</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient's age at tumor diagnosis</measure>
    <time_frame>Two years</time_frame>
    <description>For each tumor we will correlate the previous outcome measures to the patient's age at tumor diagnosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient's total tumor burden</measure>
    <time_frame>Two years</time_frame>
    <description>For each tumor we will correlate the previous outcome measures to the patient's total tumor burden</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Type of clinical vHL in the patient's family (e.g. type 1, type 2)</measure>
    <time_frame>Two years</time_frame>
    <description>For each tumor we will correlate the previous outcome measures to the type of clinical vHL found in the patient's family.</description>
  </other_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Von Hippel-Lindaus Disease</condition>
  <arm_group>
    <arm_group_label>von Hippel-Lindau disease</arm_group_label>
    <description>Patients with von Hippel-Lindau disease who have had at least one vHL-related tumor removed</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood Tumor tissue (Paraffin embedded and fresh frozen)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        vHL patients over 18 years of age who have had at least one vHL-related tumor removed, and&#xD;
        for whom a reference DNA sample (from blood or normal tissue) and tumor tissue&#xD;
        (paraffin-embedded or fresh frozen) can be obtained.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  vHL diagnosed in patient&#xD;
&#xD;
          -  Patient over 18 years of age&#xD;
&#xD;
          -  Informed consent to participate can be obtained&#xD;
&#xD;
          -  Patient has had at least one vHL-related tumor removed&#xD;
&#xD;
          -  A reference DNA sample (from blood or normal tissue) and tumor tissue&#xD;
             (paraffin-embedded or fresh frozen) can be obtained.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients under the age of 18 years&#xD;
&#xD;
          -  Patients who had not previously had a vHL-related tumor removed&#xD;
&#xD;
          -  Patients whos previously removed tumor tissue cannot be obtained or is of such a&#xD;
             quantity or quality that no exact histological analysis can be done and/or no DNA can&#xD;
             be extracted&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marie Luise Bisgaard, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Cellular and Molecular Medicine, University of Copenhagen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Cellular and Molecular Medicine, University of Copenhagen</name>
      <address>
        <city>Copenhagen</city>
        <state>Copenhagen N</state>
        <zip>DK-2200</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>November 2015</verification_date>
  <study_first_submitted>August 1, 2014</study_first_submitted>
  <study_first_submitted_qc>August 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 4, 2014</study_first_posted>
  <last_update_submitted>November 12, 2015</last_update_submitted>
  <last_update_submitted_qc>November 12, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 13, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Copenhagen</investigator_affiliation>
    <investigator_full_name>Marie Luise Bisgaard, MD</investigator_full_name>
    <investigator_title>Associate professor</investigator_title>
  </responsible_party>
  <keyword>CNS hemangioblastoma</keyword>
  <keyword>Renal Cell Carcinoma</keyword>
  <keyword>VHL germline mutation</keyword>
  <keyword>VHL somatic mutation</keyword>
  <keyword>Tumor development</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Von Hippel-Lindau Disease</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02207686
org study id: H-2-2010-012-A
nct id: NCT02207686
lead sponsor: 
has dmc: No
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.
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.
observational model: Cohort
time perspective: Retrospective
measure: Residual pVHL activity measured by amount of VHL mRNA in tumor cells
time frame: Two years
description: 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).
measure: Presence of VHL protein (pVHL) in tumor cells
time frame: Two years
description: 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).
measure: Type of second hit (somatic mutation) found in DNA from tumor cells
time frame: One year
description: 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.
measure: Patient's age at tumor diagnosis
time frame: Two years
description: For each tumor we will correlate the previous outcome measures to the patient's age at tumor diagnosis
measure: Patient's total tumor burden
time frame: Two years
description: For each tumor we will correlate the previous outcome measures to the patient's total tumor burden
measure: Type of clinical vHL in the patient's family (e.g. type 1, type 2)
time frame: Two years
description: For each tumor we will correlate the previous outcome measures to the type of clinical vHL found in the patient's family.
arm group label: von Hippel-Lindau disease
description: Patients with von Hippel-Lindau disease who have had at least one vHL-related tumor removed
Whole blood Tumor tissue (Paraffin embedded and fresh frozen)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marie Luise Bisgaard, MD
role: Principal Investigator
affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen
facility: 
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: University of Copenhagen
investigator full name: Marie Luise Bisgaard, MD
investigator title: Associate professor
mesh term: Von Hippel-Lindau Disease