Von Hippel-Lindaus Disease Clinical Trial
Official title:
Assessment of Residual VHL Function in Tumors - Can it Predict the Patients' Individual Course of Disease?
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.
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Observational Model: Cohort, Time Perspective: Retrospective