German Cancer Research Center: For childhood kidney tumors, scientists from Würzburg and Heidelberg have identified a series of previously unknown genetic causes. A lack of microRNA prevents kidney precursor cells from maturation. Instead they remain in an embryonic state in which rapid growth is one of their fundamental tasks.
Wilms tumors, also known as
nephroblastomas, are among the more common solid tumors in children.
They tend to appear before the age of six and are categorized as
embryonal tumors. The starting point in their development are kidney
precursor cells in the embryo, which evidently do not mature as they
should. Consequently, the tumor contains somewhat differing tissue
structures, which is why the man who lent his name to them, Max Wilms,
referred to “mixed tumors of the kidney” in his description in 1899.
In the search for the molecular causes of
Wilms tumors and, in particular, the genetic culprits behind their
high-risk variants, a group of scientists has now made a breakthrough.
This collaboration involved teams led by Professor Manfred Gessler,
chairman of the Department of Developmental Biochemistry at the
University of Würzburg’s Biocenter, and teams led by Marcel Kool and
Stefan Pfister at the German Cancer Research Center in Heidelberg as
well as partners both within Germany and abroad. They present their
findings in the current issue of the journal Cancer Cell.
Genetic defects slow down the molecular machinery
“Previously, three genes were known to be possible
triggers of Wilms tumors. We have now managed to identify a whole
series of other causes,” explains Manfred Gessler. These include the
genes DROSHA and DGCR8. If these are defective, this leads to a partial
deactivation of the molecular machinery responsible for creating
so-called microRNAs. MicroRNAs, for their part, are able to regulate the
function of a large number of messenger RNA molecules and thus
completely reprogram cells.
“With embryonic stem cells we already know that
without microRNAs they are not capable of transforming themselves into
cells of different tissues,” says Gessler. The same seems to be true of
Wilms tumors: in their case, individual kidney precursor cells evidently
do not manage to mature fully. Instead they remain in an embryonic
state in which rapid growth is one of their fundamental tasks so that
the kidney grows.
A genetic defect triggers various cancers
Alongside the microRNAs, two transcription factors
also attracted the attention of the teams. The proteins referred to as
SIX1 and SIX2 control the activity of other genes. Animal models had
already made it clear that they are absolutely vital to the formation of
the kidneys; they are also particularly active in Wilms tumors. “Our
findings now reveal for the first time that both genes for these
transcription factors are altered in Wilms tumors by mutations and, as a
result, the cells remain in an embryonic growth mode in this case,
too,” explains Gessler.
Third finding of the study: Tumor genes that are
known to trigger other cancers may also be responsible for Wilms tumors.
The scientists were able to show that a particular gene involved in the
development of neuroblastomas – tumors that arise from degenerated
immature cells of the sympathetic nervous system – is also activated in
Wilms tumors. “This gives real hope that treatments that are successful
for a neuroblastoma will also be effective for Wilms tumors,” says
Gessler.
In addition, some of the Wilms tumors demonstrated
a deactivation of the most familiar tumor suppressor gene TP53, which
led to dramatic genome changes accompanied by the fracture and
uncontrolled loss or multiplication of chromosomal fragments. The
prognosis for such degenerated tumors is particularly unfavorable.
Approaches for personalized treatment
The scientists involved believe that the new
findings relating to the various triggers of Wilms tumors may help to
improve treatment. Currently around 90 percent of children with the
disease survive if they receive a combination of chemotherapy, surgery,
and then further chemotherapy. The trick here is to identify patients
with so-called high-risk tumors early and to treat them more intensively
than cases with a low discernible risk of relapse. This technique
should minimize the stress on the children and any possible
consequential harm.
A histologic examination, routinely conducted
these days, and the clinical picture provide important indicators here.
But these are still not enough. “Clarifying the molecular causes offers
hope of improving the classification of tumors and of being able to use
increasingly targeted treatments within the framework of personalized
medicine,” says Manfred Gessler.
However, with some of these genetic changes that
have now been discovered it remains unclear how they contribute to tumor
development. The aim of future work will mainly be to filter out from
the abundance of candidates those that are best suited to predicting the
progression of the disease, and to develop approaches for tailor-made
treatments based on new knowledge relating to molecular networks.
Ideal combination of different areas of expertise
For the study of Wilms tumors, the various
disciplines of the teams involved complemented one another perfectly:
The Würzburg team contributed years of experience in the analysis of
Wilms tumors and one of the world’s largest collections of these tumors,
which is housed at the Biocenter. The German Cancer Research Center
(DKFZ) team provided extensive capacities and experience in
high-throughput sequencing and genome analysis. The changes they
discovered were then checked in Würzburg against hundreds of other
tumors and their function examined.
Future work will require close collaboration with
numerous pediatric clinics and pathologists as part of the German Wilms
Tumor Study and with European partners, as this is the only way that it
will be possible to collect and analyze sufficient material and data for
such tumors successfully.
This work was supported by the
Wilhelm-Sander-Stiftung foundation, the German Research Foundation, the
Federal Ministry of Education and Research, and the HIPO initiative of
the German Cancer Research Center (DKFZ-HIPO).
Mutations in the SIX1/2 Pathway and the
DROSHA/DGCR8 miRNA Microprocessor Complex Underlie High-Risk Blastemal
Type Wilms Tumors. Jenny Wegert, Naveed Ishaque, Romina Vardapour,
Christina Geörg, Zuguang Gu, Matthias Bieg, Barbara Ziegler, Sabrina
Bausenwein, Nasenien Nourkami, Nicole Ludwig, Andreas Keller, Clemens
Grimm, Susanne Kneitz, Richard D. Williams, Tas Chagtai, Kathy
Pritchard-Jones, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier
Versteeg, Tomas Acha, Maureen J. O’Sullivan, Peter Karl Bode, Felix
Niggli, Godelieve A. Tytgat, Harm van Tinteren, Marry M. van den
Heuvel-Eibrink, Eckart Meese, Christian Vokuhl, Ivo Leuschner, Norbert
Graf, Roland Eils, Stefan M. Pfister, Marcel Kool, Manfred Gessler.
Cancer Cell, http://dx.doi.org/10.1016/j.ccell.2015.01.002