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Roadkill
Study could speed detection of Kidney Cancer
Newswise — Large-scale data mining of gene
networks in fruit flies has led researchers
to a sensitive and specific diagnostic
biomarker for human renal cell carcinoma,
the most common type of kidney cancer.
In the journal Science, published early
online January 22, a team based at the
University of Chicago shows that the
biomarker known as SPOP is produced by 99
percent of clear cell renal cell carcinomas
but not by normal kidney tissue.
Physicians could use SPOP levels to confirm
or rule out a diagnosis of renal cell
carcinoma (RCC). It could also help them
determine the original source of cancers
that had spread to other organs from an
unknown primary tumor.
“This could serve as a diagnostic tool, lead
us to new drug targets and potentially help
us detect kidney cancers sooner,” said
study-director Kevin White, PhD, professor
of human genetics, and ecology and
evolution, and director of the Institute for
Genetics and Systems Biology at the
University of Chicago.
“It also confirms our strategy of using
genomics and systems-level analysis of model
organisms such as fruit flies to identify
factors that play crucial roles in human
disease.”
The study began with the fly genome. White
and colleagues, who study gene
regulation—how genes or entire networks of
genes get turned on of off—wanted to measure
the downstream effects of two key genes,
known as Eve and Ftz, that control early
steps in the development of flies, beginning
just after the eggs are laid.
Because Eve and Ftz regulate the activity of
other genes, and many of those genes control
the activity of additional genes, both had a
large impact. Eve influences the expression
of 1,074 different genes and Ftx impacts
1,310 genes.
When they narrowed their search to genes
directly impacted, the total fell to 235
genes. About 20 percent of those target
genes regulate transcription, the activation
of other genes, and 40 percent controlled
developmental processes.
About 150 of those target genes have human
equivalents. When the researchers ranked
those 150 genes according to their impact in
flies, the top candidate was a gene known as
CG9924, or Roadkill, the central player in a
major hub of networked genes and a crucial
component in the development of the nervous
system. SPOP, the human equivalent, is about
80 percent identical to Roadkill.
Looking closer, they determined that SPOP
appeared to play a role not just in
development but also in human cancers.
It interacts with cell signaling pathways—JNK
and RAS—that frequently go awry in multiple
human cancers.
At this point, the researchers shifted their
focus from fly genetics to human cancer.
When they screened hundreds of tissue
samples from 18 different tumor types,
acquired from patients having surgery, they
found that 85 percent of renal cell
carcinomas produced high amounts of SPOP,
while normal kidney tissue was uniformly
negative.
When they looked at 300 renal cell cancer
samples, 77 percent were positive for SPOP.
All normal kidney samples were negative.
About 75 percent of all renal cell cancers
are clear cell RCC. The researchers found
that 99 percent of the clear cell RCC
samples showed evidence of elevated SPOP.
The SPOP test even revealed that a few
tumors had originally been misdiagnosed as
clear cell RCC. Those turned out to be other
types of kidney cancer when examined more
closely by pathologists.
“These results indicate that SPOP is a
highly sensitive and specific diagnostic
biomarker for clear cell RCC,” the authors
conclude, “and can help distinguish
histological subtypes of RCC.”
It could also be used to help identify the
primary tumor in metastatic cancers,
important in treatment decisions.
The W.M. Keck Foundation, the Arnold and
Mabel Beckman Foundation, and the Searle
Funds at the Chicago Community Trust funded
the study. Additional authors include Jiang
Liu, Murad Ghanim, Christopher Brown, Ivan
Iossifov, Sujun Hua, Nicholas Negre, Michael
Ludwig Thomas Stricker Hikmat Al-Ahmadie,
Maria Tretiakova and Andrey Rzhetsky from
the University of Chicago; Lei Xue, Robert
Camp and David Rimm from Yale University;
and Montse Perera-Alberto from La Laguna
University in Tenerife, Spain.
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