One report, published in Nature
on Oct. 23, 2008, came from a
$100 million pilot project of the
Cancer Genome atlas (TCGa),
a federally funded, multicenter
collaboration. a team led by
cancer geneticist lynda Chin and
oncologist Matthew Meyerson of
the Dana-Farber Cancer Institute
and of Harvard Medical School
in boston checked for genetic
alterations in tumor samples from
206 patients with glioblastoma
multiforme, the most common
brain cancer.
The researchers detected 453
mutations in 601 selected genes.
although most of those genes were
known or suspected cancer culprits,
looking broadly at cancer’s genomic
makeup “allowed us to find things
that we didn’t expect,” Chin says.
For instance, three of the eight
most significant mutations had not
been considered consequential in
the illness. The data also hinted
that some tumors treated with the
chemotherapy drug temozolomide
(Temodar) outsmart it by acquiring
mutations in particular DNa
damage-repair genes. That finding,
if confirmed, could inspire new
ways to counter temozolomide
resistance, says Chin.
The other two genomics studies
appeared in Science on Sept. 26,
2008. Johns Hopkins university
researchers and their colleagues
scrutinized 20,661 genes in
about two dozen samples each
As scientists analyze many more tumor samples, the picture becomes easier to understand
of glioblastoma and pancreatic
cancers. They identified 748
mutations among the brain cancers
and 1,163 mutations among the
pancreatic cancers; each individual
tumor averaged about 60 genetic
alterations.
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Many of the problem genes
were not appreciated as cancer
contributors before, says oncology
researcher kenneth kinzler of the
Johns Hopkins kimmel Cancer
Center in baltimore. One gene, called
IDH1, was defective in 12 percent of
glioblastoma patients—suggesting
it is a promising drug target or a
marker for early detection.
Cancer appears to arise from
a few major genetic players that
are mutated in most tumors,
plus many minor players that are
less commonly mutated, kinzler
says. although that complex
picture seems daunting, it is still
preliminary. The genomics studies
do not tell if all the observed genetic
alterations actually foster cancer.
as scientists analyze many
more tumor samples, the picture
becomes easier to understand,
notes Meyerson, because “you see
a constant pattern of recurrence
of the same [genetic] events. That
makes it very clear that you’re not
Scientists hope
the mutations
found in
new genome
analyses will
lead to a better
understanding
of the causes
of brain and
pancreatic
cancers.
going to need a different approach
to treating every cancer.”
What’s more, mutations in most
pancreatic tumors potentially
disrupt genes within the same
12 core biochemical pathways in
the cell, the Hopkins team found.
and many TCGa brain cancers’
mutations clustered in three well-studied pathways. In such cases,
rather than developing a medicine
against each single culprit gene,
drug designers should target these
biochemical pathways, the Hopkins
scientists say.
yet Chin notes that core cancer
pathways are interconnected;
tweaking one process could trigger
responses in the others. Thus it
is crucial to first understand how
they all interact, she says.
TCGa and the Hopkins efforts
are producing valuable data,
according to Nelson. but they
only examine genes that code for
proteins—less than 2 percent of
the human genome. Scientists
should also investigate so-called
junk DNa, he says, because some
of it might regulate cancer genes.
“Without looking, we won’t know,”
says Nelson, whose lab has begun
such studies.
—Ingfei Chen
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