Researchers have identified
a rogue form of a normal gene that may increase the risk of cancer when
it acts in
combination with subtle variants of other genes.
The new find suggests
that small changes in chemical sequences of human DNA -- the master molecule
-- may interact to reduce people's resistance to cancer-causing environmental factors such as radiation, smoking
and many chemical carcinogens, the scientists say.
Although new tests for cancer risks or new
treatments are still far away, the discovery opens a promising new
door for researchers seeking to understand some of the most difficult and widespread forms of cancer.
Led by Dr. Allan Balmain
of UC San Francisco's Comprehensive Cancer Center, an international team
scientists identified a variant of a gene known as Aurora2, which normally produces an enzyme that regulates cell
The abnormal variant can increase the likelihood
of uncontrolled replication, leading to a malignant tumor, when it
occurs in combination with as many as 30 variants of other genes. Balmain and his colleagues are looking to
identify those other rogue genes, too, using tools developed for the Human Genome Project to speed progress.
Discovery of the variant gene stems from collaborative
work by cancer research teams in seven institutions in
America, Britain and the Netherlands. Details appear in the current issue of the journal Nature Genetics.
Only a few genes are
known that can act alone to sharply increase the likelihood of cancer in
humans. Two of
them -- discovered less than 10 years ago and known as BRCA1 and BRCA2 -- are now widely used as
markers in testing women for susceptibility to hereditary breast cancer when they have a family history of the
Such genes account for no more than 5 to 10
percent of all cancers, according to Balmain and his colleagues. The
vast majority of cancers are "multifactorial," resulting from several genetic and environmental factors acting in
According to Balmain, the
newly identified variant of the Aurora2 gene may not be dangerous by itself,
but when it
is inherited along with abnormal variants of other genes, the combination can lead to trouble: the lungs of smokers
who might not otherwise develop malignant tumors, for example, become much more susceptible to the
carcinogens in smoke.
Probing combinations of variant genes, Balmain
said in an interview, "is like picking out the components of a lock
or the tiny parts of a watch. We're trying to identify the components and the parts because it's the combination of
those gene variants that make a difference in susceptibility."
It's a complex and difficult
task that would not be possible without the gene-finding technologies developed
part of the Human Genome Project. Begun in 1989 and virtually completed this year, the project's goal has been
to determine the precise sequence of chemical bases in the roughly 30,000 genes that spell out all the proteins in
the body and govern all of human heredity.
In their new experiments, the cancer researchers
first examined mice bred to be genetically susceptible to cancer,
and those mice were then bred with mice that were highly resistant to cancer-causing chemicals.
Then, they hunted through the genes of the
offspring from those parents, seeking any specific genes that might
influence their susceptibility. The high- speed computers and other analytical tools of the Human Genome Project
made sequencing the short stretches of DNA that define all genes much faster, and those tools vastly speeded the
work of Balmain and his gene-hunting colleagues.
Their search revealed the first variant Aurora2
gene. The scientists then found the same gene in tumors from
human colon cancers. Now, the hunt for more susceptibility genes, acting together with networks of other genes,
should be much easier, they say.
Colon, breast and
skin cancers are among the types of malignancy that may be at least partly
induced by these
combinations of variant genes, according to Balmain, and pharmaceutical companies could now begin seeking
drugs to inhibit their activity.
©2003 San Francisco Chronicle