Gene Variant Tied to Increased Susceptibility to Cancer
     Researchers find other factors are also part of equation
     David Perlman
     Wednesday, August 6, 2003
     ©2003 San Francisco Chronicle

     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 of heredity
     -- 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 of
     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 as
     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