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Search for Colon Cancer Genes Pays Off

By Edward R. Winstead

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Colon Cancer

Knowing that two successful cancer drugs work by inhibiting mutant enzymes, researchers recently screened an entire family of enzyme genes to see if any were mutated in tumor cells. Today they report success.

One of the genes was mutated in a third of the colon cancers they looked at and to a lesser extent in tumors of the brain, stomach, breast, and lung. The sheer number of mutations suggests that they played a role in the cancers.

“We’ve shown that this gene is one of the most highly mutated genes in human cancer,” says Victor E. Velculescu of the Sidney Kimmel Cancer Center at Johns Hopkins University in Baltimore, who led the study.

If recent history is a guide, the prospects are good that drugs can be made to control the mutant gene, which makes an enzyme called a lipid kinase. The enzyme and others like it can help cells proliferate and invade tissues.

“It’s easier to design a drug that inhibits an enzyme than a drug that does just about anything else,” Velculescu says. The cancer drugs Gleevec and Herceptin inhibit hyperactive kinases.

The gene, called PIK3CA, was discovered a decade ago, but no one had ever reported mutations until now.

In the new study, the researchers sequenced a set of 16 genes in 234 tumors and counted DNA mutations that were associated with cancer. Only the gene PIK3CA proved to be mutated.

Subsequent studies showed that the gene was mutated in 32 percent (74 out of 234) of colon tumors. The findings are reported today online in Science.

Most of the mutations occurred in two small regions of the gene, and that’s good news from a diagnostic perspective. These “hotspots” could be added to tests that identify cancerous mutations using DNA from stool samples. DNA tests provide less information than a colonoscopy but are not invasive.

“Colonoscopy is a great procedure, but very few people do it,” says Yardena Samuels, also of Johns Hopkins and a member of the research team. “So we’re always looking for non-invasive ways to find cancers that would otherwise go undetected.”

Samuels, Y. et al. High Frequency of Mutations of the PIK3CA Gene in Human Cancers. Science Published online March 11, 2004.

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