Closest look yet at lung cancer genes

A comprehensive analysis increases from 10 to 26 the number of genes linked with lung cancer, the leading cause of cancer deaths worldwide. The new study also identifies new cellular pathways that can trigger these malignancies.

“This study gives us insights that we didn’t have before,” says oncologist Ramaswamy Govindan of Washington University in St. Louis, who was not involved in the study. “Lung cancer is many different things cobbled together,” he says. “Now we’re able to untangle the different types.”

Researchers at Washington University, Baylor College of Medicine in Houston and the Broad Institute of MIT and Harvard in Cambridge, Mass., have been collaborating on the Tumor Sequencing Project. These scientists analyzed DNA sequences from tumors in 188 people with adenocarcinoma, the most common form of lung cancer. Because of this large sample size, researchers had the statistical power needed not only to find genes that are associated with this cancer, but also to compare the particular groupings of gene mutations present in the tumors. The findings appear in the Oct. 23 Nature.

The data offer yet another reason not to smoke: Tumors from nonsmokers exhibited a maximum of four mutations; the max in smokers’ tumors was 49. “This clearly shows that cigarette smoking induces mutations,” says Li Ding of Washington University, a coauthor of the new study.

It’s well known that cigarettes are the leading cause of lung cancer. Yet about 10 percent of lung cancers occur in people who never smoked. When researchers in the new study compared the types of genes that underwent mutations, they found that some genes were mutated primarily in nonsmokers, while other genes were more likely to be mutated in smokers.

What triggers tumors is very different in smokers and nonsmokers, concludes Govindan.

Moreover, not all suspect genes turned out to be big players.

Two genes that affect tumor growth, KRAS and TP53, did turn out to be instrumental. These genes were mutated in more than 30 percent of the tumors in this new genetic snapshot of a broad population of lung-cancer patients. Yet coauthor David Wheeler from Baylor notes that some genes implicated in cancer formation, like PTEN, were seldom mutated.

Just because a mutation can cause cancer doesn’t mean it actually does, Wheeler points out. Because this study provided a glimpse of actual tumors in a population, it could pinpoint the relative abundance of particular mutations.

The new study also identified genetic networks within cells that are critical to keeping them from turning cancerous. Ding said her team found that “most mutations are clustered in a few key signaling pathways.” Researchers already knew that some of these pathways were involved in lung cancer formation, but other pathways, like a network of genes known to regulate human development, were a surprise.

“This study unearthed novel mutations that force us to think about specific treatments,” says Govindan. He points to the example of the gene EGFR, which is mutated in some adenocarcinomas. Patients with this gene mutation respond very well to treatments with a specific drug. It’s becoming clear, he says, that for effective treatment, “The key is to mold these drugs to the type of cancer.”

Newly identified mutations in both individual genes and large genetic pathways are potential drug targets. As a result, Ding predicts, more pathway-based treatments “will emerge quickly” from studies like these.