Researchers Identify 26 Genes Responsible for Lung Cancer

Each year, lung cancer kills more than 1 million people worldwide, including more than 160,000 people in the United States. Adenocarcinoma is the most frequently diagnosed form of lung cancer, accounting for 30 to 35 percent of all cases. This cancer can only be cured when surgery or radiation therapy can completely remove the tumor, but many lung cancers are diagnosed at a stage when this is not possible. Only about 17 percent of people with adenocarcinoma survive more than 5 years after diagnosis. However, the discovery of over two dozen genes associated with this type of cancer could help guide researchers in developing individualized therapies to fight the disease.

In the largest federally funded project of its kind, scientists at a dozen institutions in the United States and Germany determined the DNA sequence of 623 genes in 188 adenocarcinoma tumor samples. Then they compared the DNA sequence to the same genes in healthy tissue from the same patients, looking for genes that were most often mutated. These changes occur in the tumor and are not inherited or found elsewhere in the body, Dr. Matthew Meyerson, from the Broad Institute of MIT and Harvard and an associate professor at the Dana-Farber Cancer Institute in Boston, explained during a teleconference.

Across all the samples, the researchers found 1,000 different mutations, but found 26 genes that were most frequently mutated, most of which had never been linked with lung cancer. Some of these genes have been implicated in other cancers, such as colon cancer, leukemia and lymphoma. This discovery more than doubles the number of genes known to play a role in adenocarcinoma. Before the new research, 10 genes linked to the disease had been identified, including six of the 26 reported in this study.

Many of the mutated genes also share common biological pathways or gene networks. More than 70 percent of the tumors carried a gene affecting the mitogen-activated protein kinase or MAPK pathway. A group of compounds called MEK inhibitors that affect this pathway have already shown promise in mice with colon cancer. Nearly one-third of the tumors affected the mTOR pathway. This raises hopes of an existing drug, Rapamycin, which is already approved for use in organ transplants and kidney cancer. Another mTor inhibitor for kidney cancer, Afinitor, is currently under review by U.S. regulators. And about half of the tumors had defects in the p53 pathway, which is crucial for suppressing tumor growth. Introgen Therapeutics Inc. and other companies are currently working on drugs that affect this pathway.

The researchers also looked at the differences between gene mutations found in smokers or former smokers—who make up 90 percent of lung cancer patients—and those in non-smokers. They found that tumors for smokers had as many as 49 mutations, while none of the non-smokers had more than five mutations. “Our study could achieve a real impact on the care of lung cancer patients,” Dr. Meyerson said. “It is important to study the role of the mutated genes in the growth and survival of lung cancer cells, which will help us work toward new treatments.”

The research, known as the Tumor Sequencing Project, has important implications for the understanding, diagnosis and treatment of lung cancer, co-author Richard Wilson, director of Washington University’s Genome Sequencing Center in St. Louis, Missouri, said. “Although similar, smaller cancer gene sequencing projects have been reported, our study is the largest to date and provides the statistical power to detect significantly mutated genes.” Wilson added that this study is “just a beginning” and that “over the next few years, we expect to extend this study both in terms of the number of individual cases that we study and the extent of the cancer genome we can explore.”

Dr. Norman H. Edelman, chief medical officer of the American Lung Association, called the research another positive step in understanding cancer. “The methods of this study are powerful, and the sample is large, thus it is a good study. We can expect more of this,” he said. “The genetic basis of cancer is very complex and this represents another piece of the puzzle. Whether or not finding newly implicated genes will lead to new therapies, as the authors suggest, is, of course, something to be hoped and waited for.”

The study findings were published in the October 23 issue of Nature.