October 27, 2008

Large-Scale Genetic Study Sheds Light on Lung Cancer

Illustration of human lungs

In the largest effort of its kind, scientists have charted the genetic changes involved in the most common form of lung cancer, implicating more than a dozen new genes. The findings should help pave the way for more individualized approaches for detection and treatment.

Lung cancer is the leading cause of cancer deaths both in the United States and throughout the world. The most frequently diagnosed form of lung cancer is lung adenocarcinoma, which is extremely difficult to treat. The vast majority of patients die within 5 years of diagnosis, although earlier detection can prolong survival.

Like most cancers, lung adenocarcinoma arises from changes that accumulate in DNA over the course of a person's life. However, little is known about the precise nature of these DNA changes and how they disrupt biological pathways to trigger the uncontrolled cell growth of cancer. To gain a more complete picture, NIH's National Human Genome Research Institute (NHGRI) launched a multi-institution collaboration called the Tumor Sequencing Project consortium.

In the consortium's latest study, published in the October 23, 2008, issue of Nature, the researchers analyzed both tumor samples and noncancerous tissues donated by 188 patients with lung adenocarcinoma. The scientists sequenced the DNA to look for mutations in more than 600 genes with known or potential relationships to cancer.

Prior to the study, fewer than a dozen genes had been implicated in lung adenocarcinoma. The new study identified 26 genes that are mutated in a significant number of samples, more than doubling the number of known genes linked to this deadly disease. Several of the genes had already been associated with other types of cancers—including leukemia, colon cancer and cancer of the retina—suggesting they may contribute to multiple forms of cancer.

The team also analyzed these genetic glitches to see which biological pathways are most crucial to lung adenocarcinoma. More than two-thirds of the 188 tumors studied had at least 1 gene mutation affecting the mitogen-activated protein kinase (MAPK) pathway, indicating that it plays a pivotal role in lung cancer. New treatment strategies for some subtypes of lung adenocarcinoma might target this pathway. Many of the genes also code for cell receptors coupled to members of the tyrosine kinase family of enzymes, which are considered prime targets for new cancer therapies.

These findings suggest that certain lung cancer patients might benefit from chemotherapy drugs currently used to treat other types of cancer. For example, chemotherapy drugs known to inhibit the kinase insert domain receptor (KDR), such as sorafenib and sunitinib, might be tested in the relatively small percentage of lung adenocarcinoma patients whose tumors have mutations that activate the KDR gene.

“Our findings underscore the value of systematic, large-scale studies for exploring cancer,” said Dr. Richard K. Wilson, Director of the Genome Sequencing Center at Washington University School of Medicine, St. Louis, and a senior author of the paper. “We now must move forward to apply this approach to even larger groups of samples and a wider range of cancers.”

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