Genetic differences may explain why many Asian women who never smoked develop lung cancer

Analysis of three genetic mechanisms that cause non-small cell lung cancer might explain why East Asians respond better than other ethnic groups to a certain type of chemotherapy, a team led by UT Southwestern Medical Center researchers has found.

This type of analysis might become useful in tailoring cancer treatments to individual patients, the researchers said.

“Genetic differences may help explain why so many Asian women who never smoked develop lung cancer,” said Dr. Adi Gazdar, professor of pathology at UT Southwestern and senior author of a study appearing online in Public Library of Science Medicine .

The researchers focused on a protein called the epidermal growth factor receptor, or EGFR, which lies on a cell's surface and is involved in controlling many processes. Excessive amounts of EGFR are known to be involved in several types of cancer, including more than half of lung cancers. Several drugs that interfere with EGFR are used as chemotherapeutic agents.

Three inherited alterations, known as polymorphisms, in the gene that codes for EGFR can cause cells to make abnormally high levels of the protein, Dr. Gazdar said. One polymorphism shortens a portion of the gene, while two other abnormalities involve variations in the genetic “alphabet,” or sequences of chemical building blocks that make up the gene.

Increased levels of EGFR also can be caused by spontaneous mutations in the gene, or by an effect in tumor cells that increases the number of copies of genes coding for EGFR.

In the current study, the researchers compared the genes of 250 healthy people of various ethnicities with 556 samples of benign and cancerous lung tumors. They found that the three inherited polymorphisms were less common in healthy people from Japan and Taiwan than in healthy people of European, African or Mexican descent.

This suggests that this population normally makes less EGFR protein than people from other ethnic groups, Dr. Gazdar said.

This was true whether the East Asians lived in Asia or in the United States, indicating that it was an intrinsic genetic trait and not one that depended on diet or lifestyle, Dr. Gazdar said.

East Asians who had developed lung cancer, however, were more likely than those of other ethnicities to have the polymorphism that involved shortening part of the gene, an alteration that causes the amount of EGFR to increase.

East Asians with lung cancer also tended to have several effects occur on a single chromosome: the polymorphism that involves shortening of the gene, a spontaneous mutation that increases EGFR levels, and increased copies of the gene caused by the tumors, he said.

"They're all occurring together on a single chromosome, which results in a greatly increased amount of EGFR,” he said. “The predicted end result would be a great increase in EGFR protein production in the affected cells, driving them toward cancer.”

These findings might explain why East Asians are known to respond better than other ethnic groups to a type of chemotherapy that inhibits EGFR activity, Dr. Gazdar said.

“Cancer cells become addicted to EGFR,” he said, so these cells are much more susceptible to the cancer-killing effect of EGFR inhibitors.

This type of analysis of cancer genes might be helpful for other types of cancer and other ethnic groups, Dr. Gazdar said, possibly explaining both the different manifestations of the disease seen among ethnic groups and leading the way to matching a specific treatment to the patient.

Other UT Southwestern researchers involved in the study were Dr. Pila Estess, assistant professor of pathology; Dr. Mark Siegelman, associate professor of pathology; Dr. Jerry Shay, professor of cell biology; and Dr. John Minna, professor of internal medicine and director of the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and the W.A. “Tex” and Deborah Moncrief Jr. Center for Cancer Genetics.

Researchers from Fred Hutchinson Cancer Research Center in Seattle, Tokyo Medical University, the Center of Excellence in Aging in Chieti, Italy, and UT M.D. Anderson Cancer Center also participated, as did visiting researchers from Chiba University Medical School, Okayama University Medical School and Gifu University Medical School, all in Japan.

The work was supported by the National Cancer Institute.

http://www.utsouthwestern.edu/