Faulty cell cycle "checkpoints" that fail to respond to DNA damage effectively may contribute to the high incidence of lung cancer in African-Americans, say researchers at Georgetown University's Lombardi Comprehensive Cancer Center and the National Cancer Institute (NCI).

Their study, reported in the October 15 issue of Cancer Research, is the first epidemiological study to show the association of lung cancer risk in African-Americans and efficiency of the critical "G2/M checkpoint." While the researchers report that this checkpoint was generally less effective in the group of African-American lung cancer patients they studied, they found this risk to be especially high in African-American women and nearly a five-fold increase in lung cancer risk in women with faulty G2-M checkpoint compared to women with efficient G2-M checkpoint. The study did not found any association of this checkpoint with lung cancer risk in whites.

"Although the study has limitations, our findings suggest one possible explanation for the higher incidence of lung cancer in African Americans, who as a group smoke less than whites, yet still develop more lung cancer at comparatively younger ages," said the study's lead author, Yun-Ling Zheng, M.D., Ph.D., an assistant professor in the Department of Oncology at the Lombardi Comprehensive Cancer Center.

"Epidemiologists have long known that cancers are expressed at varying rates in different racial groups, but we are only now able to use advanced research techniques to look at the molecular reasons for these disparities," Zheng said. "The value of such research is that it can provide new tools for risk calculation."

According to a 2002 report by the Surveillance, Epidemiology, and End Results (SEER), the incidence of lung cancer in African-American men was 42 percent higher compared with the incidence in white men, and the risk of lung cancer for African-American women was 13 percent higher.

Cell cycle checkpoints are mechanisms that regulate progression through the cell cycle of growth and division, ensuring that each step takes place only once and in the right sequence. This study looked at the G2/M checkpoint, a specific point in the cell cycle that determines if the cell should temporarily halt its march toward division, allowing more time for the damage to be repaired.

This checkpoint can be activated if a cell's genetic material is damaged or if mistakes were made when DNA was replicated. A less efficient checkpoint, however, would not catch and repair all DNA abnormalities, which could lead to genetic instability and the development of cancer, Zheng said.

To conduct the study, Zheng and her colleagues at the National Cancer Institute collected information as well as blood samples from 216 patients with lung cancer and from 340 cancer-free control participants from the Baltimore, Maryland area.

They then cultured the white blood cells, exposed them to gamma radiation, which inflicts genetic damage, and then they evaluated the cell cycle checkpoint. After adjusting for age, gender and a patient's history of smoking, the researchers found that a lower level of radiation-induced G2/M arrest was associated with an increased risk of lung cancer among African-Americans.

The senior author of the study was Curtis C. Harris, M.D., of the Laboratory of Human Carcinogenesis, at the NCI, which also funded the research. Other co-authors include Zhipeng Yu, B.S., of the NCI; Christopher Loffredo, Ph.D. and Peter Shields, M.D., of Georgetown University Medical Center; Anthony Alberg, Ph.D., and Rex Yung, M.D., of Johns Hopkins Medical Institutions; and Raymond Jones, Ph.D., Donna Perlmutter M.S., and Mark Krasna, M.D., of the University of Maryland School of Medicine.

The Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and Georgetown University Hospital, seeks to improve the diagnosis, treatment and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Lombardi is one of only 39 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington DC area. For more information, go to lombardi.georgetown.edu

Laura Cavender
lsc6georgetown.edu
Georgetown University Medical Center
gumc.georgetown.edu