ATLANTA - When it is quiet - "almost too quiet" - in movies, it is a sign that something is about to go wrong for the good guys. This holds true for the genes that protect against lung cancer, as researchers at the University of Toledo in Toledo, Ohio, have learned. They identified a panel of 15 genes that could serve to predict cancer; if enough of their collective activity becomes quiet - almost too quiet -- it could mean they are being suppressed by other factors in the cell, a step that may lead to cancer.
According to lead researcher, James C. Willey, M.D., a test for these genes, in normal cells sampled via bronchoscopy, could serve as a technique to identify those individuals genetically at risk for lung cancer. In a study of 49 subjects, Dr. Willey and his colleagues were able to correctly identify the individuals with cancer 96 percent of the time. Dr. Willey presents the team's findings today in Atlanta, Georgia at the American Association for Cancer Research's second International Conference on Molecular Diagnostics in Cancer Therapeutic Development.
"Smoking causes about 90 percent of all lung cancer cases, yet only about 10 to 15 percent of heavy smokers will develop lung cancer," said Dr. Willey, an associate professor of medicine and molecular biology at the University of Toledo's College of Medicine. "We are looking for new techniques that will allow us to pick out the 10 to 15 percent of individuals at highest risk for lung cancer from the enormous pool of current and former smokers."
While advances in screening tools like high resolution coaxial tomography (HRCT) enable increasingly effective early detection of lung cancer, scanning all present or former heavy smokers is problematic and costly when, due to genetic makeup, 85 to 90 percent of them are at low risk despite smoking history, Dr. Willey said. Therefore, Willey believes that a screen to identify the 10 to 15 percent of high risk individuals should increase the accuracy of further HRCT screening. "In America alone, there are more than 40 million present or former heavy smoking individuals," Dr. Willey said.
To determine which genes are active in lung cancer, Dr. Willey and his colleagues look for levels of messenger RNA transcripts -- instructions copied from DNA that direct cells to create specific proteins. Previously, the researchers had published findings demonstrating that genes responsible for protecting lung cells from damage caused by cigarette smoke or environmental toxins are sub-optimally regulated in the normal lung cells of individuals who develop lung cancer. In this study, Dr. Willey and his colleagues put their theories to the clinical test by measuring transcript abundance (TA) of 15 genes that encode protective antioxidant and DNA repair proteins in lung airway cells taken from 25 people with lung cancer and 24 people without the disease.
Their previous research allowed them to determine the threshold levels of TA for each gene - the point at which the amount of mRNA transcripts would indicate a tendency toward cancer. In this study, they used the threshold levels as a basis to assign a value of one or zero to each of the targeted genes for an individual subject, with "zero" indicating normal TA.
If the sum total of a subject's target genes was greater than or equal to seven, the genes could collectively serve as a biomarker for lung cancer, the researchers found. Their results yielded one false negative and seven false positives among the 49 individuals assessed. According to Dr. Willey, they believe that a positive result in a subject without lung cancer may not actually be false positive, but rather could mean that the person is at an increased risk for lung cancer, which might arise later.
These results justify a larger, prospective study to determine whether this biomarker will be useful in predicting risk for lung cancer in current and former smokers. "Overall, the study showed a high degree of accuracy for picking out lung cancer patients," said Dr. Willey.
This study was funded by the National Cancer Institute. University of Toledo graduate students Thomas Blomquist, Erin Crawford, Younsook Yoon, Jeffrey Hammersley, Dawn-Alita Hernandez, Jamey Ruiz, Mohammed Al-Baghdadi, D'Anna Mullins, and Sadik Khuder all contributed to this study.
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.