By zeroing in on aberrations in two cancer-fighting genes, researchers have found a marker of cancer risk that could help doctors screen people for signs of lung cancer early enough for treatment to be effective.
Lung cancer will kill roughly 159,000 people in the United States this year, making it the deadliest malignancy. About 85 percent of patients are diagnosed too late for surgery, and they generally survive only 6 to 15 months. But when physicians catch the disease while it's still confined to the lung and nearby lymph nodes, surgery and other treatments give 60 to 80 percent of patients at least 5 more years to live.
To ascertain whether having the gene aberrations corresponds to lung cancer risk, researchers examined sputum samples taken in the 1970s from 21 people with squamous-cell cancer, some before and some after they were diagnosed. All these participants in a cancer-surveillance study had been smokers, and most had been exposed to radon gas at a work site.
All 21 turned out to have an anomaly called hypermethylation affecting at least one of two genes that encode cancer-suppressing proteins called p16 and MGMT, says study coauthor Steven A. Belinsky, a molecular biologist at the Lovelace Respiratory Research Institute in Albuquerque. Ten of these patients had hypermethylation affecting both genes, he and his colleagues report in the Nov. 1 Cancer Research.
In contrast, among another 123 smokers, who didn't have lung cancer when surveyed in the 1970s, only one-fourth showed the aberration in one of the genes, and only 3 percent had it in both, Belinsky says.
Squamous-cell cancer accounts for only about one-fourth of lung cancers. Still, "this study is encouraging," says Melvyn S. Tockman, a molecular epidemiologist at the Moffitt Cancer Center and the University of South Florida in Tampa. It establishes that hypermethylation is prevalent in some lung cancer patients and is prominent enough in sputum to be a marker of disease, he says.
In hypermethylation, a methyl molecule binds to DNA where it doesn't belong. When hypermethylation strikes the regions of DNA that normally turn on the genes for p16 and MGMT, it can silence them, Belinsky says, so neither cancer suppressor is made.
Although the cause of hypermethylation is unknown, its detection could provide physicians with a sign that cancer is present or imminent. In 11 of the 21 cancer patients, the sputum was collected 5 to 35 months before a physician diagnosed the patient's cancer, suggesting the test can indicate who's developing cancer.
"I think there is a good chance this test will be used to test high-risk people," says Adi F. Gazdar, a pathologist at the University of Texas–Southwestern Medical Center in Dallas. Anyone who has smoked a pack a day for 30 years or more would be a candidate for screening, he says.
The sputum test examines cells that had been shed from the inner lining of lung passages. Tockman says that it could well complement the helical CT scan, a procedure that is being developed to detect very small lesions in other parts of the lung.
Steven A. Belinsky
Lovelace Respiratory Research Institute
Lung Cancer Program
Albuquerque, NM 87185
Adi F. Gazdar
Building N B-206
6000 Harry Hines Boulevard
University of Texas Southwestern Medical Center
Dallas, TX 75390-8593
Melvyn S. Tockman
Moffitt Cancer Center
12902 Magnolia Drive
Tampa, FL 33612
Belinsky, S.A., et al. 1998. Aberrant methylation of p16INK4a is an early event in lung cancer and a potential biomarker for early diagnosis. Proceedings of the National Academy of Sciences 95(Sep. 29):11891-11896. Available at [Go to].
Esteller, M., et al. 1999. Inactivation of the DNA repair gene O6-methylguaine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasma. Cancer Research 59(Feb. 15):793-797. Available at [Go to].
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