Lung cancer patients whose tumor cells contain a certain mutation in a key gene are much more likely to succumb rapidly to their disease than are patients whose lung cancer cells do not have the mutation, according to a new study by Dutch researchers.
Lung cancer is the most common fatal cancer in both men and women, and is expected to kill 142,000 Americans this year. Only 13 percent of patients diagnosed with the disease are alive five years later. The discovery of a genetic mutation that apparently makes some lung tumors more aggressive could eventually help doctors give patients a more realistic prognosis and may help researchers to understand the biology of the disease and to devise more effective treatments.
The mutation studied by the Dutch scientists is present in up to one-third of cases of adenocarcinoma, a tumor that accounts for about 35 percent of all lung cancers. It causes a defect in a gene called the K-ras oncogene, which carries information directing the cell to make a protein that helps cells respond to chemical signals regulating their growth.
Oncogenes, when in their non-mutated form, are important for the normal growth and development of all human cells, and mutations in these regulatory genes have been implicated in a variety of cancers. Mutations in the K-ras oncogene are also found in 90 percent of pancreatic cancers and in about half of all colon cancers and thyroid cancers.
In the study, published in today's issue of the New England Journal of Medicine, researchers at the Netherlands Cancer Institute, the Free University of Amsterdam and two other institutions tested tumor specimens from 69 patients with adenocarcinoma of the lung. All of the patients had tumors that were surgically removed, and all were considered potentially cured at the time of surgery because there was no evidence that the cancer had spread to other organs.
The researchers used a technique called the polymerase chain reaction, or PCR, to increase the amount of DNA obtained from each specimen. Then they used artificially synthesized pieces of DNA called probes to find cells whose genes contained a mutation at a specific site on the K-ras oncogene.
DNA is a chainlike molecule, with the chain's links composed of chemicals called nucleotides that are arranged in a sequence. The sequence of a gene gives the cell the information it needs to make a protein, another chainlike molecule whose links are chemicals called amino acids.
The K-ras mutation causes a change in the sequence of three nucleotides that specify the 12th amino acid, glycine, in the regulatory protein produced by the gene. Cells containing this mutation manufacture a protein that contains the wrong amino acid at this position, spoiling the shape of the resulting protein so that it cannot exercise proper control of the cell's growth.
The tumors of 19 of the 69 patients contained the mutation. By the time the study ended, after patients had been followed for an average of three years, 12 of these 19 patients, or 63 percent, had suffered a relapse of their cancer and had died. Of the 50 patients whose tumors did not contain the mutation, 22, or 44 percent, had suffered a recurrence of their cancer, and 16, or 32 percent of those without the mutation, had died.
For patients in the study, the presence or absence of the mutation turned out to be a much better predictor of whether a cancer will recur than did the tumor's size, the presence of spread to lymph nodes, or factors such as the patient's age, sex or history of smoking.