Inflammation Appears to Be Linked to Lung Cancer

ROCKVILLE, Md., July 5 -- Some patients may be at greater risk of lung cancer because of variations in genes involved in inflammatory responses, researchers here said.

The finding may help explain how smoking tobacco -- a major environmental risk factor for lung cancer -- actually leads to the disease, according to a report published in the July 1 issue of Cancer Research.

Variations in the genes for interleukin 1-beta, interleukin 1-alpha, granulocyte macrophage colony stimulating factor, and peroxisome proliferator-activated factor-delta were associated with an increased risk of lung cancer, said Eric Engels, M.D., of the National Cancer Institute, and colleagues at M.D. Anderson Cancer Center in Houston.

Their findings come from a case-control study involving 3,283 volunteers -- including 1,553 with lung cancer.

The researchers studied a panel of 59 single nucleotide polymorphisms (or SNPs) in 37 genes involved in the inflammation pathway and found five that were significantly linked to lung cancer.

But of the five, only a mutation in the gene for interleukin 1-beta -- dubbed C3954T -- was deemed highly likely to be a true risk factor, the researchers said.

As part of their statistical analysis, Dr. Engels and colleagues calculated both significance and false positive report probabilities.

While all of the associations found were significant -- although the significance was borderline in the case of granulocyte macrophage colony stimulating factor -- only the C3954T variation had a low false positive report probability (of 0.148).

The C3954T variation was associated with a 27% increase in the risk of lung cancer, the researchers found. The odds ratio was 1.27, with a 95% confidence interval from 1.10 to 1.47, which was significant at P=0.001.

Moreover, when the analysis was restricted to heavy smokers among the cases and controls, the odds ratio became 1.59 (with a 95% confidence interval from 1.28 to 1.97), which was significant at P=0.00002 and had a false positive report probability of 0.004.

Two variations on the gene for interleukin 1-alpha were also significantly associated with risk increases of 18% and 22%, but the false positive report probabilities were higher.

"Our findings help explain how heavy smoking, for example, combines with a genetic predisposition to create a besieged environment within the lungs," Dr. Engels said. "Essentially, sustained inflammation alters the microenvironment of the lung tissue, damaging cells and altering DNA."

Interestingly, the interleukin 1-beta mutation C3954T does not cause a change in the amino acid structure of the protein, the researchers said, but it may affect levels of gene transcription or translation.

To test the effect of some of the variations in combination, the researchers also analyzed so-called haplotypes of the SNPs on the genes for both interleukin proteins.

Only one haplotype -- containing the C3954T mutation but the wild-type form of the other genes -- was significantly associated with an increased risk of cancer. The odds ratio was 1.80 with a 95% confidence interval from 1.25 to 2.59.

Since the mutation actually makes no change, one explanation for the increased risk, the researcher said, might be that the C3954T mutation is linked with another mutation that increases risk but was unmeasured in this study.

The study's strengths include its large size and the large number of genetic variations that could be analyzed. The large number of polymorphisms, however, is also a weakness, since it increases the possibility that chance will be responsible for some associations.

"A better understanding of the risks involving inflammation will lead to a better understanding of cancer prevention," Dr. Engels said.