Why Me Doc? A Polymorphism in an Antioxidant Enzyme Leads to Greater Lung Cancer Risks

David Christiani
Harvard School of Public Health
R01ES06409

Background: Dietary antioxidants and over-the-counter supplements have become very popular cancer prevention treatments in the United States in the last decade. The theory behind their use is that accumulation of reactive oxygen species can damage DNA, proteins, and lipids leading to the initiation or promotion of cancer. In mitochondria, the major site of cellular metabolism and production of reactive oxygen species, antioxidant defense is very important. The enzyme manganese superoxide dismutase (MnSOD) is the only known superoxide scavenger in mitochondria, and is thus a critical defense mechanism. Any alterations in the structure of MnSOD or the gene encoding for it may have major implications on its function.

Advance: These investigators have discovered a single nucleotide polymorphism in the MnSOD gene. This difference substitutes the amino acid valine (Val) for alanine (Ala) at position 16 of the protein. The Val allele causes MnSOD to be transported less efficiently into the mitochondria. Therefore the scientists hypothesized that individuals that produce this version of the enzyme would be more susceptible to lung cancer because of a more rapid accumulation of reactive oxygen species. Their analysis supported this hypothesis in that heterozygotes (people with one copy each of the Val and Ala alleles) were at 34% greater risk for lung cancer. The risk for lung cancer in homozygotes (people with two copies of the Val allele) was almost exactly double that at 67%.

Implication: The increased risks were statistically significant as was the gene-dose response effect. The discovery of the importance of this genetic difference adds to the growing body of evidence on why some people get lung cancer and others with nearly identical exposures and lifestyles do not. The environmental exposure that triggers the impact of the genetic difference is still a key component of this equation. Further studies may show that screening for the Val allele of MnSOD may be an effective tool for counseling people to avoid certain environmental exposures that could cause the development of lung cancer. Avoiding these exposures may prevent the cancer from occurring regardless of the individuals genetic risk.

Citation: Wang LI, Miller DP, Sai Y, Liu G, Su L, Wain JC, Lynch TJ, Christiani DC. Manganese superoxide dismutase alanine-to-valine polymorphism at codon 16 and lung cancer risk. J Natl Cancer Inst. 2001 Dec 5;93(23):1818-21.