NYU School of Medicine researchers report that a chemical in cigarette smoke causes mutations in a gene called RAS that are commonly associated with many human cancers, according to a new study. The study provides a direct molecular link between smoking a

This is the second report by Dr. Tang directly linking a chemical in cigarette smoke to mutations in a crucial gene associated with cancer. In 1996, he published a study in the journal Science showing that a carcinogen found in cigarette smoke caused mutations in a gene called P53. The new study is published in the October 16 issue of the Journal of the National Cancer Institute. "With this new study, we are now providing concrete proof that smoking causes lung cancer," says Dr. Tang. RAS is a family of genes that have many biological functions, but mainly control cell growth and development. Mutations in a RAS gene can lead to uncontrolled cell growth, and more than 30 percent of lung cancers, 90 percent of pancreatic cancers, and 50 percent of colon cancers are associated with mutations at a specific site in the gene K-RAS. Scientists, however, didn't know why these mutations were occurring at this particular site in the gene. The new study provides an answer to this longstanding question by using a mapping technique that Dr. Tang pioneered. The technique pinpoints the exact sites on DNA where damage occurs due to environmental carcinogens. Dr. Tang and colleagues from NYU and M.D. Anderson Cancer Center, in Houston, introduced the carcinogen benzo(a)pyrene diol expoxide (BPDE), a known cancer-causing chemical in cigarette smoke, to normal human lung epithelial cells and fibroblasts, another type of cell. Then they observed the effects of the chemical using their mapping technique. They found that the carcinogen preferentially bound to the K-RAS gene at a mutational hot-spot called codon 12, an area especially vulnerable to mutation. Moreover, the researchers found that this site was not able to repair itself very well. The chemical did not bind significantly to other members of the RAS gene family. Genes comprise codons, sequences of three chemicals that spell out the code for amino acids, the building blocks of proteins. The mapping technique relies in part on special enzymes that cut DNA where it has been damaged by the binding of a carcinogen, which is technically called a DNA adduct. Adducts cause mutations in codons. Dr. Tang says that the study's findings provide further proof that smoking does cause lung cancer because the carcinogen bound most strongly to the precise site in the K-RAS gene that is frequently mutated in lung cancer. Using the same mapping technique, he says it may be possible to discover the environmental agent or agents that are causing the gene to mutate in pancreatic cancer, which is far more commonly associated with a codon 12 mutation than is lung cancer. "If we could identify the agents that are causing the mutations, then we might be able to design effective measures to prevent this type of cancer," says Dr. Tang. In the future, Dr. Tang hopes to identify the mechanisms that make the codon in the K-RAS gene more susceptible to damage. He also plans to explore the possibility that there may be individual differences in susceptibility to damage at this site, meaning that some people may be more prone to certain types of cancer. In an editorial accompanying the study in the same issue of the Journal of the National Cancer Institute, researchers Michael J. Kelley and Susan J. Littman of Duke University Medical Center, Durham, NC, write: "…[U]nderstanding the biologic basis for frequent mutations at codon 12 of K-ras in carcinomas may identify subtle but clinically significant differences in biochemical signaling pathways that can potentially be therapeutically targeted."

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