Exposure to smoke yields fetal mutations.

Cancer can take years to develop, in large part because many steps must occur for a tumor to arise. Typically, some environmental factor causes a gene to mutate, leading to other genetic irregularities, which in the worst-case scenario result in uncontrolled cell growth. For the disease to strike a young child, this sequence of events must start very early in development, perhaps in the womb.

Some studies have associated pregnant mothers' exposure to tobacco smoke with the incidence of childhood cases of leukemia and lymphoma. A new study of blood taken from the umbilical cords of newborns now may provide a biological basis for such a link--even in a mother who doesn't smoke but lives or works with someone who does.

The results, reported in the October Nature Medicine, are the first to demonstrate smoke-induced genetic mutations in the womb. Infants born to nonsmoking mothers who were exposed to secondary cigarette smoke during pregnancy had more cancer-related mutations in a gene called HPRT than did newborns of unexposed mothers, says study coauthor Barry A. Finette, a pediatrician at the University of Vermont College of Medicine in Burlington.

Finette and his colleagues have shown that "the DNA mechanism of repair is damaged in these kids," says Steven R. Myers, a toxicologist at the University of Louisville (Ky.) School of Medicine. "This is a very good piece of work."

The gene HPRT is named for the enzyme it encodes, hypoxanthine-guanine phosphoribosyltransferase. This gene is an excellent indicator of mutations that can arise in a cell when outside influences--in this case, chemicals derived from tobacco smoke in the mother--apparently cause the DNA chain to break and reform haphazardly, Finette says. In particular, certain HPRT mutations point to misguided action by a combination of enzymes called V(D)J recombinase, or V(D)J.

"V(D)J recombinase is a critical enzyme system for rearranging DNA," Finette says. "It cuts DNA, removes pieces, and puts the other [strand] ends together."

This enzyme cluster is essential to the immune system. As children grow, they encounter viruses, bacteria, and foreign substances, and V(D)J is instrumental in reshaping DNA to encode immune system compounds that fend off the potential invaders. A recognizable type of HPRT mutation tips off scientists that this vital V(D)J activity has been disrupted.

Previous research uncovered evidence of V(D)J running amok in childhood leukemia and lymphoma. Because pediatric tumors occur early, the genetic changes associated with them may start in the womb with disruption of V(D)J activity, Finette and his colleagues suspect.

Searching for evidence of V(D)J irregularities, the investigators studied umbilical cord blood taken from 24 newborns, half of whose nonsmoking mothers were exposed to smoke during pregnancy. In the babies of the exposed mothers, they found a wide variety of mutations, including deletions of parts of the DNA chain that contain the HPRT gene. In these babies, 18 of 35 mutations analyzed were of the deletion variety. Of these, 12 were the result of V(D)J rearrangements of the HPRT gene. Of 30 mutations in the nonexposed infants, 20 were deletion mutations but only 6 were caused by V(D)J.

Researchers are now striving to determine how the body makes V(D)J. They hope to clarify its mechanism of action and why it can act on the wrong genes.

"If [the HPRT finding] is confirmed, this will add to the credibility of the epidemiological findings linking prebirth exposure to carcinogens with childhood leukemia," says Sholom Wacholder of the National Cancer Institute in Bethesda, Md. He says that future research will require more information detailing where mothers encountered the smoke and in what amounts.