Now researchers are on the verge of answers. Pioneers in a new field called ecogenetics, or molecular epidemiology, are cutting through the exasperating statistics to find genes and biological markers that reveal who is most likely to succumb to cigarettes, workplace carcinogens, fatty food or other poisons. The work follows geneticists’ success in linking single-gene defects to more than 440 human ills, including Tay-Sachs disease, cystic fibrosis and Duchenne’s muscular dystrophy. The difference between these unambiguously genetic diseases and, say cancer is that up to 80 percent of all malignancies arise not strictly from genes but also from the environment: food we eat and smoke we inhale, air we breathe, water we drink and viruses we encounter. Such cancers are, in theory, preventable. “There is cautious optimism that we can do much, much better at preventing at least 80 percent of human cancers” by identifying individuals who bear the real risks, says Frederica Perera of Columbia University.
Lethal alchemy: That won’t happen overnight, but it’s coming. Last week in Washington, at the 8th International Congress of Human Genetics, researchers from the University of Cincinnati Medical Center announced that they had discovered two human genes that may explain why only some heavy smokers get lung cancer-and predict who will fall into the deadly 7 percent. One clue came from the finding that the blood of some smokers harbors extremely toxic carcinogens (diagram). But the blood of all smokers harbors “procarcinogens,” chemicals in cigarette smoke that, when altered in some way, turns deadly. An enzyme works the lethal alchemy. Researchers led by Daniel Nebert of Cincinnati traced the enzyme to genes on chromosome 10 (humans have 23 pairs of chromosomes, or long chains of genes). Perhaps it is no coincidence that the gene is present in about 10 percent of Caucasians-approximately the percentage of smokers who get lung cancer.
Such findings stand the conventional view of cancer on its head. Textbooks describe cancer as the result of a random process: one in a million petrochemical workers who are exposed to benzene will get bladder cancer, but there is no more reason for his being singled out than there is for being the loser at Russian roulette. “But now we are beginning to see that there are explanations for the variations in how people respond to carcinogens,” says Perera. The variations stem, ultimately, from the interaction between environment and genes. The trick is to find signs of the interactions that raise or lower risk.
Ecogeneticists are racking up an impressive list of candidates. One is an “adduct” formed when a carcinogen links to DNA or hemoglobin in the blood. The adducts appear in some people but not in others, depending on their genetic inheritance. Smokers who have lung cancer, for instance, may have more chemicals glommed onto their DNA than do smokers spared the disease. Such markers–like the telltale genes on chromosome 10–could eventually be used to warn a smoker that he, and not a hypothetical one in 14, is on the road to lung cancer. And Columbia’s Perera and Regina Santella, working with Kari Hemminki of Finland, have found that Polish workers and residents exposed to high levels of air pollution varied in their levels of DNA adducts by a factor of 20 or more. The elevated concentration paralleled the high risk of lung cancer in the population.
Scientists have built a library of 400 genetic mutations caused by carcinogens. “The idea is to learn what type of DNA changes are caused by various carcinogens,” says Thomas Skopek of the University of North Carolina. Take the powerful carcinogen aflatoxin, a mold that grows on peanuts and corn. One gene on chromosome 17, implicated in more than half of all cancers, becomes mutated in many liver-cancer patients. Curt Harris of the National Cancer Institute has found that it mutates in such a specific way that the change can be traced unambiguously to aflatoxin. Screening people for the mutation can therefore reveal who has been harmed by aflatoxin, and should thus seek early diagnosis and treatment, and who has so far escaped despite their exposure to this “known human carcinogen.”
Even people who have markers indicating that a chemical has initiated cancer are not necessarily doomed. Their fate depends not only on genetic makeup but also on their immune system and diet, whether they’re spared further exposure to carcinogens, whether they’re monitored for early signs of tumors. What is a good gene and what is a bad gene depends on how you treat it. That means eating foods, such as broccoli and other sources of beta carotene, that protect against cancer, for instance.
Although cancer is the prime target, ecogeneticists have other prey. Atherosclerosis, the nation’s No. 1 killer, has a handful of almost-causes–“almost” because eating a high-fat, low-fiber diet only sometimes causes heart disease. Ecogeneticists are finding out why. A defect in chromosome 6 makes the body produce sky-high levels of an artery-clogging lipoprotein, says Kare Berg of the University of Oslo. This raises the risk of premature heart attacks; about 25 percent of the population has the gene glitch. The good news is that it “is one risk factor we can test for,” Berg says. A simple blood test will tell the tale: people with this gene defect are definitely at greater risk of heart disease. And they will certainly benefit from low-fat diets. While it’s irresponsible to say that people without the defect can wallow in fat, it may be possible to identify individuals whose genes fend off heart disease.
By the year 2000, calculates I. Bernard Weinstein of Columbia University, cancer will surpass heart disease as the leading cause of death in the United States. One in three people alive today will die of it. Ecogenetics maybe the best hope of preventing many of those deaths, by protecting susceptible people. “Molecular epidemiology is where all the excitement will be in the years ahead,” says Berg. “We will be able to say, ‘Yes, you are at risk’.” But that raises ethical quandaries. This week a House Government Operations subcommittee is expected to hold hearings on the potential misuse of genetic information-looking at such issues as whether insurers or employers may mandate screening for genetic susceptibility to cancer or other diseases. Voluntary screening is less problematic. An Individual Risk Assessment may soon become one IRA that everyone wants in his portfolio.
