"My genes made me do it" is no longer a credible alibi for contractinglung cancer. A unique controlled clinical trial among 31,848 whitemale Americans, followed for 45 years, concludes that "smoking-induced lung cancer should be attributed to smoking, not to inheritedpredisposition."The human subjects were twin brothers, a mix of identical andfraternal. The study, which largely refuted any hereditary cause ofpulmonary malignancy among inveterate smokers, was directed bymedical epidemiologist M. Miles Braun of the National CancerInstitute's Epidemiology and Biostatistics Program.Titled "Genetic component of lung cancer: cohort study of twins," thislargest-ever twin study of genes vs. carcinogens in lung cancer appearsin the current issue of The Lancet.Instead of DNA probes, and phalanxes of laboratory mice, it comparedmonozygotic (identical) human twin pairs with dizygotic (non-identical, fraternal) pairs. Because the former share completelyhomologous genomes, Braun and his colleagues reasoned, identicaltwin smokers should incur more lung cancer deaths than fraternal pairs,whose genes may be up to 50 percent dissimilar. This didn't happen.The trial enrolled about 93 percent of all white male twins born in theU.S. between 1917 and 1927, and who served in the armed forcesduring World War II. Their records _ originated by the Department ofVeterans Affairs, and updated by The National Academy of Sciences-National Research Council Twin Registry in Washington _ identifiedeach subject by twin kinship (mono- or dizygotic), cause and date ofdeath, and smoking habits.The NCI study followed up on lung-cancer mortality for all 15,924twin pairs from day of induction into the military until date of death, orDec. 31, 1990, whichever came first.As of 1990, lung cancer deaths had occurred in about 5 percent of thetwin pairs. Of these, 282 were identical sibs, including 10 pairs,compared to 399 fraternal twins, including 21 pairs.The report cited one striking statistic that dismissed the theory of "badgenes" as implicated in lung cancer: Of 47 identical twin pairs, allsmokers, over a six-year period one in each pair died of lung cancer;their brothers did not.Gene Theory Hazardous To Health?"It could be a fatal mistake," Braun warned, "for a smoker to believethat he will not develop lung cancer just because he has close relativeswho smoked for a long time and did not."Braun told BioWorld Today that pulmonary malignancies, although thelargest single cause of cancer fatalities, come after heart disease, thenumber one killer in the U.S. "Certainly," he said, "smoking increasesthe risk of heart disease death, as it does for stroke, emphysema,pneumonia and influenza. These together account for more than halfthe deaths in the general population. The proportion," Braun added, "isa little higher among smokers."The Lancet report also debunked several putative gene polymorphismmechanisms adduced to explain why "more than 80 percent of smokersliving to old age do not die of smoking-induced cancer."The idea here, Braun explained, is that one individual will haveinherited genes with certain alleles that would detoxify pollutants,whereas alleles in other individuals would create a toxic substancefrom an environmental pollutant. "Such people," he explained, "wouldbe more rapid at creating a carcinogen, the basis for a geneticallytransmitted or inherited susceptibility to tobacco smoke."On this score, he observed, "The problem with the classic twin designis that you have more environmental similarity among identical twinsthan among fraternal ones. This could potentially bias you towardfinding a genetic defect, but in our case we didn't observe it, so itwasn't really an issue."Debunking The `X factor'Jurist John Banzhaf, who teaches law at George WashingtonUniversity, is executive director of Action on Smoking and Health. Hetold BioWorld Today:"What I think this Lancet report may do is that among people whounderstand it, and are willing to believe it, it should put an end to theso-called "X factor" argument, that there's something in the genes thatboth makes you smoke and gives you lung cancer."It may also, one hopes, help persuade people who previously hadthought that because they had relatives who smoked and didn't get lungcancer that they were genetically immune to the effects of smoking." n
-- David N. Leff Science Editor
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