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The Changing Role of Tobacco in Cancer

November 2013 - Linkage Newsletter

by Shelia Hoar Zahm, Sc.D.

Fifty years after the landmark 1964 Smoking and Health: Report of the Advisory Committee to the Surgeon General, tobacco continues to be the single greatest cause of preventable cancer mortality worldwide. And yet the tobacco epidemic has been evolving: Patterns of tobacco use and the design and construction of cigarettes and other tobacco products have changed over time. DCEG has a broad-based research program focusing on how these changes have altered associations between tobacco and cancer, including a project funded by the U.S. Food and Drug Administration’s Center for Tobacco Products through the NIH Tobacco Regulatory Science Program.

Smoking-related Cancer Trends

During the earlier years of the tobacco epidemic, more men than women smoked, and men generally started smoking at earlier ages and smoked more cigarettes per day than women did. Consequently, the relative risks and the proportion of cancer due to tobacco were higher among men than among women. In recent years, scientists have noticed a disturbing trend in tobacco use; women now start smoking at a similar age and smoke similar amounts as men do.

Since this “equalization” has come about, studies are revealing the full impact of women’s changing smoking habits on health. Neal Freedman, Ph.D., M.P.H., Nutritional Epidemiology Branch (NEB), has led research within the NIH-AARP Diet and Health Study cohort showing that the relative risks of smoking for lung (Lancet Oncol 2008), bladder (JAMA 2011), esophageal (Eur J Cancer 2010), stomach (Eur J Cancer 2010), liver, and many other cancer types (Cancer 2007), as well as for overall and cardiovascular disease mortality, are now similar among men and women.

Dr. Freedman and Patricia Hartge, Sc.D., scientist emerita and former Deputy Director of the Epidemiology and Biostatistics Program, worked with the NCI Cohort Consortium to combine the NIH-AARP data with data from four other cohorts to evaluate 50-year trends in smoking-related mortality (N Engl J Med 2013) in the United States. The analysis found that the relative risks of smoking have indeed become similar in men and women for overall mortality, lung cancer, ischemic heart disease, chronic obstructive pulmonary disease, and stroke (see Figure 1). The research team is now expanding the project to evaluate several more smoking-related causes of death for inclusion in an upcoming Surgeon General’s report on tobacco planned for release in 2014.

Relative risks of lung cancer for men and women among current smokers, according to number of cigarettes smoked per day, and among former smokers, according to age at the time of quitting.

Smoking Characteristics and Cancer Risk

The introduction since 1950 of filtered and “low-tar” cigarettes was intended to reduce carcinogenicity, and yet the concentration of some carcinogens in cigarettes may have actually increased, including the bladder carcinogen β-naphthylamine as well as tobacco-specific nitrosamines. Christian C. Abnet, Ph.D., M.P.H. (NEB), Dr. Freedman, and Debra T. Silverman, Sc.D., Chief of the Occupational and Environmental Epidemiology Branch, found that the associations between smoking and cancers of the bladder and lung have strengthened with time. Despite hope that the introduction of filters and use of low-tar cigarettes would reduce the burdens of tobacco smoking, these research results indicate that the risks of tobacco to health remain extremely strong and may have even increased with time.

Neil E. Caporaso, M.D., Chief of the Genetic Epidemiology Branch (GEB), and Carolyn Reyes-Guzman, M.P.H. (GEB), are currently evaluating the risks associated with light and intermittent tobacco smoking in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial cohort and the EAGLE (Environment And Genetics in Lung cancer Etiology) case-control study. Their research efforts also include identifying the most appropriate biomarkers to characterize light and intermittent smoking.

The risks for smokers who have reduced the number of cigarettes they smoke per day but who have not quit smoking are being examined among members of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort and in the NIH-AARP Diet and Health Study. The trajectory of smoking—whether smokers increase, decrease, or stop smoking over time—may be a critical determinant of lung cancer and other smoking-related diseases.

Members of the DCEG Tobacco Working Group, which Dr. Abnet, Dr. Freedman, and Meredith Shiels, Ph.D., Infections and Immunoepidemiology Branch (IIB) co-lead, have explored whether measures of smoking other than the standard metrics (i.e., cigarettes per day, duration of smoking, pack-years) might better predict cancer risk. One interesting measure, the time to first cigarette (TTFC) after waking, is being investigated by Dr. Caporaso and Fangyi Gu, Sc.D. (GEB) using data from the EAGLE study.

Smoking-induced Inflammation

Because of the growing recognition of an etiologic role for inflammation in lung carcinogenesis, DCEG researchers, including Anil K. Chaturvedi, Ph.D. (IIB), and Dr. Shiels, are conducting ongoing studies in PLCO examining the association of circulating inflammation markers with smoking and lung cancer. Additional studies are being planned to determine whether smoking-induced inflammation contributes to the risk for other cancers.

Tobacco Metabolism and Cancer Risk

Biomarkers that capture both smoking behavior and individual variation in tobacco metabolism might help improve assessment of cancer associations compared with self-reported smoking histories. In particular, measurement errors from self-reported histories might pose problems for assessing cancers weakly associated with smoking. Dr. Amanda J. Cross, formerly of NEB, and Steven C. Moore, Ph.D. (NEB), have evaluated serum metabolites of tobacco in relation to the risk of colorectal cancer. In addition, Drs. Caporaso and Gu are identifying metabolomic markers of smoking among controls in the EAGLE study.

Tobacco Use and the Oral Microbiome

Earlier this year, DCEG researchers received funding from the Food and Drug Administration’s Center for Tobacco Products for a study on the impact of tobacco use on oral health and the oral microbiome. Drs. Abnet, Chaturvedi, and Freedman, along with Mitchell H. Gail, M.D., Ph.D., Biostatistics Branch (BB), Jianxin Shi, Ph.D. (BB), Dr. Maura Gillison of Ohio State University, Dr. Bruce Dye with the Centers for Disease Control and Prevention, Dr. Martin Blaser of New York University, and Dr. Rob Knight of the University of Colorado, are investigating how tobacco-induced changes in the bacteria of the mouth may lead to adverse health consequences, including some cancers. The oral microbiome also may serve as a biomarker of smoking that can be applied to new and emerging tobacco products. Using oral wash samples from approximately 11,000 participants in the National Health and Nutrition Examination Survey (NHANES) study, the team will investigate the association between types of tobacco use and the oral microbiome as well as the association between the oral microbiome and tobacco-related diseases. Dr. Caporaso and Guoqin Yu, Ph.D. (GEB), are conducting a methodologic study at the University of Rochester Eastman Dental Center to characterize the microbiome at various sites within the oral cavity.

New and Emerging Tobacco Products

To maintain and expand its market, the tobacco industry has developed new and emerging tobacco-related products, including electronic cigarettes, flavored cigarettes and cigarillos, dissolvable tobacco products, and hookah pipes (see Figure 2). 

Little is known about the health effects of these products, which makes their increasing popularity, particularly among young people, cause for concern. DCEG has projects under way to evaluate several of these products. 

Stephen J. Chanock, M.D., Director of DCEG, stated, “As the tobacco epidemic continues to evolve, it is important that we conduct the research necessary to evaluate the public health impact of all tobacco products, with the aim of reducing cancer due to tobacco.”

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