Correspondence

Racial Differences in Lung Cancer

N Engl J Med 2006; 354:1951-1953May 4, 2006

Article

To the Editor:

The study of ethnic and racial differences in the smoking-related risk of lung cancer by Haiman et al. (Jan. 26 issue)1 omits an analysis of important potential confounders: a family history of cancer and parental exposure to relevant harmful substances (e.g., cigarettes, radon, inhaled particulates associated with mining, and pesticides). Paternal smoking can select for epimutations in sperm2 and inhibit the production of DNA-repair enzymes such as O⁶-methylguanine-DNA methyltransferase and MLH1,3 causing heritable but nonfamilial susceptibility to cancer that is detectable in nonsmoking progeny as microsatellite instability, reduced DNA repair, early-onset cancer, or specific mutation patterns within tumors.4 The association of achondroplastic germ-line mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) — somatic homologues of which characterize bladder tumors in nonsmokers — with excess ancestral cancer5 mirrors this epistatic model of transgenerational carcinogenesis.

Since each racial or ethnic group has its own family-smoking dynamic,6 uncontrolled epigenetic–environmental interactions could contribute to apparent variations in cancer susceptibility. It may be timely to hypothesize about polymorphisms affecting carcinogen metabolism, yet it is also pertinent to note that lung cancer was extremely rare in all ethnic groups just two centuries ago. The elimination of noxious exposures through legislation and education may thus remain a surer strategy than genomic research for reducing lung cancer in racial and ethnic minorities.

Richard J. Epstein, M.D., Ph.D.
Yongzhong Zhao, Ph.D.
University of Hong Kong, Hong Kong, China
repstein@hku.hk

6 References

1. 1

   Haiman CA, Stram DO, Wilkens LR, et al. Ethnic and racial differences in smoking-related risk of lung cancer. N Engl J Med 2006;354:333-342
   Full Text | Web of Science | Medline

2. 2

   Pembrey ME, Bygren LO, Kaati G, et al. Sex-specific male-line transgenerational responses in humans. Eur J Hum Genet 2006;14:159-166
   CrossRef | Web of Science | Medline

3. 3

   Suter CM, Martin DI, Ward RL. Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 2004;36:497-501
   CrossRef | Web of Science | Medline

4. 4

   Suzuki K, Ogura T, Yokose T, et al. Microsatellite instability in female non-small-cell lung cancer patients with familial clustering of malignancy. Br J Cancer 1998;77:1003-1008
   CrossRef | Web of Science | Medline

5. 5

   Stoll C, Feingold J. Do parents and grandparents of patients with achondroplasia have a higher cancer risk? Am J Med Genet 2004;130:165-168
   CrossRef | Web of Science

6. 6

   Gittelsohn J, Roche KM, Alexander CS, Tassler P. The social context of smoking among African-Americans and white adolescents in Baltimore City. Ethn Health 2001;6:211-225
   CrossRef | Web of Science | Medline

To the Editor:

Haiman and colleagues highlight metabolic differences as potential explanatory factors for the increased susceptibility to lung cancer of African-American and Native Hawaiian cigarette smokers in California and Hawaii. Differing cigarette preferences may also be a factor. The proportions of African-American and Native Hawaiian smokers who prefer mentholated cigarettes (74 percent and 55 to 83 percent, respectively) is markedly higher than the proportions of whites and Latinos (16 percent and 19 percent, respectively).1,2 A previous California study found an increased risk of lung cancer among male smokers of mentholated cigarettes, as compared with the risk among male smokers of nonmentholated cigarettes (odd ratio, 1.45).3 African Americans (primarily smokers of mentholated cigarettes) have also been found to take in 30 percent more nicotine per cigarette than do whites.4 During the 1990s, California increased cigarette taxes and implemented bans on smoking in public places, resulting in marked reductions in cigarette consumption. Smokers of mentholated cigarettes may find it easier to maintain their usual nicotine intake by inhaling more deeply per cigarette without excessive irritation of the throat. The effects of menthol on the addictiveness and health effects of cigarettes warrant further attention.

Jonathan Foulds, Ph.D.
Jill M. Williams, M.D.
Kunal K. Gandhi, M.B., B.S., M.P.H.
University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08901
jonathan.foulds@umdnj.edu

Dr. Foulds reports having received payment as an expert witness for plaintiffs in litigation against tobacco companies.

4 References

1. 1

   Giovino GA, Sidney S, Gfroerer JC, et al. Epidemiology of menthol cigarette use. Nicotine Tob Res 2004;6:Suppl 1:S67-S81
   CrossRef | Web of Science | Medline

2. 2

   Maddock JE. Smoking and tobacco use in Hawaii: facts, figures and trends. Honolulu: Hawaii State Department of Health, 2003.
   

3. 3

   Sidney S, Tekawa IS, Friedman GD, et al. Mentholated cigarette use and lung cancer. Arch Intern Med 1995;155:727-732
   CrossRef | Web of Science | Medline

4. 4

   Perez-Stable EJ, Herrera B, Jacob P III, Benowitz NL. Nicotine metabolism and intake in black and white smokers. JAMA 1998;280:152-156
   CrossRef | Web of Science | Medline

Author/Editor Response

With regard to the comments of Dr. Foulds and colleagues: there are well-known differences in the type and brand of cigarettes preferred by racial or ethnic groups in the United States. The literature on whether smokers of mentholated cigarettes have a greater risk of lung cancer than do smokers of nonmentholated cigarettes has been equivocal, with two studies finding no association.1,2 Dr. Foulds and colleagues point to one study that found a modest association among men (risk ratio, 1.45; 95 percent confidence interval, 1.03 to 2.02). In our study, we observed that the risk of lung cancer among African-American and Native Hawaiian smokers is two to three times that of smokers in other populations. Considering that one study3 showed that 75 percent of African-American smokers favor mentholated cigarettes, as compared with 20 percent of Latino smokers, then we would expect the relative risk of lung cancer among smokers of mentholated cigarettes to be perhaps seven times that of smokers of nonmentholated cigarettes. The upper limit of the confidence interval (2.02) in the study by Sidney et al.4 rules out an effect of this magnitude.

Drs. Epstein and Zhao present an interesting hypothesis regarding the role of transgenerational epigenetic phenomena in the alteration of racial or ethnic variability in the risk of lung cancer. Unfortunately, we are not able to address this hypothesis in the Multiethnic Cohort Study, since we did not collect information about parental exposures. In addition to parental exposures associated with the risk of lung cancer (e.g., cigarettes, radon, and inhaled particulates associated with mining) that Drs. Epstein and Zhao mention, other exposures, such as dietary factors, may also result in a preprogramming of genes that alters susceptibility to carcinogens in cigarettes. These exposures would need to be widely distributed across racial or ethnic populations and would need to have strong effects in order to account for even a small fraction of the large differences in risk that we observed among racial and ethnic groups. These profound differences in risk need to be explained, and although genomic and epigenomic research has been proposed as a possible avenue of future research, we can all agree that the removal of cigarette smoking in all populations would have the greatest effect on public health.

Christopher A. Haiman, Sc.D.
Daniel O. Stram, Ph.D.
University of Southern California, Los Angeles, CA 90033
haiman@usc.edu

Loïc Le Marchand, M.D., Ph.D.
University of Hawaii, Honolulu, Honolulu, HI 96817

4 References

1. 1

   Carpenter CL, Jarvik ME, Morgenstern H, McCarthy WJ, London SJ. Mentholated cigarette smoking and lung-cancer risk. Ann Epidemiol 1999;9:114-120
   CrossRef | Web of Science | Medline

2. 2

   Stellman SD, Chen Y, Muscat JE, et al. Lung cancer risk in white and black Americans. Ann Epidemiol 2003;13:294-302
   CrossRef | Web of Science | Medline

3. 3

   Giovino GA, Sidney S, Gfroerer JC, et al. Epidemiology of menthol cigarette use. Nicotine Tob Res 2004;6:Suppl 1:S67-S81
   CrossRef | Web of Science | Medline

4. 4

   Sidney S, Tekawa IS, Friedman GD, Sadler MC, Tashkin DP. Mentholated cigarette use and lung cancer. Arch Intern Med 1995;155:727-732
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   K. K. Gandhi, J. Foulds, M. B. Steinberg, S.-E. Lu, J. M. Williams. (2009) Lower quit rates among African American and Latino menthol cigarette smokers at a tobacco treatment clinic. International Journal of Clinical Practice 63:3, 360-367
   CrossRef

2. 2

   Y. Zhao, R. J. Epstein. (2008) Programmed Genetic Instability: A Tumor-Permissive Mechanism for Maintaining the Evolvability of Higher Species through Methylation-Dependent Mutation of DNA Repair Genes in the Male Germ Line. Molecular Biology and Evolution 25:8, 1737-1749
   CrossRef