Salud Pública de México

Tobacco smoking and cancer: The promise of molecular epidemiology

Tobacco smoking and cancer: The promise of molecular epidemiology

AUTORES

Sophia S. Wang, B.S., (1) Jonathan M. Samet, M.D., M.S. (1)

(1) Department of Epidemiology, Johns Hopkins University School of Hygiene and Public Health. Baltimore MD, United States of America.

RESUMEN

El desarrollo neoplásico es un proceso multietápico que comprende cambios genéticos múltiples. En este trabajo se hace una revisión de los estudios sobre la epidemiología molecular del tabaco. S e revisan los conceptos actuales del modelo carcinogénico multietápico, así como su utilización en estudios observacionales. Finalmente se analiza el ejemplo relativo a los benzopirenos.

ABSTRACT

Neoplasic development is a multistage process that includes multiple genetic changes. In this article the authors review studies on molecular epidemiology of tobaco. Current concepts of the multistage carcinogenic model are reviewed, as are their use in observational studies. Finally, benzo[a]pyrene are analyzed as an example.

Introducción

A half-century has passed since researchers identified the epidemic of lung cancer and the first investigations on its causes were implemented. During these 50 years, tobacco smoking has been identified not only as a cause of lung cance r but also of cancers of the oral cavity and larynx ­both sites of direct smoke deposition­ and of cancers of more remote sites including the stomach, the pancreas, and the urinary bladder.1 Smoking is also a suspect cause of the acute leukemias, cancer o f the liver, and cancer of the uterine cervix.

Using straight-forward and easily completed questionnaires on smoking history, epidemiologists have now conducted numerous investigations on tobacco smoking and cancer. This research on tobacco and cancer has largely been accomplished u nder a simplistic and empiric epidemiological model regarding the relationship between exposure and disease. The findings of these investigations have definitively established tobacco smoking as causing a number of different types of cancer (Table I). Dat a from the American Cancer Society studies (CPS-I & II) demonstrated increased risk for mortality in current male and female smokers from specific cancers. For most types of cancer caused by cigarette smoking, the risk for smokers rises with the numbe r of cigarettes smoked per day and with the duration of cigarette smoking. Table II illustrates this risk with lung cancer serving as an example. Age of starting smoking also affects risk, primarily by increasing the duration of smoking. Comparing cancer mortality risks in CPS-II to CPS-I in part reflects a trend over time of the younger age of starting to smoke. The consistent evidence for exposure-response relationships supports the causality of the associations of tobacco smoking with cancer, meeting o ne of the widely applied criteria for causality in interpreting epidemiologic evidence.

 

 

Using straight-forward and easily completed questionnaires on smoking history, epidemiologists have now conducted numerous investigations on tobacco smoking and cancer. This research on tobacco and cancer has largely been accomplished u nder a simplistic and empiric epidemiological model regarding the relationship between exposure and disease. The findings of these investigations have definitively established tobacco smoking as causing a number of different types of cancer (Table I). Dat a from the American Cancer Society studies (CPS-I & II) demonstrated increased risk for mortality in current male and female smokers from specific cancers. For most types of cancer caused by cigarette smoking, the risk for smokers rises with the numbe r of cigarettes smoked per day and with the duration of cigarette smoking. Table II illustrates this risk with lung cancer serving as an example. Age of starting smoking also affects risk, primarily by increasing the duration of smoking. Comparing cancer mortality risks in CPS-II to CPS-I in part reflects a trend over time of the younger age of starting to smoke. The consistent evidence for exposure-response relationships supports the causality of the associations of tobacco smoking with cancer, meeting o ne of the widely applied criteria for causality in interpreting epidemiologic evidence.

Tumor initiators and promoters are not limited in their actions to the initiation and promotion stages; they contribute to the development of genetic events throughout the carcinogenic process. Initiators cause the genetic changes neces sary for carcinogenesis, and promoters propagate these genetic events. This sequence of events may occur many times before the carcinogenic process is completed.

The consistency and extent of the evidence has supported conclusions by the US Surgeon General, the World Health Organization, and other institutions on the carcinogenicity of tobacco smoke. These conclusions and the supporting evidence have been the principal basis for implementing widespread programs for smoking prevention and cessation. Thus, throughout the world, the health risks of cigarette smoking are now widely appreciated; in many countries, packages are labeled with the health risks of smoking; and advertising of cigarettes is controlled. Additionally, widespread educational campaigns seek to deter young children from starting to smoke and to motivate adult smokers to quit. In many countries, children's access to tobacco produ cts is also limited by law and the Food and Drug Administration in the United States has proposed regulations now being implemented to control the access of youth to cigarettes.

While the wealth of observational data has proved sufficient for the broad purpose of controlling tobacco-caused cancers, a number of key issues related to tobacco smoking and lung cancer remain to be addressed. Tobacco smoke is known to contain a number of carcinogens but the specific mechanisms by which components of tobacco smoke cause cancer have yet to be characterized. New research approaches to active tobacco smoking and cancer, however, are now showing that there are numerous ex ogenous and genetic factors determining how exposure to tobacco smoke leads to cancer. Attempts to understand the relationship between tobacco smoke and cancer have resulted in the development of additional models for research which we will integrate into the original epidemiological model in the course of this paper. The two models of interest are the multistage carcinogenic model, which details the steps required for cancer development, and the molecular epidemiology model of biomarkers, which affords a framework for investigating the sequence of changes from normal to malignant cells and identifyig the roles of environmental and genetic factors.

The widely held multistage model of carcinogenesis implies multiple stages at which tobacco smoke could act, but the effects of various smoke components in affecting the postulated multi-stage process remain to be described. As our know ledge of the sequence of genetic changes that leads to cancer has advanced, we have an expanded biologic understanding of the multistage process and the investigational challenge of learning how tobacco smoke effects tumor suppressor genes and oncogenes. Observational evidence has documented familial aggregation indicative of a genetic basis for lung and other cancers; we are also now searching for the genetic factors related to carcinogenesis that determine susceptibility to tobacco smoke. Candidate gene s determine rates and pathways of carcinogen metabolism and rate of DNA repair.

The transformation of normal cells into clinical cancers can be conceptualized as a multiple-step process affected by the metabolic activation of procarcinogens into ultimate carcinogens; the transfer of carcinogenic compounds across cell membranes; the susceptibility of the cell to carcinogenic change (i.e., cell replication); DNA binding and repair; factors affecting tumor growth; and immunologic destruction of tumor cells.

Advances in the techniques of molecular and cellular biology, largely applied over the last decade, have now begun to provide insights into such issues. The findings of this research have the potential to identify determinants of suscep tibility and to identify the genetic and other changes resulting from tobacco smoke that ultimately result in the transformation from normal to cancerous cells. The anticipated evidence will likely bring new approaches to the control of tobacco-caused can cers, including molecular screening tools for identifying the earliest stages of disease, and the capability of identifying genetically susceptible individuals. Specific markers may allow the attribution of cancer to tobacco smoke in individuals, thereby providing a causal link that might facilitate compensation through litigation or other means.

In this paper, we focus on this new line of investigation and highlight studies conducted with the "molecular epidemiology" paradigm. The findings of the epidemiologic literature on tobacco smoking and cancer have been well summarized in the reports of the US Surgeon General,1,5,7 the monograph of the International Agency for Research on Cancer (IARC) on tobacco smoking,3 and in a recent monograph published by the National Cancer Institute.6 Rather than reviewing this well-documented li terature, we focus on the findings of recent studies that have used the approaches of molecular epidemiology. We offer a brief review of current understanding of carcinogenesis within the context of the multistage model and summarize the evidence on tobac co smoking and cancer within this framework.

Carcinogenic models for tobacco and cancer

The multistage model of carcinogenesis

The multistage model of carcinogenesis represents a sequence of four events leading from normal cells to clinical cancer: initiation, promotion, conversion, and progression (Figure 1), during which multiple genetic events are postulated to take place. A list of definitions for relevant terms involved in the carcinogenic process are given in Table III; this list is designed to supplement the following discussion.

Tumor initiation. Tumor initiation refers to the direct effects and irreversible changes in the cellular DNA induced by initiators. Evidence of initiation includes adduct formation, mutations, and altered gene expression, and, in many cases, tumor initiation can be equated with a mutational event that leads to altered gene expression. The cells chosen for initiation and the site of the subsequent cancer are determined by the specific tumor initiator. Tumor initiation may involve the activation of proto-oncogenes and/or inactivation of tumor suppressor genes. These genes have been instrumental in the elucidation of carcinogenesis.

Proto-oncogenes/Oncogenes.

Proto-oncogenes are normal cellular genes. When a carcinogen creates a genetic event that activates a proto-oncogene, it becomes an oncogene. As an oncogene it will dysregulate cell growth and different iation pathways, promoting neoplastic development and enhancing tumor growth. For example, the protein products of the ras oncogene are involved in signal transduction pathways and transduction of growth factors. Genetic events leading to activatio n of proto-oncogenes include base-substitution mutations, chromosomal translocations, and gene amplification.9-12

Tumor suppressor genes

p53

Tumor promotion.


Biological markers allow us to identify specific com­pounds which are responsible for genetic events in the multistage carcinogenic process. Adduct formation (biological effective dose), mutations (early biologic effect), and loss of function (altered structure and func­tion) represent the actions of specific compounds. Sus­ceptibility markers determine which individuals are more likely to experience genetic events and subse­quently cancer. The sequence of biological markers that leads to possible genetic events can be integrated into the multistage carcinogenic model. The integra­tion of the two models demonstrates how identifi­cation of biomarkers not only enables us to identify genetic events but elucidates the mechanism and spe­cific compounds contributing to cancer formation.

The identification of additional compounds in to­bacco smoke is on going. Current studies are concerned with determining carcinogenic effects from specific individual compounds. This information has revealed much of what is contained in the 'black box' model_ Both the molecular epidemiological and the multistage carcinogenic models fit in the black box and have been integrated in Figure 6. Biological markers help identi­fy the mechanisms involved in forming the needed genetic events. The multistage model shows where and when these genetic events occur.

Examples of carcinogens associated with biologi­cal markers and markers associated with cancers have been illustrated in this paper. However, this is not a comprehensive list of present knowledge, but serves only as an example of the present knowledge avail­able. While extensive research has been performed on certain markers, sample sizes and extensions to the population-level are still limited. To verify these marker associations, researchers need to perform epidemio­logical studies using the molecular epidemiology ap­proach.




Active smokers are exposed to both mainstream (MS) and sidestream smoke (SS). Mainstream smoke is inhaled directly by the smoker, while sidestream smoke is emitted from the smoldering cigarette. The compounds found in the smoke are a ri ch mixture of toxic, mutagenic, and carcinogenic compounds. These compounds deposit in the body upon inhalation, primarily in the lower respiratory tract on the airways and the alveoli, and, to a lesser degree, in the upper respiratory tract. Upon deposit ion, some of these compounds are absorbed into the cells and then dispersed systemically, as demonstrated by the presence of tobacco components such as nicotine in blood, saliva, and urine.2

Multifaceted scientific research has been conducted on tobacco smoking and disease, including epidemiologic studies, and in vivo and in vitro toxicologic studies. The principal evidence characterizing tobacco smoking as a cause of cancer has come largely from observational epidemiologic studies of the cohort and case-control design. The case-control studies have been conducted on specific sites of cancer while the cohort studies have involved the follow-up of large numbers of smokers an d never smokers. Supporting toxicologic evidence has included the identification of carcinogens in tobacco smoke and in vivo and in vitro experiments which show that tobacco smoke and its components can produce malignant cells and cancers.3

The identification of tobacco smoking as a cause of cancer is one of the heralded triumphs of epidemiologic research. This success in part reflects the simplicity of characterizing exposure accurately to tobacco smoke in epidemiologic s tudies. With a few questions answered by study participants, epidemiologists have been able to accurately characterize cumulative exposure to tobacco smoke and to derive biologically relevant measures of the intensity of exposure. Duration of smoking can be readily determined, perhaps because of the addictive nature of tobacco smoking which assures a relatively fixed pattern of consumption.4 Age of starting to smoke provides a readily determined anchor point for the smoking history and persons who have st opped smoking can usually provide the age at which quitting was successful for the long term. The number of cigarettes smoked supplies a relative index of exposure and because there is a limited range of the number of cigarettes smoked across the populati on, there is little potential for misclassification. The usual quantity in a package ­20 cigarettes­ gives smokers an easy starting point to answer questions about the in tensity of their smoking. In the past, smokers seemed to report their smoking histo ry without bias, although more recently, with declining acceptability of smoking in some countries, a trend of underreporting has appeared.

Tumor promotion is a gradual process requiring prolonged exposure to the promoting agent. It occupies the greater part of the latent period of carcinogenesis and is partially reversible. Tumor promotion occurs wh en initiated cells are selectively reproduced and therefore expand clonally into visible benign tumors or loci on neoplastic cells. Initiated cells are selectively reproduced through factors that influence cell proliferation, such as altered growth and re sistance to cytotoxicity. is the most commonly studied and altered tumor suppressor gene to date.13 The site of mutagenicity on the target oncogene or tumor suppressor gene depends on the specific carcinogen. Loss of the tumor suppressor gene (i.e., < I>p53) function results in unregulated growth and an increased probability of neoplastic transformation and cancer. Tumor suppressor genes can be considered anti-cancer genes, suppressing cell proliferation and hence tumor growth. A genetic event that deactivates the tumor suppressor gene results in a continuous signal or an abnormal signal for cell proliferation and possible growth of a neoplasm. Both alleles of a tumor suppressor gene must sustain mutations to inactivate the function of these gene products.

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