Landmarks in the History of Cancer Epidemiology Peter Greenwald and Barbara K

Published OnlineFirst March 10, 2009; DOI: 10.1158/0008-5472.CAN-09-0416 Published Online First on March 10, 2009 as 10.1158/0008-5472.CAN-09-0416

AACR Centennial Series

Landmarks in the History of Cancer Epidemiology Peter Greenwald and Barbara K. Dunn

Division of Cancer Prevention, National Cancer Institute, NIH, Bethesda, Maryland

Abstract Introduction The application of epidemiology to cancer prevention is Cancer epidemiology is the study of patterns and determinants relatively new, although observations of the potential causes of cancer risk, outcome, and control in healthy or diseased of cancer have been reported for more than 2,000 years. populations. Unlike the experimental nature of most clinical Cancer was generally considered incurable until the late 19th research, much of epidemiology is inherently observational, the century. Only with a refined understanding of the nature of study of people with and without disease (1, 2). One of cancer and strategies for cancer treatment could a systematic epidemiology’s initial roles in supporting cancer research was the approach to cancer prevention emerge. The 20th century saw collection of descriptive data on cancer incidence and mortality the elucidation of clues to cancer causation from observed to identify the health effects of cancer on society. As illustrated associations with population exposures to tobacco, diet, in Figs. 1 and 2, site-specific data on the mortality of women and environmental chemicals, and other exogenous factors. With men in the United States from cancer has been collected and repeated confirmation of such associations, researchers published since 1930. Understanding mortality trends for major entertained for the first time the possibility that cancer, like cancer types has focused research efforts and public policies in many of the infectious diseases of the time, might be areas that can affect public health. prevented. By the mid-20th century, with antibiotics success- The search for associations between cancer outcomes and fully addressing the majority of infectious diseases and high measurable exposures has evolved in response to increasingly blood pressure treatment beginning to affect the prevalence sophisticated laboratory technologies to analyze ‘‘biomarkers’’ in of heart disease in a favorable direction, the focus of much tissue specimens. Molecular epidemiology is the discipline that has of epidemiology shifted to cancer. The early emphasis was on emerged to investigate such molecular factors. Biomarkers reflect exploring, in greater depth, the environmental, dietary, either the body’s response to specific environmental exposures hormonal, and other exogenous exposures for their potential (‘‘surrogates of exposure’’) or innate physiologic or genetic associations with increased cancer risk. The first major characteristics, or they serve as putative surrogates of clinical breakthrough in identifying a modifiable cancer risk factor cancer outcomes. Modern genetic epidemiology includes was the documentation of an association between tobacco approaches that focus on the molecular material of genes and smoking and lung cancer. During the past four decades, chromosomes in constitutional DNA, reflecting inherited cancer epidemiologic studies have generated population data iden- predisposition, as well as on tumor type–specific somatic genetic tifying risk factors for cancers at almost every body site, with changes. many cancers having multiple risk factors. The development Two key features of cancer epidemiology must be kept in mind if of technologies to identify biological molecules has facilitated its proper application to serving the general health and well being the incorporation of these molecular manifestations of is to be implemented. First, caution must be exercised in inferring biological variation into epidemiologic studies, as markers causality from measured associations because some factors occur of exposure as well as putative surrogate markers of cancer in association with both a real causal factor and with the disease outcome. This technological trend has, during the past two itself; and second, the ultimate goal is to improve the health of decades, culminated in emphasis on the identification of people, preferably via cancer prevention; observational data alone genetic variants and their products as correlates of cancer does not accomplish this. Whenever possible, data generated from risk, in turn, creating opportunities to incorporate the epidemiologic studies, however sophisticated, must be integrated discipline of molecular/genetic epidemiology into the study into clinical research, in which experimental manipulation of the of cancer prevention. Epidemiology will undoubtedly continue implicated risk factors can be evaluated for its effect on cancer contributing to cancer prevention by using traditional outcomes. In this article, we take a historical approach to surveying epidemiologic study designs to address broad candidate areas key areas of epidemiologic investigations into cancer risk, always of interest, with molecular/genetic epidemiology investiga- with an eye to the implications of study findings in terms of public tions honing in on promising areas to identify specific factors health. Our goal is not to be totally comprehensive; rather, we wish that can be modified with the goal of reducing risk. [Cancer to delve into selected epidemiologic research endeavors with a Res 2009;69(6):2151–62] critical eye grounded in a modern scientific perspective. We hope in this way to elicit the relevance of historical study findings in terms of their relevance to current and future epidemiologic investigation and especially in relation to their effect on public health.

Requests for reprints: Peter Greenwald, Division of Cancer Prevention, National Cancer Institute, NIH, 6130 Executive Boulevard, Suite 2040, Bethesda, MD 20892-7309. Tobacco Phone: 301-496-6616; Fax: 301-496-9931; E-mail: [email protected]. I2009 American Association for Cancer Research. The establishment of tobacco as a carcinogen is one of the signal doi:10.1158/0008-5472.CAN-09-0416 achievements in epidemiology. Observational studies published as www.aacrjournals.org 2151 Cancer Res 2009; 69: (6). March 15, 2009

Cancer Research

Figure 1. Landmarks in the history of cancer epidemiology (1900–present). early as the 1700s suggested an association of tobacco with nasal molecular epidemiology. This field integrates molecular biology cancer among snuff workers (3), and mouth and lip cancers among and cancer genetics with classic epidemiologic study designs, pipe smokers (4). The strongest evidence supporting tobacco allowing the identification of individuals or groups at increased risk exposure as an etiologic factor for various cancers emerged from or increased vulnerability to exogenous risk factors, i.e., those who 20th century epidemiologic studies. In 1912, Isaac Adler published may benefit from targeted cancer prevention or treatment his observation that smoking tobacco may have been linked to strategies (11). reported increases in lung cancer cases in local hospitals (5). By the One example of the variability of risk among populations 1950s, strong epidemiologic and experimental evidence indicated emerged from the long-held knowledge that association of CYP1 that cigarette tar and other tobacco constituents produced by enzymes with cancer risk due to tobacco exposure is due to the burning the product and inhaling the smoke were responsible for involvement of these enzymes in activating carcinogens such as cancers of the lung (6, 7) and that an unequivocal association polynuclear aromatic hydrocarbons. Specific CYP1A1 polymor- existed between smoking and lung cancer, especially when phisms (MspI and Ile462Val polymorphisms) were associated with considering duration of smoking (6, 8). These seminal studies increased lung cancer risk in the Japanese population, whereas only from the work of Ernst Wynder and Richard Doll (6, 8) eventually the CYP1A1-MspI polymorphism was strongly associated with risk led to the recognition by the U.S. Surgeon General and other public in Western populations (10). health institutions and medical societies of the dangers of tobacco As early as the 1980s, the National Cancer Institute has directed use in any form. This, in turn, led to important public health antismoking efforts based on population data supplied by programs to discourage people, especially young people, from epidemiologists. The two largest efforts involved a clinical trial beginning smoking and to encourage those who currently smoke (Community Intervention Trial for Smoking Cessation) and a state to quit. level intervention program to address policy-driven initiatives to From 1950 to the present, epidemiology has played a critical role promote smoke-free environments, counter tobacco advertising in the search for the etiologic factors responsible for the dramatic and promotion, limit tobacco access and availability, and increase increase in lung cancer incidence and mortality during the 20th tobacco prices through new excise taxes (American Stop Smoking century. Animal studies identified cigarette smoke constituents, Intervention Study). The Community Intervention Trial for including polynuclear aromatic hydrocarbons, that have carcino- Smoking Cessation and American Stop Smoking Intervention genic initiator-promoter activity (9). Eventually, mechanistic Study showed that a multi-tiered approach could decrease the studies elucidated the numerous carcinogenic genetic alterations prevalence of smoking and increase the quit rate among current in relevant biological pathways: xenobiotic metabolism, control of smokers (12–14). genomic instability (including DNA repair mechanisms), cell cycle checkpoints, apoptosis, telomere length, control of the microenvi- ronment by elements such as metalloproteinases, inflammation, Diet/Body Mass Index/Physical Activity and growth factors (10). Complete answers to the question of Although the associations between diet and disease have been cancer susceptibility would have to await the development of known for centuries (e.g., limes to prevent scurvy in British sailors),

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Landmarks in the History of Cancer Epidemiology

Figure 1 Continued. not until the results of rigorous epidemiologic studies were controversies involves the association of dietary fat with breast reported in the 1970s and 1980s did compelling evidence for the cancer: does an increase in the consumption of dietary fat increase breadth of the association emerge (15–17). The application of the risk of breast cancer, and does a low-fat diet confer lower risk? epidemiologic methods to diet/cancer studies is relatively new A multitude of studies (case-control, cohort, meta-analyses) because of the difficulty in determining the effects of specific spanning two decades attempted to resolve the issue without dietary factors on risks of chronic diseases, especially at the reaching conclusive agreement (22, 23). The dietary fat-breast individual level. Initially, diet/cancer epidemiology involved eco- cancer controversy exemplifies the challenges of basing cancer logical studies of populations and suggested broad associations, prevention recommendations solely on observational epidemio- such as that of red meat intake and increased colon cancer risk logic studies; the need for clinical trials to test results suggested in (18). Migrant studies provided a unique tool that, in the early days observational studies is critical to clarify the role of lifestyle choices of diet/cancer epidemiologic research, focused on contrasting in cancer risk, especially in the face of conflicting epidemiologic disease outcomes displayed by similar populations in different findings. ‘‘ecological’’ settings. An early migrant study comparing the rates of Occasionally, epidemiologic findings seem to be inconsistent with gastric and colon cancers in Japanese migrating to the United clinical trial results, but in fact, the apparent conflict at times seems States (19) indicated lower rates of gastric cancer and higher rates to have resulted from the failure to consider individual variability. In of colon cancer the longer immigrants lived in the United States. the case of the association between h-carotene and lung cancer, Patterns similar to that for colon cancer were seen for cancers of conflicting evidence in results from epidemiologic studies (foods the breast, uterine corpus, and ovary among women and for containing h-carotene reduce lung cancer risk) and prospective prostate cancer among men. clinical trials such as the Alpha-Tocopherol, Beta-Carotene (ATBC) By the mid-1990s, evidence from numerous large population Cancer Prevention Study, which suggested that h-carotene in studies suggested a strong association between a high intake of supplements promotes lung cancer risk among smokers, catalyzed vegetables and fruits and reduced risks of cancers of the breast, intense discussions to discern reasons for the inconsistency (24). A prostate, colorectum, lung, stomach, and other sites (20). Also in possible explanation for this apparent conflict emerged from the 1990s, the National Cancer Institute initiated a community- pharmacogenomic studies conducted post-trial in the ATBC cohort. based partnership based on epidemiologic and intervention In most cases, a GSTM1 null genotype is associated with a higher risk studies—the 5 A Day For Better Health Program (5 A Day)—to of lung cancer when compared to a GSTM1-present genotype, encourage increased vegetable and fruit intake among Americans; regardless of treatment or years of smoking. Furthermore, the an evaluation in 2000 indicated a slow but steady increase in positive association between smoking duration and lung cancer vegetable and fruit consumption among American consumers is greater among GSTM1-null individuals than those with a since the program’s inception (21). GSTM1-positive genotype. h-carotene supplementation confers an Beyond overall diet, the association of cancer risk with specific increased risk of lung cancer at every duration of smoking with one dietary factors, including individual nutrients, has also been exception: in individuals with a GSTM1-null genotype. Although all evaluated. Conflicting results have led to controversies over the GSTM1-null individuals who fall into the longest smoking duration rolesofsuchdietaryfactors.Oneofthelongest-running category have a significantly elevated risk of lung cancer compared www.aacrjournals.org 2153 Cancer Res 2009; 69: (6). March 15, 2009

Cancer Research to GSTM1-positives, this risk is somewhat lower in those who have neither supplement, taken alone or together, prevented prostate had h-carotene supplementation (25). In addition to identifying a cancer and that the supplements are unlikely ever to produce the subgroup that might benefit from an intervention, this study 25% disease reduction on which the study was designed. exemplifies how clues from classic epidemiology can be obscured in Furthermore, a small, statistically nonsignificant increase in cases the absence of in-depth characterization of individuals likely to of prostate cancer was observed in men older than age 50 taking experience a benefit (or harm). Clearly, one size doesn’t fit all. The only vitamin E, and a similar statistically nonsignificant increase in success of dietary components as interventions must be examined in cases of adult onset diabetes occurred in men taking only selenium terms of the gene-environment interactions involved in modulating (27). This negative result of SELECT, by not confirming secondary the preventive outcomes in epidemiologic studies and in clinical end points in the hypothesis-generating clinical trials (26, 28), once trials. The ATBC prospective randomized controlled trial of two again reinforces the importance of designing prospective clinical promising nutrients exemplifies the limitations of the prior trials to test putative preventive agents specifically for their efficacy hypothesis-generating observational data and reinforces the impor- against given cancer end points. tance of basing dietary recommendations on prospective clinical In addition to confirming or refuting the benefits of specific trials, whenever possible. bioactive foods during the past decade, epidemiologic and clinical An important secondary finding in ATBC was the reduction in studies have yielded evidence linking diet, body mass index (BMI) prostate cancer incidence in men receiving a-tocopherol. A and obesity, and physical activity to cancer risk. In a recent secondary end point from another randomized controlled trial, systematic review and meta-analysis of 221 data sets with 282,137 which proved negative for its primary end point of testing selenium incident cancer cases from prospective observational studies, BMI for the prevention of skin cancer, was a reduction in prostate was linked with an increase in the risks of common and less cancers in men receiving selenium (26). Together, these secondary common cancers, with associations differing between the sexes and outcomes from two prevention trials laid the foundation for the among ethnic groups (29). Epidemiologic studies indicate the National Cancer Institute’s second phase 3 trial for the prevention benefits of physical activity as an intervention for obesity, a known of prostate cancer. The Selenium and Vitamin E Cancer Prevention cancer risk factor, with the strongest evidence of an inverse Trial (SELECT), through its factorial design, tested each nutrient relationship being for breast cancer, especially among postmeno- separately and together in comparison to placebo. Following a pausal women (30). Intervention strategies that address the effect recent independent review of study data, it was announced that of each lifestyle factor have been suggested by cancer prevention

U.S.

Figure 2. Cancer death rates for women in the United States (1930–2004).

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Table 1. 2007 WCRF/AICR dietary recommendations

Recommendations for cancer prevention

1. Be as lean as possible without becoming underweight 2. Be physically active for at least 30 min every day 3. Avoid sugary drinks. Limit consumption of energy-dense foods (particularly processed foods high in added sugar, or low in fiber, or high in fat) 4. Eat more of a variety of vegetables, fruits, whole grains and legumes such as beans 5. Limit consumption of red meats (such as beef, pork and lamb) and avoid processed meats 6. If consumed at all, limit alcoholic drinks to two a day for men and one a day for women 7. Limit consumption of salty foods and foods processed with salt (sodium) 8. Do not use supplements to protect against cancer Special population recommendations

9. It is best for mothers to breastfeed exclusively for up to 6months and then add other liquids and foods 10. After treatment, cancer survivors should follow the recommendations for cancer prevention

NOTE: Taken from the World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. Washington, DC: AICR, 2007. research. The second report of the World Cancer Research Fund/ subsequent series of case-control studies ultimately linked this rare American Institute for Cancer Research developed lifestyle cancer to the synthetic estrogen (35). recommendations based on research in each lifestyle domain (see Later investigations of the association of estrogen with a variety Table 1; ref. 31). The report used systematic literature reviews of of chronic diseases offer an interesting twist to our understanding of epidemiologic and experimental studies, with assessments of the the importance of study design for exposing true relationships strengths and weaknesses of each study, to determine a between exposures and disease outcomes. Estrogen has long been recommendation based on the best available evidence in 20 viewed as a carcinogen in the breast, in part from associations lifestyle domains. In the same report, the World Cancer Research noted in epidemiologic studies devoted to estimating the correla- Fund/American Institute for Cancer Research issued recommen- tion between endogenous serum estrogen levels and breast cancer dations on specific bioactive foods shown in epidemiologic and risk (36). Overall, case-control and prospective observational studies clinical studies to reduce cancer risk at specific sites (see Table 2). show that higher levels of endogenous serum estrogens are asso- Each of the recommendations was based on the best available ciated with increased breast cancer risk (36, 37). The actual estrogen scientific evidence. exposure of the breast is presumed to be reflected in several Although relatively new, studies of diet, BMI, and physical surrogate markers of exposure (e.g., early age at menarche, older age activity in relation to cancer prevention have yielded important at menopause, nulliparity, older age at first live birth, and findings showing promise for reducing the effect of cancer on postmenopausal obesity) for which an association with breast society by encouraging healthy lifestyle choices. Increased research in these areas, especially in molecular epidemiologic approaches to basic nutritional science, should supply sound scientific data to Table 2. WCRF/AICR 2007 recommendations for cancer- assist policymakers in developing public health strategies. preventive bioactive foods in relation to specific tissue sites

Reproductive Factors and Cancer Risk Foods Tissue site

The idea that hormones that control normal growth in target Non-starchy vegetables Mouth, pharynx, larynx, organs can, under the wrong circumstances, contribute to esophagus, stomach neoplastic transformation has been entertained for a long time, Allium vegetables Stomach and is most evident in hormone-related cancers: breast, endome- Garlic Colorectum trium, ovary, and prostate (32). Estrogen, the best studied hormone Fruits Mouth, pharynx, larynx, of those implicated in carcinogenesis, is involved in several esophagus, lung, stomach different cancer types. Foods containing folate Pancreas The carcinogenic properties of estrogen are evident in Beatson’s Foods containing carotenoids Mouth, pharynx, larynx, lung h 1896observation that oophorectomy is associated with the Foods containing -carotene Esophagus Foods containing lycopene Prostate regression of breast tumors (41). The development of vaginal Foods containing vitamin C Esophagus clear-cell adenocarcinoma following intrauterine exposure to Foods containing selenium Prostate diethylstilbestrol in daughters whose mothers were treated with this drug to prevent spontaneous abortion and premature delivery was a key early epidemiologic observation of the carcinogenic NOTE: Taken from the World Cancer Research Fund/American Institute effect of estrogens (33, 34). The classic epidemiologic approach of for Cancer Research. Food, Nutrition, Physical Activity, and the tracking the cancers on a case-by-case basis, accompanied by Prevention of Cancer: a Global Perspective. Washington, DC: AICR, 2007. detailed questioning, led to an initial report of six cases. A www.aacrjournals.org 2155 Cancer Res 2009; 69: (6). March 15, 2009

Cancer Research cancer risk has been noted (38). These ‘‘risk factors’’ have been activity has been interpreted as ameliorating CHD risk. This benefit incorporated into clinically applicable models to assess breast from estrogen use observed in epidemiologic studies with regard to cancer risk level (39). Although observational studies of postmen- heart disease, together with the benefit to multiple other organ opausal use of exogenous estrogen (hormone replacement therapy) systems (e.g., bone, skin, brain, and vaginal epithelium), led have not consistently reported an association, current and longer prominent clinical researchers to declare that estrogen was a key duration of estrogen use is associated with increased breast cancer antiaging drug and to encourage all menopausal women to take it, risk (40). This epidemiologically demonstrated association, together despite the absence of a prospective randomized clinical trial of with early observations that oophorectomy is associated with breast this hormone for this purpose (46). tumor regression (41), stimulated the development of antiestrogenic The ‘‘great estrogen conundrum’’ (47) pits the antithetical out- agents—selective estrogen receptor modulators and aromatase comes involving breast cancer and cardiovascular disease against inhibitors—for breast cancer treatment and prevention (42, 43). each other. As the level of scientific evidence for the two disease In contrast to breast cancer, other estrogen-responsive chronic outcomes advanced from observational to experimental, widely diseases, such as coronary heart disease (CHD), have been shown held views of estrogen’s overall benefits underwent major revision. in observational studies to exhibit an inverse relationship with The observational findings favoring estrogen use for the heart estrogen levels. Premenopausal women have higher levels of were not substantiated in prospective trials, such as the Heart and estrogen and a lower frequency of CHD than age-matched men Estrogen/progestin Replacement Study (48), although the general- (44), with the risk of CHD increasing dramatically after menopause izability of this finding was limited by the fact that the Heart and as estrogen levels drop precipitously. Epidemiologic evidence Estrogen/progestin Replacement Study cohort consisted of women suggested that higher endogenous estrogen levels or exogenous with pre-existing CHD. Publication of the Heart and Estrogen/ estrogen intake are associated with lower rates of CHD but higher progestin Replacement Study in 1998 was followed by a moderate risk of breast cancer. Thus, in the Nurses’ Health Study, a decline in hormone replacement therapy use (Fig. 3; ref. 49). The prospective observational cohort study of 70,533 postmenopausal Women’s Health Initiative, a well-designed randomized controlled women, participants with no pre-existing heart disease who were trial using hormone replacement therapy as a prospective taking oral conjugated estrogen, had a decreased risk of major intervention in healthy postmenopausal women (50), clarified the coronary events (45). Based on its ability to decrease levels of association between estrogen and these two chronic disease cholesterol, a presumed surrogate biomarker of CHD, estrogen outcomes. The epidemiologic data regarding increased risk of

Figure 3. Cancer death rates for men in the United States (1930–2004).

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Landmarks in the History of Cancer Epidemiology

Figure 4. The effects of the Heart and Estrogen/progestin Replacement Study and the Women’s Health Initiative on hormone replacement use by postmenopausal women.

breast cancer were borne out in the Women’s Health Initiative and Brian Henderson support an association between hormone estrogen plus progestin trial. In contrast, the observational data levels and prostate cancer risk, despite difficulties encountered in pertaining to CHD were contradicted (50), indicating that much of establishing such a link (52). In contrast, a well-conducted the apparent benefit seen in the epidemiologic studies was likely prospective case-control study nested in the Physicians’ Health due to biases inherent in their weaker study design (46). Together, Study showed that when levels of hormone and sex hormone- these two adverse disease outcomes, shown at a higher level of binding globulin were adjusted simultaneously, a strong trend of evidence in the Women’s Health Initiative than in the earlier, obser- increasing prostate cancer risk was observed with increasing vational studies, had downstream ramifications—massive cessation testosterone levels. Such epidemiologic evidence for testosterone of hormone replacement use by postmenopausal women, exceeding involvement in prostate cancer risk, coupled with the availability of that following publication of the Heart and Estrogen/progestin the drug finasteride, which inhibits 5a-reductase, the enzyme that Replacement Study (Fig. 3; 49). The decrease in breast cancer catalyzes conversion of T to dihydrotestosterone, led to design of incidence noted 1 year later in 2003 has been attributed to this the Prostate Cancer Prevention Trial (PCPT), first large phase 3 widespread change in medical practice (51), vindicating the imple- trial of its kind (53); this trial showed a reduction in prevalent mentation of this critically important trial, and emphasizing the prostate cancers in men receiving the 5a-reductase inhibitor. necessity of implementing the highest level of study possible in addressing epidemiologic questions (46). The results of the Women’s Health Initiative emphasize the importance of adhering to the prin- Occupation/Environment ciples of evidence-based medicine in evaluating inputs, both risk- Astute physician observations underlay the recognition of inducing and risk-reducing, in relation to disease outcomes (Fig. 4). potential associations of occupational exposures to natural and Prostate cancer, the most common adult cancer in men in the man-made agents with cancer. Such ‘‘occupational cancers’’ were United States, is hormone-dependent, with its growth depending identified through observational epidemiologic methods as early as on testosterone (T) and its more active metabolite dihydrotestos- 1700, when Bernardini Ramazzini, an Italian physician, published terone (32). This dependency is evidenced in the successful use of De Morbis Artificum Diatriba (Diseases of Workers), a comprehen- androgen ablation/blockade for palliation of advanced disease. sive study of the hazards of exposure to chemicals, dusts, metals, Overall, epidemiologic studies by investigators such as Ronald Ross and other agents among workers in 52 occupations (54). This is www.aacrjournals.org 2157 Cancer Res 2009; 69: (6). March 15, 2009

Cancer Research considered the first study of what would become occupational differences in factors other than genotype may also influence medicine. A more focused epidemiologic study was published in susceptibility to occupational and environmental carcinogens. For 1775 by Percival Pott of Saint Bartholomew’s Hospital in London, example, susceptibility to lung cancer associated with asbestos who described cancer of the scrotum in chimney sweeps, caused by exposure is greatly increased by cigarette smoking (68). constant exposure to soot (55). One of the longest-term studies of the environmental effects on Links between modern occupational exposures and cancer cancer is the Life Span Study of atomic bomb survivors. The Life continue to be suggested by epidemiologic studies. In some cases, Span Study was established to study the long-term carcinogenic notably the links between asbestos and mesothelioma (56) and effects of radiation on the survivors of the bombings of Hiroshima between vinyl chloride monomer and angiosarcoma of the liver and Nagasaki. The cohort consists of 120,321 registered residents of (57), the rarity of the cancer facilitated the recognition of the Hiroshima and Nagasaki who were within 2.5 km (f54,000 association. Links between occupational exposures and more survivors), between 2.5 and 10 km (f40,000 survivors), or more common cancers—such as between aromatic amines and bladder than 10 km (26,580 survivors) from the hypocenter at the time of cancer (58) or between asbestos exposure and lung cancer (59)— bombing. Analysis of diagnoses of solid cancer between 1958 and were less obvious and were only brought to public attention 1998 found 17,448 first primary cancers, and f11% were through the efforts of perceptive clinicians and epidemiologists. associated with atomic bomb radiation exposure (69). Radiation- Quantitative assessment of exposure is difficult, posing chal- associated increases in cancer rates were also found to persist lenges to epidemiologic investigation of occupation/cancer rela- throughout the survivors’ lifetimes. Forty-eight percent of the tionships. Whereas individuals usually can describe their smoking cancers among survivors receiving doses of at least 1 Gy were histories and eating habits reasonably well, they are often relatively attributable to radiation exposure; f18% of the excess cancers ignorant about their work exposures. Moreover, because of long occurred among individuals in the dose range of 5 to 200 mGy. latency periods between exposure and cancer diagnosis and The Life Span Study provides the best quantitative risk estimates of because working conditions change over time, data on current the carcinogenic effects of radiation exposure in humans and is workplace exposures may not reflect those experienced by past a major source of epidemiologic data used for radiation risk workers. Epidemiologists often have had to rely on proxy measures assessment and establishment of radiation protection guidelines. of exposure in studies of occupational cancer. For example, the epidemiologic studies which showed that physicians who special- ized in radiology prior to 1950 were at increased risk of leukemia Infectious Agents because of high ionizing radiation exposure relied primarily on The idea that infectious agents might cause some cancers has knowledge of typical radiation protection practices in different existed for more than a century, but not until the 1950s did time periods, rather than on specifics about the exposure of researchers seriously begin to evaluate such associations (70, 71). At particular individuals (60). Difficulty in obtaining accurate exposure the global level, the estimated percentage of cancers associated with data remains a problem today, hampering recent efforts such as infections is between 10% and 20%, with the implicated organisms the determination of whether occupational exposures to pesticides ranging from viruses and bacteria to parasites, such as Schistosoma (61) and electromagnetic fields (62) influence cancer risk. haematobium, a risk factor for bladder cancer (72). By the 1980s, the Occupational cancers represent only f5% of all cancers in development of new methodologies, including PCR, facilitated developed countries (55), and the number of cases is expected to documentation of associations between the presence of certain decrease in future years because of improvements in industrial viruses and bacteria in tumor tissue and reproductive and gastric hygiene. Nevertheless, occupational cancers are significant because cancers, respectively (71). Using this knowledge, observational people will continue to suffer and die from them during the next studies, such as the National Health and Nutrition Examination few decades as a result of past exposures, and they are more readily Survey, included molecular epidemiologic studies that helped define preventable than cancers caused by tobacco, diet, or other lifestyle the breadth of infection in the U.S. population. For example, factors. National Health and Nutrition Examination Survey data showed Molecular epidemiology (see below) has increased our under- that almost one-half of women 14 to 44 years of age were infected standing of genetic differences in susceptibility to occupational and with the human papillomavirus (HPV), which is responsible for environmental carcinogens. For example, among men at high risk practically all cases of cervical cancer (and possibly squamous cell of bladder cancer because of tobacco smoking and occupational skin and other cancers; refs. 72, 73). Population studies also exposure to aromatic amines, susceptibility to this cancer is influ- suggested an association between hepatitis B and liver cancer, enced by polymorphisms in the genes for glutathione-S-transferase especially in the presence of aflatoxins in the diet (74). In addition, a M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and N-acetyl population study indicated a strong link between Helicobacter pylori transferase 2 (NAT2; ref. 63). Polymorphisms in GSTM1 and the infection and family history of gastric cancer (75). manganese superoxide dismutase (MnSOD/SOD2) gene influence Some rarer cancers also have been associated with infectious mesothelioma risk in asbestos-exposed persons (64). Differences in agents. EBV, a member of the herpesvirus family, infects >95% of all myeloperoxide (MPO) genotypes modify the risk of lung cancer in humans and can cause mononucleosis in adolescents. EBV was asbestos-exposed workers (65). Polymorphisms in GSTT1 and in the isolated from Burkitt lymphoma, an aggressive B-cell lymphoma; gene for cytochrome P450 2E1 (CYP2E1) have been associated with although rare, Burkitt lymphoma accounts for nearly half of all variations in mutagenic risk in workers exposed to vinyl chloride childhood cancers in equatorial Africa. EBV has also been detected (66). Among never-smokers, individuals who are homozygous for in nasopharyngeal carcinoma, non-Hodgkin lymphoma in AIDS the GSTM1-null allele have been found to be at increased risk of patients, and T-cell and Hodgkin lymphomas. EBV is hypothesized developing lung cancer as a result of exposure to environmental to enhance genomic instability, leading to increased likelihood of tobacco smoke (67). Exposure to tobacco smoke through direct the c-myc translocation characteristic of Burkitt lymphoma (76). smoking was covered in a previous section of this review. Individual In nasopharyngeal carcinoma, EBV is associated with alterations

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Landmarks in the History of Cancer Epidemiology in expression of the Bcl-2 and TP53 genes (77). Another member of person with cancer, especially for breast, prostate, colorectal, lung, the herpesvirus family, Kaposi sarcoma-associated herpesvirus, is and stomach cancers (88). The effect of heritability (that portion of consistently detected in all forms of Kaposi sarcoma and in a risk that is due to inherited genes) was statistically significant only specific subset of lymphoproliferative disorders (78). for prostate (42% of risk), colorectal (35%), and breast (27%) cancer. The human T-cell leukemia virus-1 is the etiologic agent of adult The authors concluded that the environment was the ‘‘overwhelm- T-cell leukemia-lymphoma. Infection with human T-cell leukemia ing contributor to the causation of cancer’’ in these twin virus-1 is endemic in sites in southern Japan, the Caribbean, Central populations, precipitating considerable debate (87, 89). Of note, and South America, and parts of Africa and the Middle East. The the notion that heritability fails to explain a large proportion of virus is transmitted by breast-feeding, sexual activity, or exposure cancer incidence and mortality is not new, having been suggested to infected blood. The viral gene tax encodes a transcriptional in multiple earlier investigations (90). transactivator that immortalizes CD4+ lymphocytes, renders them The strong association of lung cancer with tobacco presents an resistant to apoptosis, and also induces angiogenesis (79). unusual challenge to the disentanglement of genetic contributions Cancer prevention strategies that developed in response to from environmental contributions. In the Scandinavian twin study epidemiologic and clinical findings on infectious agents include (88), lung cancer risk was increased in the twin of an individual lifestyle changes, such as reducing exposure to infectious agents, as with lung cancer, although the heritability was limited. A well as immunization by vaccine. Vaccines for cancer prevention systematic review of case-control, cohort, and twin studies have received increased attention since 1981, when the hepatitis B designed to assess the role of family history in lung carcinogenesis vaccine was developed to prevent hepatitis and also prevented liver led to a similar conclusion of only a minor genetic contribution cancer (80). The etiologic association between HPV and cervical (91). The assumption that the environmental factor, smoking, is cancer had been established by the research of Harald zur Hausen similarly concordant in monozygotic and dizygotic twins is not dating back to the 1970s. The importance of this discovery, evi- supported by the data, with a stronger concordance for denced in zur Hausen’s receipt of the 2008 Nobel prize in Physiology monozygotic twins. Furthermore, men show similar lung cancer or Medicine, laid the foundation for work such as that of Douglas concordance ratios for monozygotic and dizygotic twins, consistent Lowy and John Schiller, who developed an HPV vaccine consisting of with a strong shared environmental influence. the major structural viral protein L1 (virus-like particles; ref. 81). One Although twin studies offer insight into genetic contributions such HPV vaccine has been tested in clinical trials, is Food and Drug to cancer, the rarity of twins limits the effect of twin studies on Administration–approved, and is being distributed among those research, necessitating reliance on alternative analytic approaches. at risk for cervical cancer (82, 83). Presently, a vaccine against Family-based association studies. The aggregation of specific H. pylori (84) is in early-phase testing in small numbers of people. cancers or constellations of cancers in families is a necessary but Early results from this controlled, single-blind phase 1 clinical trial in insufficient criterion for inferring genetic contribution to disease 57 volunteers suggest that the vaccine is safe and potentially useful; (87). Astute clinical observations of ‘‘cancer’’ families led to the the authors recommended further clinical study (84). identification of genetic syndromes such as the Li-Fraumeni (92) and Lynch (hereditary nonpolyposis colorectal cancer) syndromes (85).

Genetic Epidemiology Modern Molecular Genetic Epidemiologic Studies A century ago, the prevailing view was that cancer was an Genome-wide linkage analysis has successfully superimposed inevitable result of an individual’s genetic destiny. By the 1960s, molecular biological tools on the pedigree approach to map the epidemiologic evidence suggested that up to 90% of cancers were actual genes responsible for cancers with monogenic, ‘‘Mendelian,’’ strongly associated with avoidable factors, i.e., factors other than inheritance patterns (93). Analysis of families with multiple, inherited predisposition. Recent years have seen a resurgence of usually early onset cancer cases by linkage approaches such as research emphasis on genetic contributions. The modern field positional cloning has identified genes that are mutated in BRCA1 BRCA2 of genetic epidemiology evolved out of the recognition that some affected individuals. and in breast and ovarian MLH1 MSH2 cancers cluster within families (85), implicating an inherited cancer syndrome, and in hereditary nonpolyposis APC component in human carcinogenesis and suggesting that a similar colorectal cancer, and in familial adenomatous polyposis genetic contribution might occur in nonfamilial, sporadic cancers. were identified in this manner. Such highly penetrant gene Parallel developments in high-throughput genotyping technologies variants are implicated in only a small percentage of cancers. and accompanying analytic computational methods enabled Most cancers are complex, quantitative traits reflecting the researchers to identify the actual physical locations and identities interplay of common variations in multiple genes (epistasis), each of implicated genetic factors, rather than simply establishing the conferring only minor increases in risk, as well as interactions existence of genetic contributions to carcinogenesis (86). with environmental factors (93, 94). Candidate-gene studies are hypothesis-based, involving the Traditional Studies Documenting Genetic selection of genes and polymorphisms based on criteria such as Contributions to Carcinogenesis gene function or location in a region of linkage (93). Overall, this Twin studies. An early laboratory for studying genetic ‘‘gene-by-gene functional candidate gene approach’’ (94) has had contributions to complex human traits, including diseases such limited success; with rare exceptions, including those discussed as cancer, was recognized in identical (monozygotic) twins. Given above, few polymorphisms show consistent associations with the shared environment in twins, differences in phenotypic cancer from one study to another (95). An example is a recent concordance between monozygotic and dizygotic twins were breast cancer candidate gene study that examined variants in 11 attributed to genetic factors (87). A key study analyzing data from genes encoding proteins in the estrogen metabolic pathway (96). 11 cancer sites in 44,788 Scandinavian twin pairs revealed only a Although single factor analyses suggested a possible association moderate increase in overall risk of the same cancer in a twin of a of CYP1B1_1294_GG with risk, no significant associations were www.aacrjournals.org 2159 Cancer Res 2009; 69: (6). March 15, 2009

Cancer Research observed by multifactor analyses. Candidate gene approaches Thus, GWAS has the potential to localize cancer risk to specific to lung cancer risk must necessarily separate genetic from chromosomal regions. Its central assumption, however, that a environmental (tobacco) contributions (97). Thus, an XRCC1 marker in tight linkage disequilibrium with a polymorphism that (DNA repair gene) polymorphism shows significant association directly influences cancer risk will always be detectable in asso- with risk overall but especially in nonsmokers, whereas heavy ciation with disease at an appropriate sample size, has been smokers show inverse risk (97). In addition, a recent study of gene- challenged (105, 106). GWAS is not self-sufficient, and embracing environment interactions identified polymorphisms in the nicotinic GWAS should not be taken as a rejection of earlier strategies. GWAS acetylcholine receptor gene cluster on chromosome 15q24 with and candidate-gene investigations should proceed side-by-side. effects on smoking quantity, nicotine dependence, and the risk The scientific paradigm of confirmation and validation must of lung cancer and peripheral artery disease in populations of apply to GWAS, with ultimate confirmation coming from alternate European descent (98). technologies. The value of GWAS will be to direct investigations to The genome-wide association study (GWAS) approach is promising sites containing plausibly causative genes for candidate- agnostic, requiring no prior knowledge of position or function of gene investigations, more refined regional mapping, and detailed a marker (91, 99). Putative cancer-associated loci are localized by functional analyses. exploiting their tight linkage disequilibrium with known single nucleotide polymorphisms that are densely distributed throughout the genome and serve as surrogates for the polymorphism of Conclusion: Implications for Cancer Prevention interest (100). To economize on cost and the large sample size Epidemiologic research has successfully identified numerous required for statistical validation of complex disease association, putative and some confirmed causal factors in specific cancers. analysis is restricted to a subset of ‘‘tag single nucleotide Where the strength of association is indisputable, as between polymorphisms’’ that capture most of the linkage in a region tobacco and lung cancer, observational knowledge has stimulated (100). Other cost-conserving measures include multistaged designs efforts at control of the implicated factor. For this discipline to have a (sequential GWAS analyses; refs. 99–102), minor allele frequencies meaningful effect on its sister field of cancer prevention, decisions of z0.1, and odds ratios for effect sizes of z1.3 (94). Still, a sample regarding the design of epidemiologic studies, including the size of z1,000 cases is required, necessitating collaboration among selection of putative risk factors for evaluation, need to be made multiple individual projects (100). prospectively with an eye to the implications of study findings for Supporting evidence for a strong genetic component in prostate subsequent clinical and public health research evaluating potential cancer, GWAS implicated the 8q24 locus in this disease, as well as interventions. colorectal, breast, and ovarian cancers (102, 103). GWAS of men aged V60 years at diagnosis and with a family history revealed seven loci on multiple chromosomes associated with prostate Disclosure of Potential Conflicts of Interest cancer, two of which (8q24 and 17q) had previously been reported No potential conflicts of interest were disclosed. (99). A GWAS study of breast cancer in high-risk Ashkenazi Jewish BRCA women who were negative for a mutation showed the Acknowledgments strongest disease association with 6q22.33, but also a significant association with FGFR2 (chromosome 10q25.3-q26; ref. 104). A Received 9/29/2008; revised 12/8/2008; accepted 2/3/2009; published OnlineFirst 3/10/09. Breast Cancer Association Consortium study showed strong, The costs of publication of this article were defrayed in part by the payment of page consistent associations of FGFR2 and three other genes (TNRC9, charges. This article must therefore be hereby marked advertisement in accordance MAP3K1 LSP1 with 18 U.S.C. Section 1734 solely to indicate this fact. , and ) with breast cancer (101). In addition, lung The authors are grateful to Dr. Kenneth Buetow and Darrell Anderson for generous cancer susceptibility was mapped to 15q24-25.1 by GWAS (7). contributions to the scientific and technical preparation of this article.

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Landmarks in the History of Cancer Epidemiology

Peter Greenwald and Barbara K. Dunn

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