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Discovering the causes of cancer and the means of prevention

Director's Corner on Global Health - Stephen J. Chanock, M.D.

DCEG sustains a productive partnership with China for cancer research.

A substantial fraction of DCEG’s research is conducted internationally, with investigators pursuing compelling questions driven by unusual cancer patterns or exposures in Asia, Africa, Central America, South America, and Eastern Europe. In this issue of Linkage, we highlight activities in China, where DCEG has been collaborating with Chinese colleagues for more than 30 years.

Investigation of global cancer incidence and mortality patterns provides clues to cancer etiology and supports the development of cancer control strategies.

Together, we have sought to identify causes of elevated cancer rates and, subsequently, to formulate and conduct etiologically based cancer control strategies that could provide benefits on a global level. Our research in China focuses on a range of cancers—notably lung cancer, breast cancer, gastrointestinal tumors, and lymphoma—as well as important risk factors, such as genetic susceptibility, indoor air pollution, nutrition, occupational exposures, physical activity, and viruses. Simultaneously, we have built strong ties with the NCI Center for Global Health to enhance scientific training and research resources in China.

Insights from Cancer Maps

DCEG researchers have worked closely with scientists in China to investigate the etiologic basis of distinctive cancer patterns across the most populous country in the world. When China opened “its doors” to Westerners in the 1980s, NCI epidemiologists, led by Joseph F. Fraumeni, Jr., M.D., and colleagues from DCEG were among the first to visit and forge strong collaborations, many of which continue today. In the United States, maps plotting cancer deaths already had highlighted geographic regions with high or low mortality rates, which, in turn, generated the underlying hypotheses for new studies. Chinese cancer maps illustrated interesting patterns of risk for cancers of the lung, esophagus, and stomach and set the course for investigations with DCEG that continue to this day.

An example of a cancer map illustrates stomach cancer mortality among males in China between 1973-1975. The counties with the highest rates are shown in red.

Lung Cancer Among Never-smoking Women

Beginning with studies in Shanghai and Shenyang, DCEG has investigated the observed excess of lung cancer among nonsmoking women in China, which is several-fold higher than rates in the United States. Based on case-control and cohort studies conducted in Xuanwei, where lung cancer incidence among nonsmokers is the highest in the world, Qing Lan, M.D., Ph.D., M.P.H., and collaborators established that indoor air pollution from coal used for cooking was associated with the observed elevated risk. When families ventilated the stoves or switched to outdoor portable stoves, lung cancer rates in this region decreased substantially. These studies provided important evidence for the International Agency for Research on Cancer (IARC), which classified coal-combustion products as an established carcinogen in 2006.

A Chinese woman cooks indoors over a fire pit with smoky coal in Xuanwei, China.

A Chinese woman cooks indoors over a fire pit with smoky coal in Xuanwei, China.

A new case-control study was subsequently launched to identify which constituents of coal contribute to the striking excess in this region and to quantify the relationship between lung cancer risk and coal use, exposure to polycyclic aromatic hydrocarbons, genetic susceptibility, and gene-environment interactions. Currently, the portfolio also includes studies of occupational and environmental exposures in nonsmoking women in collaboration with Vanderbilt University and the Shanghai Cancer Institute.

Dr. Lan and her colleague Nathaniel Rothman, M.D., M.P.H., M.H.S., have co-led an international consortium to identify lung cancer susceptibility alleles in nonsmoking women. To date, they have identified susceptibility alleles not observed in smokers.

Upper Gastrointestinal Cancers

Esophageal and gastric cancer rates in China are among the highest in the world, causing up to 20 percent of all deaths in some high-risk areas. Nearly all of the esophageal malignancies are esophageal squamous cell carcinomas (ESCC), and two-thirds of the gastric cancers are adenocarcinomas arising in the gastric cardia. During the past 30 years, DCEG investigators Philip R. Taylor, M.D., Sc.D., Sanford M. Dawsey, M.D., and Christian Abnet, Ph.D., M.P.H., Acting Chief of the Nutritional Epidemiology Branch, have collaborated with the Chinese Academy of Medical Sciences and the Shanxi Cancer Hospital and Institute to conduct a series of etiologic and early detection and treatment studies of these upper gastrointestinal cancers. Initially, the investigators observed that daily supplementation with a micronutrient combination of selenium, vitamin E, and beta-carotene significantly reduced total mortality and gastric cancer mortality in a randomized intervention trial of 30,000 participants. This observed effect persisted for 10 years beyond the study supplementation period. Observational studies in the same population showed an inverse association between serum selenium levels and the risk of both esophageal and gastric cardia cancers, suggesting that community-wide selenium fortification may be one way to protect the population from these cancers.

Map shows an area of high risk for esophageal cancer.

Map shows an area of high risk for esophageal cancer.

Dr. Abnet also has shown a consistent association between tooth loss, poor oral hygiene, and increased risk for ESCC and gastric cancer in these high-risk populations. He has studies under way to determine whether the bacterial flora of the oral cavity plays a direct role in this association. Findings from the DCEG team have informed our understanding of ESCC progression, and the team has developed screening techniques that are now used by the Chinese government among 200,000 asymptomatic adults each year to find and remove curable precursor lesions. The careful collection of biospecimens in studies of upper gastrointestinal cancers has enabled DCEG investigators to pursue genetic analyses of germline susceptibility alleles and somatic alterations of both precancerous and cancer tissue.

Mitchell H. Gail, M.D., Ph.D., and colleagues at the Peking University School of Oncology and the Beijing Institute for Cancer Research led an intervention trial in the Linqu County of China, where gastric cancer accounts for 42 percent of all cancer deaths. Continued follow-up from this trial, which began in 1994, has demonstrated that short-term antibiotic treatment for Helicobacter pylori (or H. pylori) significantly reduced the incidence of gastric cancer, an effect that persisted up to 15 years post-intervention. Read more about this work on H. pylori.

Another cancer that occurs more frequently in China but is relatively uncommon in the United States is biliary tract cancer, the incidence of which has increased remarkably in recent years. DCEG has invested in a population-based, case-control study of biliary tract cancer in Shanghai in collaboration with the Shanghai Cancer Institute. The study has shown that gene variants and health conditions related to inflammation are associated with increased risk, whereas tea drinking and aspirin use are associated with reduced risk. Jill Koshiol, Ph.D., who is leading the study, is capitalizing on recent methodological advances to reliably measure circulating and local immune response biomarkers in order to examine the role of inflammation more directly.

Lessons from Studies on Cancer Subtypes

Recently, female breast cancer rates have increased in China, where historically women experienced much lower rates than in the West. In particular, rates among younger Asian women have approached or even surpassed those of Western women. Xiaohong Rose Yang, Ph.D., M.P.H., is collaborating with colleagues from the Chinese Academy of Medical Sciences, the Shanxi Cancer Hospital and Institute, and the Chinese University of Hong Kong to characterize molecular subtypes of breast cancer and their relationship with known breast cancer risk factors among Chinese women.

Another important effort is focusing on the distribution of lymphoma subtypes, how these differ in China, and clues as to their etiology. The most common histologic subtype of non-Hodgkin lymphoma in both Asians and Caucasians is diffuse large B-cell lymphoma. However, some subtypes, such as NK/T-cell lymphoma, have a substantially higher incidence among Asians. DCEG investigators have initiated AsiaLymph to evaluate occupational and environmental exposures, genetics, lifestyle, and infectious agents in relation to different lymphoma subtypes.

Special Exposure Patterns

DCEG has a longstanding commitment to investigate occupational and environmental exposures in China, often in settings where both high and wide-range exposure levels can provide important insights into the mechanisms underlying and the risks for specific cancers. For instance, DCEG investigators from the Occupational and Environmental Epidemiology Branch, including Drs. Lan and Rothman along with Chief Debra Silverman, Sc.D., and other colleagues have collaborated on studies of benzene, formaldehyde, trichloroethylene, and particulates (e.g., coal combustion products and diesel exhaust), all of which are relevant to exposures in the United States. Many of these studies have been conducted in collaboration with investigators from Utrecht University in Germany and the University of California at Berkeley. The study findings contributed to the classification of these exposures as carcinogenic by such organizations as IARC and the U.S. National Toxicology Program as well as foundational observations for determination of regulations by the U.S. Environmental Protection Agency.

In collaboration with the Shanghai Cancer Institute and Vanderbilt University, Charles Matthews, Ph.D., and Steven Moore, Ph.D., M.P.H., have established a series of studies to investigate the impact of physical activity on cancer risk. They developed a questionnaire to characterize the unique types of physical activity among the Chinese population. The questionnaire was validated using accelerometer data and physical activity logs collected from study participants and is available to other researchers conducting epidemiologic investigations in China. The study also includes biospecimens, which are being analyzed to evaluate whether characteristics of physical activity are associated with circulating biomarkers linked to cancer risk.

Altogether, the vast array of DCEG’s collaborative research efforts in China has significantly advanced understanding of the causes of many cancers. Along the way, we have helped to inform cancer control and early detection strategies that are relevant not only for the Chinese but also for populations across the globe. As the work in China continues, we look forward to new insights into the etiology of different cancers that could serve as the foundation for translational research and more preventive measures.

Return to the Fall 2014 issue of Linkage.