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Discovering the causes of cancer and the means of prevention

Obesity: A Provocative Question and the Search for Answers

July 2011 - Linkage Newsletter

NCI Director Harold Varmus, M.D., created the "Provocative Questions" initiative to assemble a list of important topics and advances that will stimulate NCI's research communities to use laboratory, clinical, and population sciences in effective and imaginative ways. One question particularly resonates for DCEG investigators: What molecular mechanisms underlie the association of obesity with the risks of cancer?

Obesity has become a major public health problem in the United States and elsewhere in the world, affecting rates of cardiovascular disease, endocrine disorders such as diabetes, and cancer. Many studies have documented the contribution of obesity to the incidence of (and death from) a number of cancers, including colon, breast (in postmenopausal women), endometrium, kidney, esophagus (adenocarcinoma), gastric cardia, pancreas, gallbladder, and liver. How this happens—what the mechanisms are that underpin these associations—is poorly understood.

Apple and pear body shapes are often used to describe variations in fat storage.Obesity is not a singular condition that affects our health, and many factors modify its effects. These factors include age—when a person first becomes obese and for how long; physical activity—how much and how often we move around; and our ethnic/racial makeup— which can affect the way we gain and maintain weight. Furthermore, specific biomarkers may mediate the obesity-cancer links, such as hormones and a range of metabolites (i.e., the substances left when the body breaks down food, drugs, or other chemicals). Thus, understanding obesity's role in cancer requires a multifaceted research approach.

Cancer Sites

DCEG investigators are conducting wide-ranging research on obesity and cancer risks. Emerging technologies, such as high-throughput assays and the large-scale collection and storage of biospecimens, have been especially helpful in allowing investigators to examine these relationships as never before. Endometrial cancer draws attention because it shows one of the strongest relationships to obesity of all the cancers. Louise A. Brinton, Ph.D., Chief of the Hormonal and Reproductive Epidemiology Branch (HREB), Dr. Mia M. Gaudet of the American Cancer Society (a former fellow in HREB), Mark E. Sherman, M.D. (HREB), and colleagues are using high-throughput technologies for a metabolomic assessment of body mass index (BMI) and the risk of endometrial cancer in DCEG's Polish Women's Health Study. From a panel of 69 study metabolites (including 15 amino acids, 45 acylcarnitines, and 9 fatty acids), the investigators discovered 7 metabolites significantly associated with the risk of endometrial cancer, even when adjusting for BMI. "This study provides the first evidence that metabolomic profiles in serum can be used to disentangle the biologic mechanisms that influence this obesity-related cancer," said senior author Dr. Sherman.

Table showing World Health Organization classifications for obesity corresponding to body mass index (BMI). Underweight < 18.50; Normal range = 18.50 to 24.99; overweight = 25.00 to 29.99; obesity class I = 30.00 to 34.99; obesity class II = 35.00 to 39.99; and obesity class III is greater or equal to 40.00.

The incidence of esophageal adenocarcinoma (EAC), another obesity-related cancer, has been rising more rapidly than any other cancer in the United States. Scientists have hypothesized that obesity causes a mechanical change in esophageal sphincter tone, which allows gastroesophageal reflux, a known risk factor for EAC. A recent investigation by Christian C. Abnet, Ph.D., M.P.H., Nutritional Epidemiology Branch (NEB), within the NIH-AARP Diet and Health Study of more than 500,000 subjects, found that individuals with high levels of obesity have a significantly increased risk of EAC compared with people whose weight falls within the normal range. Dr. Abnet and colleagues also are investigating whether body shape and fat distribution are independently associated with risk for EAC and gastric cardia adenocarcinoma. So far, the data indicate an increased risk of EAC associated with both high BMI and high waist-to-hip ratio, whereas gastric cardia adenocarcinoma is associated only with high BMI.

Philip R. Taylor, M.D., Sc.D., Genetic Epidemiology Branch, and colleagues are investigating biomarkers associated with Barrett's esophagus (BE), a lesion that is a precursor to EAC, in a study at the National Naval Medical Center in Bethesda, Maryland. Efforts are being made to identify biomarkers for BE diagnosis, susceptibility states, and progression to dysplasia or EAC.

The incidence of thyroid cancer also has increased significantly in the United States since the early 1980s, and until recently, the connection between obesity and thyroid cancer remained uncertain. However, Cari Meinhold Kitahara, Ph.D., Radiation Epidemiology Branch (REB), and other DCEG investigators pooled data from five prospective U.S. studies comprising approximately 850,000 subjects and found that high BMI increased the risk of thyroid cancer in both men and women (see Figure 1).

The prevalence of prostate cancer, the most common cancer in men in the United States, appears to be rising around the world, but the etiologic role of obesity has remained elusive. A recent review of existing data led by Ann W. Hsing, Ph.D., Infections and Immunoepidemiology Branch, revealed an increased incidence of high-grade prostate cancer and a decreased incidence of low-grade tumors associated with obesity. In addition, prostate cancer mortality was consistently associated with obesity in several studies. Research findings have suggested that obesity may influence the risk of prostate cancer through its effects on androgen metabolism and interaction with other risk factors, such as insulin resistance, diabetes, inflammation, and genetic susceptibility.

Figure 1 shows the estimated hazard ratios and confidence intervals (CIs) for thyroid cancer risk according to body mass index (BMI). BMI is the weight in kilograms divided by the square of the height in meters.

In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort, Demetrius Albanes, M.D. (NEB), and other investigators found a strong positive association between fasting serum insulin concentrations and the risk of prostate cancer. Despite the association of diabetes with higher rates of many other cancers, Neal D. Freedman, Ph.D., M.P.H., and Gabriel Lai, Ph.D., both of NEB, and their colleagues recently confirmed that diabetes is associated with lower rates of incident prostate cancer. The mechanism of the association between diabetes and a decreased risk of prostate cancer may involve insulin metabolism or genetic pathways.

Cancer Mechanisms

Weight distribution may provide a clue to the mechanism by which obesity is tied to the risk of cancer. Fat located around the body's midsection may operate differently than body fat overall, and waist circumference (WC) represents a measure that accounts for the accumulation of abdominal fat. Using the NIH-AARP Diet and Health Study, Dr. Michael F. Leitzmann, formerly of NEB, Steven C. Moore, Ph.D. (NEB), and colleagues examined WC and BMI in relation to cause-specific death. Increased abdominal fat as measured by WC was related to a higher risk of several major causes of death, including lung cancer and chronic respiratory disease, independent of BMI (see Figure 2).

Physical activity and sedentary behavior also may have differential effects on risk associated with obesity, giving clues to mechanism. Using information recorded by a lightweight accelerometer used for the National Health and Nutritional Examination Survey (NHANES) in 2003–2004, Charles Matthews, Ph.D. (NEB), and colleagues reported the first objective data on the amount of time spent in overall sedentary behaviors in a nationally representative sample. After adjusting for the effect of exercise, the amount of daily sedentary time was linked to levels of C-reactive protein, insulin, and other cardio-metabolic biomarkers. According to Dr. Matthews, "To understand the mechanisms linking physical activity and carcinogenesis, we have to expand our repertoire of exposure assessments so that we can look at the effects of too much sitting, not just too little exercise."

In addition, excess weight may operate differently across the life span—a special concern given the increasing prevalence of overweight and obesity among children, adolescents, and young adults each year. Current DCEG research includes a systematic investigation within the NIH-AARP Diet and Health Study, led by Amy Berrington de González, D.Phil. (REB), Dr. Kitahara, and Dr. Moore, that seeks to relate the risk of different forms of cancer to BMI at various ages (i.e., 18, 35, and 50 years old and age at study entry) as well as to weight gain throughout adulthood. This comprehensive study will help to identify critical time periods during which obesity influences cancer induction and progression, which might help inform more effective prevention interventions.

Figure 2 shows the relative risk of death from cancer according to the waist circumference in centimeters for men and women. The analyses of waist circumference were adjusted for body mass index.

The Way Forward

Large-scale biospecimen collections are allowing molecular epidemiologists to use more advanced analyses of metabolites and other biomarkers. In addition, new tools for data collection are providing investigators with the means to think creatively and push the boundaries in linking nutrition and cancer. For example, accelerometers offer the ability to continuously record data for physical activity over specified time intervals. New web-based tools developed by DCEG and collaborators in the NCI Division of Cancer Control and Population Sciences and the Division of Cancer Prevention, such as the Physical Activities Completed over Time in 24 Hours (ACT-24) and the Automated Self-Administered 24-Hour Dietary Recall (ASA24), allow participants to enter information on physical activity or diet in a convenient, online format.

In response to the growing importance and interest in the field, NEB investigators Dr. Matthews, Dr. Moore, and Deputy Chief Rashmi Sinha, Ph.D., recently established the DCEG Energy Balance and Obesity Working Group to further interdisciplinary research. Through ongoing collaborations with the NCI Cohort Consortium and other collaborative networks, the availability of state-of-the-art methods and tools is allowing DCEG investigators to contribute to the search for mechanisms underpinning the association of obesity with the risks of cancer.