ScienceWeek

4. ENVIRONMENTAL FACTORS

ENVIRONMENT AND CANCER: WHO ARE SUSCEPTIBLE?

Frederica P. Perera (Columbia University, US) discuss environment and cancer, the author making the following points:

1) Most cancer results from the interaction of genetics and the environment (1-3). That is, genetic factors by themselves are thought to explain only about 5% of all cancer (3). The remainder can be attributed to external, "environmental" factors that act in conjunction with both genetic and acquired susceptibility. This is an optimistic message for cancer prevention in that exposure to environmental carcinogens -- tobacco smoke, dietary constituents, pollutants (in the workplace, air, water, and food supply), drugs, radiation, and infectious agents -- is theoretically preventable. But it challenges scientists to document environment-susceptibility interactions and policy-makers to rapidly translate this knowledge into public health interventions. The pressure is great: 560,000 people die of cancer every year in the United States (6.6 million worldwide), and almost 1.4 million new cases are diagnosed in the United States annually (4).

2) The two parallel approaches in prevention are (i) strategies to help individuals modify hazardous lifestyles or use chemoprevention, and (ii) reduction of involuntary exposure to carcinogens, usually through regulation. Both approaches have been stymied by our inability to explicitly address risks to sensitive subsets of the population. Historically, policy-makers such as the U.S. Environmental Protection Agency have based their decisions on the assumption that all individuals in a population have the same biologic response to a specified dose of a carcinogen. These policymakers are only now becoming aware of the need to account for interindividual variation in susceptibility, especially as it affects risks to children (5).

3) In summary: Acting in concert with individual susceptibility, environmental factors such as smoking, diet, and pollutants play a role in most human cancer. However, new molecular evidence indicates that specific groups -- characterized by predisposing genetic traits or ethnicity, the very young, and women -- may have heightened risk from certain exposures. This is illustrated by molecular epidemiologic studies of environmental carcinogens such as polycyclic aromatic hydrocarbons and aromatic amines. Individual genetic screening for rare high-risk traits or for more common, low-penetrant susceptibility genes is problematic and not routinely recommended. However, knowledge of the full spectrum of both genetic and acquired susceptibility in the population will be instrumental in developing health and regulatory policies that increase protection of the more susceptible groups from risks of environmental carcinogens. This will necessitate revision of current risk assessment methodologies to explicitly account for individual variation in susceptibility to environmental carcinogens.

References (abridged):

1. F. P. Perera, J. Natl. Cancer Inst. 88, 496 (1996); F. P. Perera and I. B. Weinstein, J. Chron. Dis. 35, 581 (1982)

2. R. Doll, Carcinogenesis 17, 177 (1996)

3. S. Venitt, Clin. Chem. 40, 1421 (1994) [Abstract] ; A. G. Knudson, Cancer Res. 45, 1437 (1985)

4. Cancer Facts and Figures (American Cancer Society, Atlanta, GA, 1997)

5. L. R. Goldman, Environ. Health Perspect. 103 (suppl. 6), 13 (1995); C. Bearer, Future Child. 5, 11 (1997)

Science 1997 278:1035

Related Background Brief:

IN UTERO DNA DAMAGE FROM ENVIRONMENTAL POLLUTION IS ASSOCIATED WITH SOMATIC GENE MUTATION IN NEWBORNS. Transplacental exposure to carcinogenic air pollutants from the combustion of fossil fuels is a growing health concern, given evidence of the heightened susceptibility of the fetus. These mutagenic-carcinogenic pollutants include aromatic compounds such as polycyclic aromatic hydrocarbons that bind to DNA, forming chemical-DNA adducts. The authors have investigated the genotoxic effects of transplacental exposure in humans by analyzing aromatic-DNA adducts and the frequency of gene mutations at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in umbilical cord and maternal blood samples. The authors show, in a cross-sectional study of 67 mothers and 64 newborns from the Krakow Region of Poland, that aromatic-DNA adducts measured by 32P-postlabeling are positively associated with HPRT mutant frequency in the newborns (á = 0.56, P = 0.03) after controlling for exposure to tobacco smoke, diet, and socioeconomic status. In contrast to the fetus, HPRT mutations and DNA adducts do not reflect similar exposure periods in the mother, and the maternal biomarkers were not correlated. Adducts were higher in the newborn than the mother, indicating differential susceptibility of the fetus to DNA damage; but HPRT mutation frequency was 4-fold lower, consistent with the long lifetime of the biomarker. The authors suggest these results provide the first demonstration of a molecular link between somatic mutation in the newborn and transplacental exposure to common air pollutants, a finding that is relevant to cancer risk assessment. F. Perera et al: Cancer Epidemiology Biomarkers & Prevention 2002 11: 1134.

Related Background Brief:

THE RELATIONSHIP BETWEEN GENETIC DAMAGE FROM POLYCYCLIC AROMATIC HYDROCARBONS IN BREAST TISSUE AND BREAST CANCER. A number of polycyclic aromatic hydrocarbons (PAH) are widespread environmental contaminants that cause mammary cancer experimentally. The authors investigated whether exposure and susceptibility to PAH, as measured by PAH DNA adducts in breast tissue, are associated with human breast cancer. The authors carried out a hospital-based case-control study using immunohistochemical methods to analyze PAH DNA adducts in tumor and non-tumor breast tissue from cases and benign breast tissue from controls. The subjects were white, African-American and Latina women without prior cancer or treatment, including 119 women with breast cancer and 108 with benign breast disease without atypia. PAH DNA adducts measured in breast tumor tissue of 100 cases and in normal tissue from 105 controls were significantly associated with breast cancer (OR=4.43, 96% CI 1.09 18.01) after controlling for known breast cancer risk factors and current active and passive smoking, and dietary PAH. There was substantial interindividual (17-fold) variability in adducts overall, with 27% of cases and 13% of controls having elevated adducts. The odds ratio for elevated adducts in tumor tissue compared with control tissue was 2.56 (1.05 6.24), after controlling for potential confounders. Adduct levels in tumor tissue did not vary by stage or tumor size. Among 86 cases with paired tumor and non-tumor tissue, adducts levels in these two tissues were highly correlated (r=0.56, P < 0.001). However, the corresponding associations between case-control status and adducts measured in non-tumor tissue from 90 cases and in normal tissue from 105 controls were positive but not statistically significant. Overall, neither active nor passive smoking, or dietary PAH were significantly associated with PAH DNA adducts or breast cancer case-control status. The authors suggest these results indicate that genetic damage reflecting individual exposure and susceptibility to PAH may play a role in breast cancer; but more research is needed to determine whether the findings are relevant to causation or progression of breast cancer. A. Rundle et al: Carcinogenesis 2000 21:1281

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