© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 10, 773,
May 17, 2000
© 2000 Oxford University Press
IN THIS ISSUE |
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutation of the ATM (A-T-mutated) gene. Individuals with one mutated ATM gene, called A-T carriers, have an increased risk of breast cancer. The ATM protein is activated in response to double-stranded breaks caused by ionizing radiation, and the activated protein is involved in the regulation of various cell cycle checkpoints. In this issue, Khanna (p. 795) reviews the molecular structures of the ATM gene and ATM protein. She describes how the activated ATM protein signals the presence of DNA damage by phosphorylating target proteins involved in cell cycle arrest and by interacting with protein complexes containing BRCA1 and other DNA repair proteins. Analysis of ATM mutations suggests that different mutations are associated with A-T and with cancer. Khanna notes that null mutations lead to A-T, and dominant negative missense mutations predispose the A-T carrier to cancer.
Gene Methylation and Breast Cancer
Evidence suggests that the retinoic acid receptor ß2 (RAR-ß2) gene is a tumor supressor gene, and its expression is reduced in many malignant tumors. Widschwendter et al. (p. 826) analyzed eight breast cancer cell lines and 16 breast cancer biopsy specimens to investigate whether methylation could reduce the expression of RAR-ß2. The authors found that the 5' region of the RAR-ß2 gene was methylated in many breast cancer cell lines and tumors, and demethylation of cell lines with 5-aza-2'-deoxycytidine restored inducibility of RAR-ß2 by all-trans-retinoic acid. They conclude that knowing the methylation status of the RAR-ß2 gene may facilitate chemoprevention by treatment with a demethylating agent and retinoic acid.
In an accompanying editorial, Sporn (p. 780) points out that the results of Widschwendter et al. suggest both a mechanism that could explain the lack of efficacy of retinoids and a practical strategy for making them more effective. Sporn adds that developing demethylating agents that are effective in chemoprevention is one of many challenges facing basic and clinical pharmacologists.
p53 Mutational Hotspots and Smoke Components
Polycyclic aromatic hydrocarbons, or PAHs, are ubiquitous byproducts of the combustion of all types of organic matter and are carcinogenic components of tobacco smoke. Benzo[a]pyrene diol epoxide (B[a]PDE) is a metabolically activated form of the ubiquitous PAH compound benzo[a]pyrene. Previous studies have shown that B[a]PDE reacts strongly with the p53 tumor suppressor gene, which is mutated in 60% of human lung cancers, to produce a highly specific spectrum of mutations. Smith et al. (p. 803) report that diol epoxides of five other common PAHs with structural similarities to benzo[a]pyrene produced damage to p53 similar overall to that produced by B[a]PDE, but with individual variations. The authors conclude that activated PAH components of tobacco smoke—in addition to the classic reference compound benzo[a]pyrene—may contribute substantially to the mutational spectrum of p53 in human lung tumors.
In an accompanying editorial, Hecht (p. 782) points out that the Smith et al. study provides important support for the key role of metabolically activated carcinogens in the induction of human lung cancer.
"Little is known about the relevant exposures, DNA binding, and repair of damage induced by a complex mixture of PAHs in vivo."
—Smith et al.
Patterns of Melanoma Mortality Among Whites
Jemal et al. (p. 811) describe the changing patterns of melanoma mortality rates among whites between 1950 and 1994 and assess the relationship between geographic patterns and UV radiation (UV-B) level. From 1950–1954 through 1990–1994, melanoma mortality rates increased by 191% among men and 84% among women. Mortality rates peaked in women born in 1930 through 1950 and in men born in 1935 through 1950. Mortality showed a strong North–South gradient in the 1950–1969 study period; however, the gradient weakened in the study period from 1985 through 1994. The researchers conclude that melanoma mortality in the United States reflects the complex interplay of UV radiation levels in each geographic region, the geographic mobility of the population, and risk awareness and early detection.
Cervical Cancer Screening in Low-Resource Settings
Establishment of high-quality programs based on Pap smears, or cytology, to screen for cervical cancer in underdeveloped areas can be difficult for a variety of reasons. In a low-resource setting in South Africa, Kuhn et al. (p. 818) compared the accuracy of testing for DNA from human papillomavirus (HPV) infection, which is strongly associated with risk of cervical cancer, with that of cytology. They found that HPV DNA testing was comparable in sensitivity to cytology in detecting cervical lesions as confirmed by colposcopy, but cytology was more specific for detecting high-grade lesions. The authors conclude that HPV DNA testing may be more practical than cytologic testing in low-resource settings.
Dietary Fat and Breast Cancer
The association between dietary fat intake and breast cancer has generated considerable debate. To extend the prospective epidemiologic evidence on this question, Velie et al. (p. 833) examined the association of adult dietary intake of fat and fat subtypes with breast cancer risk in a large, prospective cohort of postmenopausal women. The authors observed no overall association between breast cancer and adult intake of total fat or any fat subtype. When analyses were restricted to women with no history of benign breast disease, however, they observed a positive association of total fat intake with breast cancer. The association appeared to be attributable to unsaturated fat intake and oleic acid intake in particular. The authors conclude that, although there was no association between fat and breast cancer in the overall cohort, the observed positive association among women with no history of benign breast disease is provocative and warrants further study.
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