© 2005 Oxford University Press
IN THIS ISSUE
EGFR Gene Mutations in Lung CancersTo clarify the role of mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancer pathogenesis, Shigematsu et al. (p. 339) sequenced the EGFR TK domain of non–small-cell lung cancers (NSCLCs), normal lung tissue samples, and other epithelial cancers from patients in Japan, Taiwan, the United States, and Australia. They found an EGFR TK domain mutation in 21% of the NSCLCs but not in nonmalignant lung tissue from the same patients or in the other carcinomas. EGFR TK domain mutations were more frequent in never smokers versus ever smokers, in adenocarcinomas versus cancers of other histologies, in patients of East Asian ethnicity versus other ethnicities, and in females versus males. None of the NSCLCs had mutations in both the EGFR TK domain and KRAS, an EGFR signaling pathway gene that is frequently mutated in lung cancers.
In an editorial, Sellers and Meyerson (p. 326) discuss the need for a comprehensive and global view of human cancer genomes. They note that emerging data relating ethnicity to differences in somatic cancer mutations underscores the importance of conducting clinical trials with broad representation across ethnic groups.
Physician Predictors of Mammographic Accuracy
Because the association between physician experience and the accuracy of screening mammography in community practice is not well studied, Smith-Bindman et al. (p. 358) identified characteristics of U.S. physicians associated with the accuracy of screening mammography. They found that, after adjusting for various patient characteristics, physician characteristics were strongly associated with mammography specificity. Higher specificity was associated with at least 25 years, compared with less than 10 years, since receipt of medical degree and with a high focus on screening mammography compared with diagnostic mammography. Higher overall accuracy was also associated with more experience, a high focus on screening mammography, and a high volume of mammograms interpreted annually. The authors conclude that raising the annual volume requirements in the U.S. Mammography Quality Standards Act might improve the overall quality of screening mammography.
Comparing Colorectal Cancer Screening Strategies
Although the efficacy of colorectal cancer screening is generally accepted, there is a lack of agreement about the preferred strategy for routine screening. Segnan et al. (p. 347) conducted a multicenter trial in Italy to compare the participation and detection rates associated with five different colorectal cancer screening strategies among 55–64 year olds at average risk of colorectal cancer. The subjects were randomly assigned to a biennial immunologic fecal occult blood test (FOBT) delivered by mail, a biennial FOBT delivered by general practitioner or a screening facility, the patient's choice of FOBT or "once-only" sigmoidoscopy, a "once-only" sigmoidoscopy, or sigmoidoscopy followed by biennial FOBT. The authors found that the participation rates for all screening arms were similar, but that the detection rate for advanced neoplasia was three times higher following screening by sigmoidoscopy than by FOBT.
In an editorial, Church (p. 328) discusses the novel aspects of this study and questions whether theoretical models of screening behavior would predict the surprising finding that subjects who were given a choice between screening methods did not have a higher screening participation rate than subjects who were not given a choice.
Breast Density, Bone Mineral Density, and Breast Cancer Risk
In separate studies, women with a high mammographic breast density or high bone mineral density (BMD)—markers of cumulative exposure to estrogen—have been shown to be at increased risk of breast cancer. In a cross-sectional study and a nested case–control study, Kerlikowske et al. (p. 368) found that breast density was not correlated with hip or spine BMD and that neither hip BMD nor spine BMD was associated with breast cancer risk. Women with high breast density had an approximately threefold increased risk of breast cancer compared with women with low breast density, regardless of hip or spine BMD. The authors conclude that breast density is strongly associated with an increased risk of breast cancer, but BMD, although a possible marker of lifetime exposure to estrogen, is not. Thus, a component of breast density that is independent of estrogen-mediated effects may contribute to breast cancer risk.
Tamoxifen Treatment and the Risk of Endometrial Cancer
Tamoxifen treatment of breast cancer is associated with an increased risk of endometrial cancer. To clarify tamoxifen-related risks of endometrial cancer in premenopausal women, long-term users of tamoxifen, and women several years after the end of tamoxifen treatment, Swerdlow et al. (p. 375) conducted a case–control study. They found that, overall, compared with no treatment, tamoxifen treatment was associated with an increased risk of endometrial cancer. They also found that the risk of endometrial cancer adjusted for treatment duration did not diminish in follow-up for at least 5 years after treatment ended. The authors conclude that there is an increased risk of endometrial cancer associated with longer tamoxifen treatment and that the risk extends well beyond 5 years, which should be considered clinically for both premenopausal and post-menopausal women during treatment and for at least 5 years after treatment.
DNA Damage, DNA Nucleotide Pool, and Lung Cancer
The level of 8-oxoguanine (8-oxoG), a general marker of oxidative DNA damage, in DNA depends on how quickly it is formed and removed and whether its incorporation into DNA can be prevented by the elimination of a precursor molecule (8-oxodGTP) from the nucleotide pool. Speina et al. (p. 384) determined the contribution of removing 8-oxoG from the DNA (excising activity encoded by hOGG1) or eliminating damaged precursors (8-oxoGTPase activity encoded by hMTH1) to the level of 8-oxoG in DNA from tumors and surrounding normal lung tissues from non–small-cell lung cancer patients. The authors found that the 8-oxoG level and hOGG1 activity were lower in tumor DNA than in DNA from normal lung tissue, whereas the hMTH1 activity was higher in tumors than in normal lung tissue. The authors conclude that several components contribute to the maintenance of 8-oxoG levels in DNA, with the greatest contributor being the removal of 8-oxodGTP from the cellular nucleotide pool by hMTH1.
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