Prostate cancer

The

new england journal

of

medicine

review article

mechanisms of disease

Prostate Cancer
William G. Nelson, M.D., Ph.D., Angelo M. De Marzo, M.D., Ph.D., and William B. Isaacs, Ph.D.
From the Departments of Oncology (W.G.N., A.M.D., W.B.I.), Pathology (W.G.N., A.M.D.), and Urology (W.G.N., A.M.D., W.B.I.), Johns Hopkins University School of Medicine, Baltimore. Address reprintrequests to Dr. Nelson at Rm. 151, Bunting-Blaustein Cancer Research Bldg., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans St., Baltimore, MD 21231-1000, or at bnelson@ jhmi.edu. N Engl J Med 2003;349:366-81.
Copyright © 2003 Massachusetts Medical Society.

p

rostate cancer is a leading cause of illness and death among men in the United States and Western Europe.Autopsy series have revealed small prostatic carcinomas in up to 29 percent of men 30 to 40 years of age and 64 percent of men 60 to 70 years of age.1 Moreover, the risk of prostate cancer is 1 in 6 and the risk of death due to metastatic prostate cancer is 1 in 30.2 (Fig. 1 shows multiple foci of prostate cancer.) With widespread screening for prostate-specific antigen (PSA) and digital rectalexamination, as well as early treatment of localized prostate cancer, however, the age-adjusted rates of death due to prostate cancer have begun to decrease.3,4 In 2002, an estimated 189,000 men received a diagnosis of prostate cancer, and there were an estimated 30,200 deaths due to prostate cancer.2 Dietary factors, lifestyle-related factors, and androgens have long been recognized as contributorsto the risk of prostate cancer. During the past decade, molecular studies have provided unexpected clues as to how prostate cancers arise and progress. The identification and characterization of genes associated with inherited susceptibility to prostate cancer and of genes in prostate-cancer cells that tend to have somatic alterations hint that infection or inflammation of the prostate contributesto the development of prostate cancer. Newly recognized mechanisms by which environmental carcinogens might promote the progression of prostate cancer and new insights into the way in which androgen receptors modulate the phenotype of prostate-cancer cells have emerged. In this article, we review recent discoveries in the genetics of prostate cancer and in the acquired molecular defects thataccumulate in prostatic-carcinoma cells.

diet, lifestyle, and prostate cancer
In a study of the risk of cancer among 44,788 pairs of twins in Sweden, Denmark, and Finland,5 42 percent of cases of prostate cancer (95 percent confidence interval, 29 to 50 percent) were attributed to inheritance, with the remainder most likely attributable to environmental factors. Epidemiologic evidence alsosupports a major contribution of environmental factors to the development of prostate cancer. The incidence of prostate cancer and mortality due to prostate cancer are high in the United States and Western Europe, with the highest rates among black men in the United States, whereas lower rates are more characteristic of Asia.6 The risk of prostate cancer among Asians increases when they immigrate toNorth America — again implicating the environment and lifestyle-related factors in causing prostate cancer in the United States.7-9
carcinogens in the diet

The lifestyle-related factor that represents the most likely culprit in the promotion of prostate cancer in the United States is diet. The typical U.S. diet is rich in animal fats and meats and poor in fruits and vegetables. In the HealthProfessionals Follow-up Study, a

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n engl j med 349;4

www.nejm.org

july 24, 2003

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mechanisms of disease

prospective cohort study involving 51,529 men, increased total fat intake, animal fat intake, and consumption of red meat were associated...