ABSTRACT
The realization that genetic factors play a role in determining a man’s risk of developing prostate cancer is at least 50 years old; however, the epidemiological search for the specific genetic variants responsible has only begun recently (Figure 2.1). In this review, we summarize the knowledge gained initially during the premolecular era, and then the surge of new information since the mid-1990s resulting from the application of rapidly emerging technologies in molecular genetics. All genetic variants that affect prostate cancer risk lie along a continuum of penetrance, which can be defined as the probability of an individual experiencing the disease phenotype during a specified
time interval, given a particular genotype. It is useful to divide the discussion of genetic factors into those with relatively high and low penetrance, however, because the behavior of variants at either end of the spectrum produce different patterns of occurrence within populations and, therefore, lend themselves to different methodological approaches. Our focus here is on germline variants; other chapters in this volume discuss somatic gene variants that might contribute to prostate carcinogenesis through acquired mechanisms alone. We also focus on genetic determinants of etiology rather than prognosis, although the two are related; good discussions on genetic determinants of prostate cancer aggressiveness can be found in the literature.1,2
The relative importance of genes versus environmental factors in prostate cancer etiology is a
matter of common misunderstanding. We will argue that there is evidence to suggest that both genetic and environmental factors are very important in prostate cancer; indeed, the interaction of genes and the environment is most likely at play in most individual cases of the disease, and is the basis for the wide variation in penetrance itself. The ubiquity of these interactions means that for any group of prostate cancer cases, such as those occurring in the US, the sum total of cases attributable to individual risk factors can greatly exceed 100%. A recent study of monozygotic versus dizygotic twins estimated that 42% of prostate cancer cases are attributable to hereditable factors, a figure that was among the highest for any cancer site.3 However, two important points must be noted: 1) 42% represents the sum total contribution of all genetic variants, not just one or two; and 2) the principle of interacting causes means that all or most of these 42% of cases equally could be said to have been caused by environmental factors, in that without the presence of both the genetic variant and the environmental exposure, the case would not have occurred. In fact, epidemiologists long ago observed by studying migrants that prostate cancer risk appears to be unusually sensitive to changes in environment. Among JapaneseAmerican immigrants, for example, the risk of prostate cancer already begins to approach the risk for US-born Japanese Americans, even among men who migrated after the onset of adulthood.4
