Prostate cancer genetics

Abstract

Prostate cancer (PCa) is one of the commonest cancers in men and a major cause of cancer-related mortality. Family history is the strongest known risk factor for developing PCa. This is illustrated by the observation that a man with one close relative (such as a father or a brother) with PCa has approximately twice the risk of developing PCa when compared to a man with no family history. A man with two close male relatives affected has a fivefold increase in lifetime risk. This degree of relative risk and the increase in its magnitude indicate a strong genetic component to disease development. However, unlike other cancers such as breast, ovarian, and colonic cancers, the search for mutations in candidate genes is proving to be more elusive. Uncovering the genes that predispose to PCa among families where disease is clustered has been the objective of many research groups over the past 15 years. Epidemiological and twin studies support a role for the genetic predisposition to PCa. Familial cancer loci have been identified, but discovery of the genes that cause familial prostate cancer (FPC) remains largely elusive. Unraveling the genetics of PCa is challenging and is likely to involve the analysis of numerous predisposing factors, which may be manifestations of multiple mutagenic pathways. Increased familial risk of prostate cancer could be due to the inheritance of multiple moderate-risk genetic variants. Although the study of hereditary prostate cancer (HPC) has increased our understanding of its genetic etiology, many issues remain largely unresolved. This difficulty with identification of PCa predisposition genes may be due to a number of reasons. PCa, in terms of total prevalence, is a very common condition, and it may not be far wide of the mark to say that the majority of prostates in the Western world will eventually harbor some cancer cells. The disease varies significantly in the spectrum of aggressiveness. We do not know, with absolute conviction, which patients who have been diagnosed with PCa require treatment. It is against this quandary that genetics could play its influence. PCa is diagnosed in the later years of life; therefore, obtaining DNA samples from living affected men for more than one generation is often not possible, and linkage in large pedigrees may be unfeasible. The presence within high-risk pedigrees of phenocopies (individuals with PCa but without the genetic alteration) weakens the linkage results. The genetic heterogeneity of this complex disease (the fact that different pedigrees may be due to different genetic mutations) and the uncertainty regarding the optimal genetic model could render linkage results inaccurate, making gene identification difficult.