by Graham Casey and George Stark Cleveland Clinic Foundation United States The genetics of inherited prostate cancer are complex, and family linkage studies suggest that mutations in at least six different genes may be involved.
		The taming of cancer of the prostate gland through genetic methods of risk analysis, early detection, and tailor-made treatment are at hand, we believe. Prostate cancer is the most common neoplasm among men in western society, with a mortality rate second only to lung cancer. The incidence varies substantially across ethnic groups, and African American men have the highest rates among all groups studied.

The causes of prostate cancer, still poorly understood, reflect complex interactions between genetic and environmental factors. Inheritance is clearly important: men whose fathers and grandfathers have had prostate cancer are two to three times more likely to develop the disease than men with no such family history.

The ethnic and family contributions to the probability of contracting prostate cancer reveal that there is a strong genetic basis for this disease, as there is for all cancers. With new and rapidly evolving technologies at our disposal, we are poised to enter a new age of discovery in the genetics of prostate cancer. It will offer major benefit to patients, including better ability to predict who will get the disease and more effective treatments for those who have it.

The genetics of inherited prostate cancer are complex, and family linkage studies suggest that mutations in at least six different genes may be involved. The first such gene, HPC2/ELAC2, was identified only recently and little is yet known about its role in the development of the disease.

Mutations in this gene, identified in two families, probably inactivate the normal function of the protein, somehow leading to prostate cancer. HPC2/ELAC2 is related to a family of proteins that are involved in repairing DNA damaged by exposure to ultraviolet light, giving us a hint of its possible function.

A better understanding of how mutations in HPC2/ELAC2 predispose individuals to prostate cancer will have to await the fruits of more research. With the sequence of the human genome now known, more genes that contribute to hereditary prostate cancer will soon be identified. These discoveries will provide the basis for a battery of tests to identify men at high risk of developing this disease.

Such tests involve the analysis of tiny quantities of DNA, obtained from white blood cells, for the presence of inactivating mutations, and would provide men with a risk estimate for developing prostate cancer. Mutations are identified today by DNA sequence analysis. But this method will be superseded in the near future by new technologies that permit the simultaneous analysis of thousands of different mutations in the DNA of one person.

Linkage study
The family linkage studies that led to the identification of regions of the genome involved in prostate cancer depended upon genetic analysis of families with multiple cases of early onset of the disease. So far, we have probably identified genes containing mutations that eliminate the normal function of the protein and therefore confer a high risk in carriers, but are infrequent in the general population.

In addition to these extremely damaging mutations, there is growing evidence that normal, more subtle variations in certain genes, present in many individuals, may predispose them to prostate cancer. Such variants confer only a modest increase in risk as they affect the normal function of the gene only subtly. They would be expected to occur much more frequently in the population than the inactivating mutations found in familial prostate cancer.

For example, two common variants in the HPC2/ELAC2 gene may be involved in five per cent of the prostate cancers in the general population. Other variants that have been implicated in increasing the risk of contracting prostate cancer include variants of genes involved in the androgen metabolism pathway. Androgens are growth hormones that drive prostate cell growth and differentiation, and genetic variants that lead to increased circulating androgens are thought to increase prostate cancer growth.

Variants in genes in other metabolic pathways involved in the growth of prostate cells, such as Vitamin D – which, in contrast to androgens, has antiproliferative effects on the prostate – are also under vigorous scrutiny. More associations are likely to be found in the next few years. Once again, tests would involve the analysis of tiny quantities of DNA from blood, but this time using rapid methods to identify specific variants to provide risk estimates.

Aggression
The aggressiveness of prostate tumours may also have a genetic basis. Aggressiveness varies widely among patients. Some cancers progress rapidly to invasive, life-threatening disease, while others remain indolent for many years.

The two most important genetic risk factors for developing prostate cancer, ethnicity and family history, are also associated with aggressiveness. African American men have more aggressive forms of prostate cancer at initial diagnosis more often than men of any other ethnic group; approximately double the rate of Caucasians.

The ability to identify men at risk of developing more aggressive forms of prostate cancer would be beneficial, indicating that it is appropriate to apply more aggressive therapies at an earlier stage. Once the effect of a gene variant has been defined, changes in lifestyle may also be effective in reducing risk. For example, in breast and ovarian cancer, genetic risk can be reduced by minimising exposure to the oestrogens, which can stimulate the growth of such tumours.

As with all cancers, the likelihood of a cure is improved substantially if prostate cancer is detected early. Further understanding of the genetics of prostate cancer will lead to the use of ‘markers’ whose analysis will supplement that of the prostate-specific antigen (PSA). The death rate from prostate cancer in the US has begun to show a modest reduction (approximately five per cent) in recent years. Some attribute this fall at least in part to the more widespread use of the PSA test, although this conclusion remains controversial. Cancer arises from a complex combination of mutations in some genes and abnormal levels of expression of others, both leading to altered cellular function.

Molecular profiling is an emerging technology that can be used to measure changes in the expression of thousands of genes in a single experiment. The application of molecular profiling to prostate tumours and to the normal prostate epithelium from which they arise will lead to a better understanding of the changes in gene expression involved in prostate cancer. The goal of these studies is two-fold: to identify markers for the early detection of disease, and to develop custom-made treatments of individual cancers, by directing therapies towards the specific genetic ‘Achilles heels’ of specific tumours.

The applications of modern genetic methods to prostate cancer will advance the assessment of risk, provide early detection, and guide the treatment. We are unlikely ever to eradicate prostate cancer completely, but taming it should soon be within our grasp.