What’s the cause of prostate cancer? Well, we really don’t know. We do have some associations, some important risk factors. Obviously male gender is the most important one. Aging is important as well. As you can see, this is just one population. This is in the inner-city Detroit population in African-Americans and in Caucasians. The increasing incidence of prostate cancer as a function of age. Nowadays about 10-15% of patients will be diagnosed under the age of 50. There has been a tendency for younger patients to be diagnosed, obviously because of the use of PSA. Probably more than any other malignancy there is a relationship, a strong relationship, with age. Race and ethnic background is important as well. This is a slide that demonstrates the incidence patterns of prostate cancer around the world. The highest rates of prostate cancer are seen in African-Americans, particularly in inner-city African-Americans, where the rates may be as high as 100-fold greater than that seen in Japan or China. Part of this is genetic but part of it is probably environmental as well because migration studies from areas of low incidence to areas of high incidence have given rise to incidence rates that are intermediate. Either in that generation or subsequent generations, suggesting that environmental exposures are important as well. Leading the pack there are dietary factors, most importantly dietary fat. Not proven but we suspect very strongly that dietary fat, and in particular animal fat, is important in the development or progression of prostate cancer. Endogenous hormones and growth factors are important as well, most importantly testosterone – male hormone. You need testosterone around for the prostate to develop. It’s permissive for the development of prostate cancer. What’s been debated for many years is whether different levels of testosterone in the blood give rise to different likelihood’s of developing prostate cancer subsequently. The answer to that question is yes. There is probably a relationship between levels of testosterone and the likelihood of developing prostate cancer; as described in the Physician’s Health Study where there was a relationship between free testosterone levels and the subsequent development five, ten, fifteen, twenty-years later of the development of prostate cancer.

Growth factors are important as well. The most important of which so far has been insulin-like growth factor 1. There is a relationship between the level of IGF1 and likelihood of developing subsequent prostate cancer. Genetic factors, much like other epithelial adult tumors, are important as well. This is best described within the context of the Health Professional Follow-up Study. A cohort study of 50,000 health professionals asked at the beginning of the study, “Do you have a close family member with prostate cancer? A father or a brother?” The people were subsequently followed and as you can see, those individuals with a positive family history had a two to three-fold higher likelihood of developing prostate cancer as they were observed.

Now why is genetics important? In this study from the Cleveland Clinic of 1,000 men who came in with prostate cancer that were treated for their prostate cancer, those individuals who gave a positive family history did poorer with treatment than did patients with no family history of prostate cancer. Perhaps there are some genes involved in familial prostate cancer that give rise to a more aggressive phenotype. That is the hypothesis that is suggested by this data. Now genetics is a complex thing. Part of the story here is familial prostate cancer, much like familial breast cancer, familial colon cancer. Familial prostate cancer probably represents 5-10% of prostate cancers overall and this is what it looks like. This is a man who came to me at the age of 68 with prostate cancer. We took a family history; he had three brothers with prostate cancer, three cousins with prostate cancer. This is likely the result of inheritance of a rare allele in the population that gives rise to a high likelihood of developing the disease. There are a number of loci thus far that have been associated with familial prostate cancer, one of which is on chromosome 1Q. We don’t yet know what the gene is that’s involved in this particular subset of familial prostate cancer. Now there are other genetic factors as well, and one of the things that we’ve studied has been variations in the androgen receptor gene, specifically a repeat sequence within the androgen receptor gene which gives rise to variable likelihood’s of developing prostate cancer. In this particular case, individuals who have fewer glutamine repeats within the androgen receptor have a higher likelihood of developing prostate cancer than those that have many glutamine repeats within the androgen receptor. This is one of multiple genetic factors that are involved in the complex genetic framework of this heterogeneous disease.