Genetics of Prostate Cancer: Role of Family History

Diptasri M. Mandal, Ph.D.

Prostate Gland and Its Function
The prostate is a male sex gland. About the size of a walnut and weighing less than an ounce, the prostate gland surrounds the urethra, a tube that transports urine from the bladder and out of the body. The gland is located below the bladder and in front of the rectum. The prostate gland produces a thick fluid that forms part of the semen, which nourishes and helps with transporting sperm. This gland has two distinct tissue types: glandular tissue and muscular tissue. Glandular tissue in the prostate gland produces the fluid and the muscular tissue promotes the male ejaculation.

Cancer of the Prostate
For a healthy person, cells grow and divide to produce more cells when the body needs them. Cancer of the prostate is caused if the cells keep dividing when new cells are not needed. This excess tissue forms a clump that is called a tumor. The tumor can be benign (not cancerous) or malignant (cancerous). In malignant (cancerous) tumors, cells divide out of control. They invade and destroy nearby healthy tissue. If the cancer spreads from the original tumor to other areas, it is called metastasic.

Incidence and Mortality
Prostate cancer is the most frequently diagnosed malignancy occurring in as many as 15% of men in the United States. The American Cancer Society estimates that during 2005  approximately 232,090 new cases of prostate cancer will be diagnosed in the United States. It is the second leading cause of cancer death in men, exceeded only by lung cancer. The American Cancer Society estimates that 30,350 men in the U.S. will die of this disease during 2005.

Risk Factors for Prostate Cancer
A risk factor is anything that increases a person's chance of developing a disease. A number of possible risk factors for the occurrence of prostate cancer are being actively explored to understand how these factors cause cells in the prostate gland to become cancerous. Some of the risk factors in prostate cancer suggested by researchers are age, race, nationality, diet, and family history. The only one possible risk factor that can be controlled is diet. A diet low in fat is associated with reduced risk of prostate cancer. Also, the intake of lycopene or other compounds in tomato-based products may reduce the risk of prostate cancer. The risk of developing prostate cancer increases with age. More than 70% of all prostate cancers are diagnosed in men over age 65. Race is also considered to be a major risk factor. African Americans have the highest prostate cancer incidence rates in the world. Interestingly, the disease is common in North America and Northwestern Europe and is rare in Asia, Africa, and South America. So, probably diet has a major role to play in the incidence of prostate cancer.

Importance of Family History in Prostate Cancer
Recent genetic studies suggest that hereditary factors may be responsible for 5%-10% of prostate cancers. The risk increases in relatives of affected men. Men with a first degree relative with prostate cancer have a two to three fold increase in risk relative to the general population. This means that a brother, father, or son of a prostate cancer case has a risk of prostate cancer that is approximately double the population risk. Male relatives with two first-degree relatives have a five-fold increased risk, whereas, a family history of three first-degree relatives with prostate cancer gives rise to an increased risk of 11-fold in male relatives. Therefore, relatives with a stronger family history would be more likely to have prostate cancer over relatives of a single case, which means the more cases in a family the higher the risk to other male relatives. Therefore, the familial aggregation of prostate cancer is useful in studying the inherited risk to the disease. In addition, relatives of early onset cases would have a higher risk of having prostate cancer over that of later onset cases. It was also found that brothers of cases diagnosed under the age of 65 had a six-fold increased risk of developing prostate cancer under the age of 65 themselves. So, the three important modifiers of risk related to familial history of prostate cancer are: (1) the age of the man at risk, (2) the age of the affected relative, and (3) the number of relatives with prostate cancer. The following criteria have been defined for diagnosing hereditary prostate cancer:

1. a cluster of three or more first-degree relatives with prostate cancer; or
2. prostate cancer in each of three generations in the paternal or maternal lineage; or
3. two or more first- or second-degree relatives with prostate cancer under the age of 55.

Search for Genes in Prostate Cancer
Recent advances in genetic research focus on genes linked to hereditary prostate cancer. Data from independent studies suggested evidence for both autosomal dominant pattern of inheritance and X-linked or autosomal recessive modes of inheritance.  Males in families with X-linked or recessive modes of inheritance for prostate cancer have a higher risk if they have an affected brother(s) with prostate cancer than if their father is affected.

The genetic studies performed to date, mostly on Caucasian families, suggest that seven potential prostate cancer genes are involved in Hereditary Prostate Cancer (HPC), which means that genetic risk factors may differ among families. Three of them are located on chromosome 1(HPC1, PCAP and CAPB) and the other four are located on chromosome 17 (HPC2), chromosome 20 (HPC20), chromosome 8 and the X chromosome (HPCX). Thus far, the search for prostate cancer genes resulted in the identification of three genes (RNASEL at HPC1 region, MSR1 on chromosome 8, ELAC2 at HPC2 region).  However, no single susceptible gene is by itself responsible for a large portion of familial prostate cancers and data were used only from the Caucasian population.

Complexities in Prostate Cancer Research to Identify Genes
The disease is very complex due to the existence of more than one gene and decreased penetrance.  (Penetrance is the probability that an individual carrying a disease gene is affected.  Sometimes an individual who carries a gene for prostate cancer may not show symptoms.)  Moreover, sporadic and hereditary cases may co-exist in some families. Thus far, genetic research studies to identify genes have been performed on Caucasian Americans.  Interestingly, confirmatory studies have usually failed to find the suggested genes in a different population.  A large number of families from different populations with family histories of multiple affected prostate cancer cases are needed to confirm suggested genes and to find any new gene that may exist in the population. 

Use of Genetic Family Study in Prostate Cancer Prevention
Once the genes are identified, additional family data are needed for identification of specific mutations in families and for determining the penetrances of different mutations. This information helps us to estimate an individual's risk in a family with a history of prostate cancer. The main problem associated with the mortality in prostate cancer is that most of the time it is diagnosed at an advanced stage when the cancer is metastasized to other organs. The detection of existing genes or finding new genes will improve the detection and diagnosis of this cancer at an earlier age when the cancer is curable. Findings from genetic family studies will allow testing to identify men with specific genetic risk factors, and this in turn will help with cancer prevention strategies.

How to Learn More:
http://www.cancer.org/

http://www.cancer.med.umich.edu/prostcan/genes01.htm

http://www.cancerpage.com/cancers/default.asp?channel=Prostate_Cancer