Genetics of Prostate Cancer

Risk Factors of Prostate Cancer

A man’s lifetime risk of developing prostate cancer is 1 in 7. Some men with prostate cancer remain asymptomatic and die from unrelated causes. This is because the cancer occurs when the man is already at an advanced staged and the tumor grows slowly.[1] Treatment can be administered when it starts becoming symptomatic and although not cured, it can be controlled. The person may die of other diseases because they are more severe and the person is at an advanced age.

The estimated number of men who have prostate cancer that is present but not detected or diagnosed during a patient’s lifetime is greater than the number of men who have clinically detected disease. Many tests have been designed to understand better the genetic and biologic mechanisms that determine why some prostate cancers remain clinically silent while others cause severe life threatening illness.[1]

*Modified from National Cancer Institute Data

 

Differences in Incidence Among Populations Worldwide

Prostate cancer exhibits tremendous differences among populations worldwide. There is a 60 to 100-fold difference in incidence of cancer in countries with low rates of prostate cancers when compared to countries with high rates of prostate cancer.[2] In Asia, men have an age adjusted incidence rate of 2 to10 cases per 100,000 men. African American men have highest incidence of prostate cancer with a 60% higher incidence than white men.[3]

Among white men, northern European countries have higher incidence than other countries.  These differences may be due to multiple factors. They include genetic, environmental, access to healthcare as well as differences in screening and treatment. Differences in screening practice may also affect prostate cancer diagnosis. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in 1 brother leads to an early diagnosis in second brother using PSA screening. This may account for prostate cancer diagnosis in younger men seen in national incidence data.

 

Risk Factors

The three most recognized risk factors are age, race, and family history of prostate cancer.

 

Age

Age is an important risk factor for prostate cancer. It is rarely seen in men younger than 40 years old. The probability of being diagnosed with prostate cancer is 1 in 325 for men 49 years or younger. 1 in 4 men aged 50-59 years. 1 in 17 for men aged 60-69. 1 in 10 for men aged 70 and older with an overall lifetime risk of 1 in 7.[1]

 

Race

The risk of developing and dying from prostate cancer is higher among blacks, intermediate among whites, and lowest among Asians.[5,6] Race is further addressed in differences in incidence among populations worldwide.

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Family History

As with breast and colon cancer, prostate cancers cluster in families.[7-11] Five to ten percent of prostate cancer is believed to be caused by high-risk inherited genetic factors. A person who has a brother or father with prostate cancer, increases his risk of prostate cancer. The relative risk for a person with a brother with prostate cancer is 3.14. It is 2.35 when he has a father who has prostate cancer and 2.25 with any relative with prostate cancer.

Most of this data has been obtained from Swedish population based family cancer database that contain more than 11.8 million men and among whom 26,651 men who are verified with prostate cancer and of which 5,623 were among related families.[12] The RR increases to 8.5 when a father and two brothers are affected and increases to 17.7 when three brothers are diagnosed with prostate cancer. The risk also increases with age in affected families and is about 5% by age 60, 15% by age 70, and 30% by age 80. As compared to the normal population, where the risk is 0.45%, 3% and 10% by the same ages in the general population.

The risk of prostate cancer also increases in men who have a family history of breast cancer in a mother or sister. These clusters of prostate cancer in some families may be due to genetic mutations such as BRCA1 and BRCA2 genes.[13-16] Members of such families may benefit from genetic counseling.

 

Other Modifiers of Prostate Cancer Risk

Some dietary risk factors may have affect on prostate cancer risk. These include fat and or meat consumption,[17] lycopene,[18-19] and dietary products including calcium and vitamin D.[20] Phytochemicals and plant-derived compounds may play a role in prostate cancer prevention.[21] Asian men typically consume soy products that contain phytoestrogens and this may contribute to lower incidence. Alcohol does not increase risk of prostate cancer however smoking may increase the risk. Obesity may also increase risk of prostate cancer. One study found that there was an increase in prostate cancer risk with Vitamin E supplement.

 

Risk of Developing a Second Cancer after Developing Prostate Cancer

Risk of developing a second cancer after developing prostate cancer Radiation therapy as initial treatment of prostate cancer was found to increase bladder and rectal cancers as well as carcinoid malignancies. There is also an excess risk of pancreatic cancer and melanoma. In the Swedish study of 18,207 men with prostate cancer, 560 developed a second malignancy and the RR was increased for colorectal, kidney, bladder, and squamous cell carcinoma. Having a family history of prostate cancer increased the risk of bladder cancer, myeloma, and squamous cell skin cancer.

 

Inheritance of Prostate Cancer Risk

There are studies that have suggested that familial clustering of disease among men with early onset prostate cancer was best explained by the presence of a rare frequency of 0.003 autosomal dominant, highly penetrant gene allele. Hereditary prostate cancer genes were predicted to account for almost 50% of all patients who have prostate cancer diagnosed at age 55 years or younger.

 

The 4K Score

The 4K score is a novel blood test that can accurately identify risk of aggressive prostate cancer. Screening for prostate cancer using serum PSA has identified a significantly increased number of men who have prostate cancer and has resulted in treatment and subsequently a decline in prostate cancer mortality. However, there has been an increase in morbidity from treatment.   Several tests have been developed to try and separate those men who have aggressive cancer that received treatment from those men that have latent cancer who may never need treatment. Because of this, the US preventive services task force recommended against routine screening. However 22-33% of men do have high-grade disease at presentation. Without screening, these men lose opportunity for cure. The 4K score test from Opko lab Nashville TN, is a new blood test that accurately identifies risk for prostate cancer. It is especially important for clinical tool, in men who have negative biopsy, continue to have abnormal DRE and elevated PSA level, and are trying to make a decision whether to go for a repeat biopsy.

PSA is the most common test for detection of prostate cancer but it has limitations. PSA can be elevated due to inflammation, trauma, and benign disease. In order to improve accuracy of PSA, serial evaluation of PSA and documentation of its increase [PSA velocity], subtypes such as free and total PSA and supplementation of PSA with other markers have been introduced to improve accuracy of PSA. The 4K tests measure four Prostate specific Kallikrein in blood: total, free intact, human Kallikrein 2 (hK2). The blood test results are combined in an algorithm with patient age, Digital exam [nodules, no nodules], and prior negative biopsy [yes or no] to give physician a personal score for each patient. The 4k score test predicts risk from <1% to >95% for a man with risk of aggressive prostate cancer. By providing information to improve decision making before ordering prostate biopsy, the 4K score test can help avoid an unnecessary prostate biopsy while still identifying men at risk for aggressive prostate cancer. The 4K test has undergone extensive clinical study for over 10 years and has been studied in over 10,000 patients in Europe and has been replicated recently in the US in 26 urology centers with 1000 patients. It is now FDA approved and available for clinical use.

The test is done on a sample of blood which can drawn by a Urologist or a lab and performed by OPKO lab at its facility in Nashville, TN. It does not diagnose prostate cancer but provides patient with a risk analysis of having an aggressive form of prostate cancer. This along with clinical information can help Urologist determine next steps for the patient.

If you would like to learn more about the 4K Score Test, you can visit their website by clicking here or going to 4kscore.opko.com.

 

Acknowledgements: 

Reviews in urology 2015, 17 [1] pg 3-13.  Spunn et al.

References: 

British Journal of Cancer 2010, 103708-714.

BMC Medicine 2008 6:19

BMC Cancer 2010 10:635

Cancer. 2010 June 1; 116(11): 2612-2620. Doi: 10.1002/cncr.25010.

BJU Int. 2013 Sep;112(5): 602-9. Doi: 10.1111/j. 1464-410X.2012.11690.x.Epub 2013 Feb 28.

Eur Urol. 2013 Nov;64(5):693-9. Doi: 10.1016/j.eururo.2013.04.040. Epub 2013 May 2.

Prostate. 2014 Feb;74(3):250-9. Doi: 10.1002/pros.22746. Epub 2013 Oct 26.

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