Hereditary prostate cancer
How common is prostate cancer? 1
Every fifth man in Sweden will be diagnosed with prostate cancer during his lifetime, resulting in approximately 10 000 diagnoses each year. It is the most common type of cancer amongst Swedish men, but also overall. Most men get diagnosed late in life and in 2005 the median age for diagnosis was 69 years. Prostate cancer is uncommon in men before 50 years of age.
What causes prostate cancer? 1
A major cause of cancer is DNA damage, which can occur during DNA replication or be due to environmental factors. DNA damage occurs all the time and most of the time it is repaired. But with age comes an accumulation of DNA damage, and in turn a higher likelihood that a normal cell transforms into a cancer cell. Age is therefore the leading risk factor for cancer.
The frequency of prostate cancer varies a lot between different parts of the world. A western lifestyle, with a high intake of animal fat, red meat, and dairy products, increases the risk of prostate cancer. Genetic factors also contribute to this difference, including those seen between ethnic groups.
Underlying genetic factors1
Genetic factors are known to play a role in the development of prostate cancer. The extent to which they play a role varies from small to very large. Families with several cases of prostate cancer, or in which someone was diagnosed at a relatively young age, hereditary prostate cancer may be suspected. A man whose father was diagnosed with prostate cancer has a 1.5 to 3 times higher risk of prostate cancer compared to the average man. The more men in the family with prostate cancer, the higher the risk. Another indication of heredity is a combination of cases of prostate, ovarian, breast, pancreatic, or male breast cancer in the same family.
In some men with prostate cancer the underlying cause can be tied to a pathogenic variant (mutation). According to current national guidelines, men diagnosed with metastatic prostate cancer (and/or Gleason score 5) before 60 years of age with one or more first-degree relatives* with breast, ovarian, prostate, or pancreatic cancer should therefore be offered genetic testing.
An underlying pathogenic variant in the BRCA2 gene can be identified in approximately 5 – 10% of the men fulfilling these criteria. This gene is also associated with hereditary breast, ovarian, and pancreatic cancers. Men with a pathogenic variant in BRCA2 have approximately three times the normal risk for prostate cancer and often experience early onset. Therefore, guidelines recommend that men that meet the above criteria undergo genetic testing of the BRCA2 gene. A strong family history of related cancers may warrant genetic testing for those diagnosed with prostate cancer up to age 65. The BRCA2 gene is included in the GeneMate® test for hereditary cancer.
Pathogenic variants in the HOXB13 gene are also associated with hereditary prostate cancer. Men with a specific variant (G84E) in this gene have a risk similar to that of men with a pathogenic variant in BRCA2. Sweden has the highest reported frequency of the G84E variant, which is found in 1.3% in the general population and in 4.5% of men with prostate cancer. However, according to national guidelines, the scientific basis is still insufficient to be able to offer genetic testing of the G84E variant in HOXB13. Thus, genetic testing is only recommended as part of research studies to date.
In addition, pathogenic variants in the MSH2 gene (associated with Lynch syndrome) and the BRCA1 gene contribute to a moderately increased risk of prostate cancer. However, the increase in risk is not sufficient to motivate prostate cancer screening according to national guidelines. The BRCA1 and MSH2 genes are included in the GeneMate® test for hereditary cancer.
Risk-reducing measures in healthy carriers
Healthy men with a pathogenic variant in BRCA2 or the G84E variant in HOXB13 (when identified through a research study) should be recommended prostate cancer screening from 40 years of age. The first screening visit should include a PSA test and palpation. If PSA is <1 µg/l, men are recommended a PSA test every second year. If PSA is 1 – 1.9 µg/l, men are recommended a PSA test every year. If PSA is ≥ 2 µg/l, men are recommended MRI of the prostate and palpation. If no cancer is detected the man should have yearly follow ups.
Risk-reducing measures for men without a variant
Healthy men that test negative for a pathogenic variant in BRCA2 or the G84E variant in HOXB13 may in some cases be recommended the same screening measures as carriers based on their family history. Such is the case when there are at least two relatives with prostate cancer. One of these men must be a brother or a father to the healthy man and the other must be a first-degree relative* to the affected man (for example a grandfather or an uncle of the healthy man). At least one man should have been diagnosed before 75 years of age.
*First-degree relatives are parents, siblings, and children.
Anna Hellquist, Genetic Counselor at iCellate Medical AB, PhD Cell and Microbiology