Originally published 10/18/2015
Prostate cancer (PCa) is considered one of most hereditable cancers, meaning one or more genes that increase likelihood of developing PCa can be passed from parents to children. The problem is, identifying which specific gene variants remains elusive.
In December, 2022 the British Journal of Cancer published a research paper by Cardoso, et al. that offers a ray of hope.[i] The researchers used a next-generation DNA analysis technique called whole-exome sequencing to identify DNA sequences of multiple affected members of 45 families with a history of PCa.
One factor that stood out was a variant in a gene called PRUNE2. When PRUNE2 is normally expressed, its action serves to prevent PCa. However, when a mutation in the gene occurs, it does not function normally, so patients carrying a defective PRUNE2 mutation are potentially more vulnerable to PCa, in this case, early-onset PCa.
Interestingly, not all the variants were identical (there were 10 different mutations among 13 patients with PRUNE2 mutations), but it appears that any mutation may cripple the normal expression of the gene so it is unable to protect the patient.
Since this variant can be passed on from parents, the authors theorize that PRUNE2 mutations may represent “…a novel prostate cancer predisposition gene.”
Although today’s science does not yet have a way to repair mutated genes so they function normally, identifying the precise culprits is a noteworthy first step.
Prostate cancer is the most common non-skin cancer among men. In addition to the risk factors of increased age and being African American, researchers have long known that a third factor is a family history of first degree relatives (a father or brother) who had this disease. First degree relatives share about half of their genes, so it’s not surprising that they might also share vulnerability for specific PCa gene mutations. Two recent studies help us understand the extent of the risk.
The European Randomized Study of Screening for Prostate Cancer provides a demographic data pool on prostate cancer. The ERSPC is the largest long-term randomized trial of screening for prostate cancer. Over 160,000 European men are enrolled, and those in the intervention arm are screened every 2-4 years and followed over time. A team of researchers examined data from the Swiss arm to evaluate the impact of a positive family history (defined as first-degree relatives) as a risk factor for the incidence and aggressiveness of prostate cancer in their population.[ii] Men whose PSA reached a threshold of 3 ng/ml were biopsied. Out of 4,932 participants, 334 (6.7%) reported a family history. During an average follow-up of 11.6 years, 18% of the family history group was diagnosed with PCa, compared with only 12% of the men who reported no family history. Most of those found to have PCa were diagnosed with low grade disease. According to the authors, “Our results suggest that men with a positive [family history] are at increased risk for low grade but not aggressive PCa.”
While the vast majority of PCa diagnosed today tends to be lower risk, a study from the University of Michigan shows that men diagnosed with PCa before age 55 may have a different type of prostate cancer that is 1.5 times more likely to be life-threatening, and that appears to have a strong family history component.[iii] There has been a steep rise in the proportion of newly diagnosed men with this early onset PCa, a rise not accounted for by widespread PSA screening alone. There may be a subtype of PCa that is more aggressive in younger men, so by the time it is detected, it may have rapidly progressed to a point at which it is more dangerous. This would explain the higher rate of PCa-specific death among men diagnosed at younger ages. The authors suggest that men whose fathers or brothers experienced early onset PCa undergo genetic testing to learn if they carry gene variants for this type of PCa. Such genetic risk prediction may be more useful for younger men than for those ages 65 and older.
Our Center offers 3T multiparametric MRI, which has the ability to detect more aggressive tumors while they are still small and contained within the gland. Men with a family history of PCa who choose to have genetic testing, especially whose fathers were diagnosed with early onset disease, can take advantage of a baseline prostate scan on our advanced equipment, and continue to monitor with a combination of PSA testing and a recommended annual scan.
NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.
[i] Cardoso M, Maia S, Brandão A, Sahasrabudhe R et al. Exome sequencing of affected duos and trios uncovers PRUNE2 as a novel prostate cancer predisposition gene. Br J Cancer. 2022 Dec 23.
[ii] Randazzo M, Müller A, Carlsson S, Eberli D et al. A Positive Family History as risk factor for Prostate Cancer in a Population-based Study with organized PSA-Screening: Results of the Swiss ERSPC (Aarau). BJU Int. 2015 Aug 31. doi: 10.1111/bju.13310. [Epub ahead of print]
[iii] Salinas CA, Tsodikov A, Ishak-Howard M, Cooney KA. Prostate cancer in young men: an important clinical entity. Nat Rev Urol. 2014 Jun;11(6):317-23.