Predictive genetic tool developed to better inform men whether and when to take PSA blood test.
Prostate cancer detection currently relies on the prostate-specific antigen (PSA) screening blood test, which has been proven to reduce deaths from the disease. However, PSA testing is a poor screening tool because it can also produce false positive results and encourages over-detection of non-aggressive, slow-growing tumors.
An international team has now developed a genetic tool that has been proven to be able to predict the age of onset of aggressive prostate cancer, a disease that kills more than 26,000 American men annually.
The new tool may potentially be used to guide decisions about who to screen for prostate cancer and at what age.
The team used genome-wide association studies (GWAS) to determine whether a man’s genetic predisposition to developing prostate cancer could be used to predict his risk of developing the aggressive and lethal form of the disease.
GWAS search individual genomes for small variations, called single-nucleotide polymorphisms (SNPs), that occur more frequently in people with a particular disease than in people without the disease. Hundreds or thousands of SNPs can be evaluated at the same time in large groups of people. In this case, researchers used data from over 200,000 SNPs from 31,747 men of European ancestry participating in the ongoing international PRACTICAL consortium project.
Genotype, prostate cancer status and age were analyzed to select SNPs associated with prostate cancer diagnosis. Then the data was incorporated into a new prediction tool, the Polygenic Hazard Score, which involves survival analysis to estimate SNPs’ effects on age at diagnosis of aggressive prostate cancer. The results led to a Polygenic Hazard Score for Prostate Cancer that can estimate individual genetic risk. The Polygenic Hazard Score was then further tested on an independent dataset from the ProtecT study centered at the Nuffield Department of Surgical Sciences.
John Black, Associate Professor of Prostate Cancer at the Nuffield Department of Medicine, said: ‘The strength of this test is that an individual’s genotype does not change with age, so the polygenic hazard score can be calculated at any time and used as a tool for men deciding whether and when to undergo screening for prostate cancer.
‘This is particularly important for men at risk of developing prostate cancer at a very young age, before standard guidelines recommend screening.
‘However, we still need to study the clinical benefits before the polygenic hazard score is ready for routine use.’
First author on the paper, Dr Tyler Seibert of the University of California San Diego, said: ‘The polygenic hazard score was calculated from 54 SNPs and proved to be a highly significant predictor of age at diagnosis of aggressive prostate cancer.
‘When men in the ProtecT dataset with a high polygenic hazard score were compared to those with average PHS, their risk of aggressive prostate cancer was at least 2.9 times greater.
‘And when we account statistically for the effect of the GWAS having disproportionately high numbers of men with disease compared to the general population, we estimate that the risk defined by the polygenic hazard score is 4.6 times greater.’
The full paper, ‘Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large-scale cohorts’, can be read in the BMJ.
Funding for this research came, in part, the U.S. Department of Defense (grant w81xwh-13-1-0391), the Research Council of Norway, KG Jebsen Stiftelsen and South East Norway Health Authority.
- University of Oxford