Prostate cancer is the most heritable type of cancer. However, little is known about which genes cause some men to have a high risk of developing prostate cancer. A total of 130 research groups worldwide have now joined forces to analyse the genetic data of thousands of people with prostate cancer. The results suggest that one region of the genome is as strongly associated with prostate cancer among men as another region is associated with breast cancer among women. This discovery paves the way for targeted screening of men with an unfavourable genetic profile, similar to screening for breast cancer.
Prostate cancer is the most common type of cancer affecting men, with more than 160,000 men diagnosed annually worldwide. In addition, prostate cancer is also one of the most heritable types. However, men are not screened for the disease simply because no screening methods are reliable enough. Researchers have collected new genetic data from more than 70,000 men with prostate cancer and compared the data with those from more than 52,000 healthy men.
“Previous studies identified more than 100 gene variants that each slightly increases men’s risk of developing prostate cancer – but combined, they can have a considerable effect. The previous studies especially identified gene variants in a region of the human genome called chromosome 8q24. However, its significance has not been explored in detail. By analysing even more people with prostate cancer than before, and in greater detail, we have now succeeded in zooming more closely into this region,” explains Karina Dalsgaard Sørensen, Professor with Special Responsibilities, Department of Clinical Medicine, Aarhus University.
Fourfold greater risk
The researchers have thus identified 12 very specific gene variants that may explain 25% of the heritability of prostate cancer. Combined with the existing knowledge in the field, 40% of the heritability of prostate cancer can now be explained.
“We can therefore also develop a genetic test that can reliably identify the men who have a high risk of developing prostate cancer and then ensure that they are offered regular check-ups.”
The study was a genome-wide association study that compared genetic data from many men with and without prostate cancer. The genetic material was comprehensive and of high quality because 130 research groups globally pooled data from their individual studies.
“We could therefore identify the most frequent gene variants among men with prostate cancer. We also zoomed in on the genetic variation in the chromosome 8q24 region, which previous studies had shown contains many of the gene variants.”
Gene variants on chromosome 8q24 are associated with several types of cancer, including prostate cancer. The researchers found 12 genetic risk variants for prostate cancer within a relatively small region of the genome.
“The results show that men with many of these variants have a fourfold greater risk of developing prostate cancer. Cumulatively, these 12 variants comprise 25% of the total genetic risk.”
Will also investigate circulating tumour DNA
In addition to the genetic factors, age and lifestyle are also important in determining who develops prostate cancer, similar to other types of cancer. The reason this study is especially relevant is that the genetically determined risk in prostate cancer is estimated to be 40%, which is much greater than for other types of cancer.
“Now that we have identified 12 important variants, the next step is trying to understand their biological function. Why do the variants in this region trigger prostate cancer? Understanding this may enable us to find pharmaceutical targets for new anti-cancer treatments or methods to prevent the cancer from developing.”
The studies also enable other types of studies on which Karina Dalsgaard Sørensen and her Danish colleagues are focusing. They will try to understand how prostate cancer metastasizes (spreads to other sites in the body) and why it can resist treatment. The genomic data are especially important for this.
“Prostate cancer only becomes dangerous once the cancer metastasizes and resists treatment. We are thus focusing on discovering and sequencing the circulating tumour DNA in the bloodstream because it has leaked from the tumour cells. If we can achieve this, we may also be able to understand the underlying mechanisms that develop resistance and perhaps develop drugs and treatment strategies that can inhibit these mechanisms.”
Men follow recommendations
In addition to potentially determining the mechanisms enabling prostate cancer to develop in the long term, this new knowledge may help now in detecting cancer early so it can be treated and cured before it metastasizes. Men are not currently routinely screened for prostate cancer because the screening methods are simply not reliable enough. An existing screening method measures the prostate-specific antigen (PSA) concentration in the blood.
“Because PSA is present naturally in men, a man with a naturally high level of PSA may be diagnosed with prostate cancer and therefore may be treated unnecessarily. However, if we assess a man’s risk based on his genetic profile, we can confine testing to the men with the greatest risk of developing prostate cancer. They can then be routinely checked by measuring their PSA concentration.”
The Danish researchers are testing this method in a research project in the Central Denmark Region in which 5000 men have volunteered to undergo genetic testing. The men with the least favourable genetic risk profile (threefold greater risk) will then be offered regular PSA tests. The first 4000 men have already been tested, and the results are very promising.
“Although the study is still ongoing, we have already had initial success: the men in the high-risk group are actually following the recommendations made after the genetic testing. This is a very positive initial result because experience shows that men consult a doctor less often and later.”
Another study of prostate cancer diagnosis is underway in the Central Denmark Region. In this trial, selected doctors are evaluating the Stockholm-3 (STHLM3) test, a new multistep blood-based test used in Sweden that can detect the early development of prostate cancer more precisely than the standard PSA test. The trial began in 2018 and is expected to run for 2 years.
“The new blood test considers more and different parameters than the PSA result, including age and heritability through genetic testing. In this respect, the new blood test is a far more personalized method of detecting prostate cancer in the future, and we are very optimistic and excited about the results of this research project.”
“Germline variation at 8q24 and prostate cancer risk in men of European ancestry” has been published in Nature Communications. In 2016, the Novo Nordisk Foundation awarded a grant to a co-author, Karina Dalsgaard Sørensen, Professor with Special Responsibilities, Department of Clinical Medicine, Aarhus University, for the project Genome-Wide CRISPR-Cas9 Screening for Drug Resistance Mechanisms and Identification of Novel Predictive and Monitoring Biomarkers for Castration Resistant Prostate Cancer.