The genetics of prostate cancer
At the annual meeting of the Society of Urologic Oncology (SUO) held in the fall of 2023, Dr. Catalona gave an invited lecture to urologic oncologists on the Genetics of Prostate Cancer. This article is a condensation and simplification of the lecture on this interesting and important topic for our readers.
We inherit our genetic material (DNA) called genomes from our parents through the fusion of their sex cells (egg and sperm). These cells are called germ cells. What each individual inherits at birth does not normally change throughout their life—this is our germline. If you were a poker player, you know you have to play with the hand of cards you have been dealt. The same is true for the genes you have “been dealt.” There are variations of the germline that predispose us to be susceptible to various cancers, including prostate cancer. These variations are termed endogenous because they come from within. There are also separate somatic variations that include DNA changes acquired by external environmental exposure that are not passed on to our offspring. The accumulation of these somatic DNA changes over time also can cause or promote cancer.
The current status of prostate cancer research in this area is to conduct genome-wide association studies (GWAS) that involves testing millions of Single Nucleotide Polymorphisms (SNPs, pronounced “snips”) for their statistical association with prostate cancer. The measure of the strength of the association for each SNP is called its P value or “weight.” Each human has 4 to 5 million SNPs.
This SNP data allows one to calculate polygenic risk scores that estimate the combined effects of the many low-risk SNPs that individually increase the risk by a small amount but collectively can increase the risk substantially. Polygenic risk scores are calculated by adding together the number of significantly-associated prostate cancer risk SNPs, multiplying each SNP by its statistical weight. Until very recently the best prostate polygenic risk score included 269 SNPs of the millions of SNPs that have been tested in hundreds of thousands of patients.
Although some aggressive cases occur in all of the polygenic risk- score deciles (percentiles grouped into 10 levels are called “deciles”), approximately half of the aggressive cases occur in the top 20th percentile and very few in the bottom tenth.
The “latest-and-greatest” prostate cancer polygenic risk score study soon to be published was developed in a Veterans Administration Healthcare population of nearly a million men. It includes 451 prostate cancer risk SNPs. The study has been
validated in European, African, Asian, and Hispanic populations and is a better predictor of risk across populations. This study has an improved ability to discriminate aggressive from non- aggressive cases. Adjusting for the SNPs that determine baseline blood PSA levels improves the accuracy of the prostate cancer polygenic risk score to predict the aggressiveness of the man’s cancer.
Our collaborative research group recently reported that prostate cancer polygenic risk score is associated with the early outcomes of patients on active surveillance, i.e., whether they remained on surveillance or switched to radical treatment.
There are also rare but highly penetrant non-SNP germline variants that by themselves can substantially increase the risk for cancer. Remember germline means inherited, i.e.,coming in the hand you were dealt. Some of these, such as BRCA2, are associated with an increased risk of the more aggressive forms of prostate cancer and an increased risk of dying from prostate cancer. A recent study reported on the genetic variants predisposing to metastatic or fatal prostate cancer. These variants are more frequently carried by men with a positive family history of prostate cancer and those with cancer occurring at a younger age. The two most important pathogenic mutations for aggressive prostate cancer are BRCA2 and ATM.
Ultimately, the overall risk of an individual developing prostate cancer depends on the assortment of all of the risk-associated variants he has inherited.
For BRCA2 carriers, the risk by age 85 varied from 34% to 88% between the 5th and 95th percentiles of the polygenic risk score distributions.
Study results show that for the most accurate risk prediction, the SNP polygenic risk score should be combined with rare variants.
The clinical implications of germline testing are the potential for risk-stratified screening, to inform the optimal age to initiate screening, and to determine the frequency of screening. Targeted screening has the potential to pick out aggressive prostate cancers at an early stage in men at high inherited risk, increasing their chances of survival. Germline genetic testing also has the potential to guide disease management, as it could inform decisions around the adoption of and intensity of active surveillance. Rarevariants in some genes, such as BRCA2, have implications for treatment response, that is responsiveness to certain drugs, such as PARP inhibitors and platinum-based chemotherapy. Germline testing also can inform disease risk in family members to implement what is called “cascade genetic testing.” However, in this regard, it is important to realize that many men without a known family history do carry inherited risk factors, and these men also may benefit from that knowledge.
The current National Comprehensive Cancer Center Network guidelines recommend eliciting a family cancer history of cancer and a family or personal history of high-risk germline mutations. They also recommend beginning screening at age 40 for men with germline mutations that increase the risk for prostate cancer or a family history suspicious for prostate cancer. And they recommend repeat testing at more frequent intervals of 1 to 2 years for high-risk men. For this purpose, polygenic risk scores are now commercially available in the U.S., as is testing for rare genetic variants, such BRCA2.
Turning briefly to somatic genetic testing for DNA changes acquired during life, there are several commercial extensively validated RNA-based gene expression panels for testing prostate biopsy specimens. However, they are all susceptible to possible biopsy sampling errors.
Somatic (outside or environmental events or conditions impacting one’s DNA) testing is recommended in all patients with advanced prostate cancer. Ideally, to improve accuracy, it should be performed along with simultaneous germline testing.
Genomic testing will continue to provide important insights into the fundamental mechanisms underlying the development and progression of prostate cancer and will lead to the discovery of new biomarkers that may have clinical implications for targeted screening and patient management.
