What if you could walk into a room full of guys and know who’s probably going to get prostate cancer? Not because you’re some sort of psychic cancer whisperer, but because you have a test. And what if you could also tell which of these guys has a high likelihood of never getting prostate cancer?
And what if these guys were young, much younger than the typical prostate cancer patient? The ones who are at high risk could start getting their PSA checked in their thirties. Men with Gleason 8, 9, and 10 cancer could have it detected and treated at its earliest manifestation. The number of men dying of metastatic prostate cancer could plummet!
One day soon, a young man and his parents may even work with “his pediatrician to determine his polygenic risk score and create a lifetime prostate cancer risk reduction strategy,” says molecular biologist and medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation (PCF). “That’s going to be the future.”
The Smith Polygenic Risk Test for Prostate Cancer is very simple for the patient; it starts with a saliva or blood sample. This score could also be obtained with a cheek swab – or any routine blood test, “although it would only need to be done once in the life of a patient,” says Simons. Step right up – spit in a tube (or get swabbed, or take a blood test), and get your prostate cancer fortune read! In this case, the fortune is in the germline DNA, the genes we are born with; all 20,000 or so of them are present even in a teaspoon or so of spit or a small vial of blood.
But here’s the key: It turns out that it’s not this one particular gene, or that gene right next to it, that suddenly determines your prostate cancer fate. It’s certain bad combinations of genes. Scientists led by Christopher Haiman, Sc.D., a PCF-funded investigator and cancer and genetic epidemiologist at the University of Southern California, have identified specific – and testable – changes, called single-nucleotide polymorphisms (SNPs) in more than 250 genes. There are many possible combinations of these SNPs, but they could raise a man’s risk of getting prostate cancer by a little, or a lot. Or, if a man doesn’t have any of these changes, it’s almost – not quite, but darn close – a genetic “get out of jail free” card. Lucky guy!
How does it work? It’s actually pretty simple, once you get past the extremely sophisticated technology that allows scientists to analyze vast amounts of information all at once.
Consider, if you will, a hand of cards in your basic game of poker. You might get dealt five completely unrelated cards. This would be like the fortunate man mentioned above – the man who will never know what it’s like to have needles stuck in his prostate for a biopsy, the man who probably won’t need many PSA tests in his life, because he’s got an extremely low risk of ever getting prostate cancer. He doesn’t have any of the bad combinations of genes.
This man, by the way, is probably Asian. Haiman and colleagues in the U.S., including William Isaacs and UK have shown that race matters in the genetic lottery of prostate cancer-causing genes. More on this in a minute.
Back to the poker game. Your imaginary hand could have three unrelated cards and a pair; it could be a pair of twos, or a pair of Aces. You could have three of a kind – three Jacks, perhaps. Or two pair – a couple of sixes and two eights.
Now, let’s raise the stakes. Let’s say you have three of a kind – three Queens, perhaps. Or a straight – five consecutive cards of different suits. Or a flush – five cards of the same suit; hearts, perhaps. In poker, four hands are more powerful than this: a full house; four of a kind; a straight flush, or – a certainty to win – a royal flush. The man who inherits this, the worst gene combination, is more likely to be of African descent, or to have a family history of prostate cancer, or a family history of other kinds of cancer. We’ve known that these are the men at highest risk of getting prostate cancer; we just didn’t know why, until now.
A man born with the genetic equivalent of a royal flush is at very high risk of getting prostate cancer. Worse, he’s at very high risk of getting aggressive, high-grade cancer. If that man waits until his mid-fifties to start getting his PSA checked, he might be diagnosed with cancer that has already spread outside the prostate.
But soon, that man will have a secret weapon: the multi-gene (polygenic) test. In the future, a young man who spits into a tube or gets a blood draw and finds out he’s got this “royal flush” combination of prostate cancer genes will be monitored closely. He will probably start getting his PSA checked when he’s in his thirties, and he may have a lower PSA threshold – a lower cutoff number for PSA that would signal the need for further testing, including an MRI and a biopsy.
How soon? Well, the answer is… soon. In PCF-funded studies, Haiman and scientists in the U.S., and scientists in the UK led by cancer geneticist and medical oncologist Rosalind Eeles, F.R.C.P., F.R.C.R., are investigating the test – hoping to confirm the results Haiman and colleagues found in the smaller study – in larger groups of men of different races. They are looking to improve the risk stratification (basically – going back to our poker game – to determine whether a man has three of a kind, a straight, etc.) and to make sure they’re looking at the right gene combinations for men of various races.
Eeles, who specializes in early, targeted screening and cancer genetics at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, is principal investigator of the PROFILE study, which correlates germline genetic profiling with targeted prostate cancer screening and treatment. In groundbreaking research using a massive genetic databank, Eeles and her team have identified risk SNPs in the genes of tens of thousands of men – those with prostate cancer, and those without. Her current study has two groups of participants aged 40-69: one is Caucasian men with a family history of prostate cancer, and the other is black men of West African or African-Caribbean ancestry.
When the risk test becomes widely available, it will assess different genetic profiles based on race. “It’s obviously silly to use a profile that’s genetically most relevant for the African-Caribbean man if you’re a European man,” notes Eeles.
Men in the PROFILE study, in addition to having their saliva analyzed, receive a PSA test, an MRI, and a prostate biopsy. The goal, Eeles says, is to make reliable predictions of risk with the test – to tell, for example, “what would his MRI look like? What would his biopsy look like? The long-term aim is that you will do a saliva test, look at the genes, and tell whether that man is high-risk or not. Then we’ll know which men to target with more intensive screening.” For countries (such as the U.S.) where MRI is expensive, “men could have the profile done first, have more intensive PSA monitoring, and have a trigger for biopsy, which will almost certainly be age-dependent.” The family history study began nearly two years ago, with funding from Movember, Prostate Cancer UK, and Cancer Research UK . Eeles and colleagues have enrolled about 250 men, and the target is 350. The UK study of black men started recently, with 25 men tested so far. Incentive for taking part in this study: if you are found to have prostate cancer, you will find out right away and get immediate treatment. Here’s a link to more information.
If you are a Hispanic man, your bad combinations of genes will probably be different from the bad combinations of a Caucasian man, and both of your bad combinations may be very different from those of a man of African ancestry.
One more thing: just because you have the key combination – the three lemons on a slot machine – doesn’t make it absolutely, 100 percent certain that you are going to develop prostate cancer, says Haiman. Other factors – diabetes, obesity, smoking, or conversely, a healthy diet and exercise – undoubtedly play at least a small role, even in men at the very highest risk. But giving men a lifetime risk, and custom-tailoring their prostate cancer screening, “is going to change everything,” says Simons. “We just don’t know by how much, and in what way; I can’t tell you how many men would start getting their PSA tested at 35, and how many would wait until 55, have a couple of tests and never need to be tested again.”
Nonetheless, “the evidence is overwhelming that we can stratify risk,” Simons continues. “We can tell a man whether he has a three-times or a ten-times higher risk versus a normal risk. We can dramatically fine-tune which men are going to need a biopsy. We can save lives. That’s why PCF is funding this: we are going to drive the national testing of this in the U.S. and the UK.
“There are men walking around in their forties with an 11-times higher risk of prostate cancer. I could tell you every one of them, if they all spit into a tube. Will all of them get prostate cancer? No; not everybody at high risk gets the disease. How many will get Gleason 9 versus Gleason 7 disease? We don’t know, but you’d still want them all to get a PSA test. With the Smith test, it becomes unethical for men at higher risk not to screen for prostate cancer.”
