What is the “dark DNA,” and why does it sound so mysterious? Is it dark like “The Maltese Falcon,” or “The Big Sleep,” or any other Humphrey Bogart film noir you can think of? Is it sinister, like the dark Web, that creepy part of the internet where illegal drugs are sold and nefarious deeds are planned?
Fear not. It’s dark for a very simple reason: nobody has shed much light on it! But that is changing rapidly, and the secrets that scientists like Paul Boutros, Ph.D., a world leader in genomics-based cancer research, are uncovering have the potential to revolutionize many aspects of prostate cancer, starting with knowing who’s at risk of aggressive cancer – many years before that cancer might be diagnosed.
“DNA encodes everything that makes us human; it’s what we pass down to our children,” says Boutros, professor of Urology and Human Genetics at UCLA’s Jonsson Comprehensive Cancer Center. “Dark DNA is the part of DNA we know the least about.”
Although scientists are learning more about the human genome all the time, most would agree that we’ve still barely tapped the surface. We’ve been deciphering the headlines: the defective genes, the infamous John Dillinger, Al Capone, and Bonnie and Clyde genes like BRCA1 and BRCA2, WNT, ATM, CHEK2, and some others that are known to cause cancer or make it more aggressive when mutated. We have focused on the protein-coding genes, which make up just a small fraction of our genome.
What about the rest of it? Well, says Boutros, “most of that DNA, we don’t really know what it does.” To be fair, there is a lot of ground to cover: The human genome, he continues, is made up of more than 3.2 billion base pairs. (These are links in the twisting chain of DNA that makes up the 23 pairs of chromosomes that dwell in the nucleus of every single cell in our body.) “That’s 10 times as many letters in the genome as there are people in the U.S., and 90 percent of it is dark! We just have very little idea what it is and how it works.” Boutros and colleagues have identified several dozen dark regions of the genome that influence prostate cancer development – the tip of the proverbial iceberg – but many more regions “remain to be discovered. In many ways, it’s a critical first chapter – but still, only a first chapter.”
This work is essential. Imagine studying the pyramids of ancient Egypt, and only knowing about the pharaohs who are buried there, but not the engineers who designed these massive mountains, the thousands of laborers who heaved the great stones into place, and certainly not the lowly servants who did the laundry, cooked the food, and carried out the plain old tasks of everyday life. Basically, you might know who got the fancy sarcophagus and the gold chariot (plus all those embalmed organs in the little jars) to use in the afterlife, but you wouldn’t know much about how those pyramids actually got built.
The dark DNA is the nuts and bolts of the germline genome – the genes we’re born with. “The genome we inherit from our parents sets the context for everything that happens in cancer,” explains Boutros. “Some people have a germline genome that’s a little better at repairing damage,” from environmental factors such as smoking or unhealthy food, “or a genome that gives them lower androgen (male hormone), or higher blood sugar. This is unique to each person.” By themselves, functional parts of the dark DNA may make just tiny differences in how our bodies deal with factors that could make us sick. “But these very small effects have a chance to amplify over decades. Over time, they gradually influence the way cells evolve and the types of damage that can accumulate. Rather than being a profound effect” – like that caused by a bad DNA damage-repair gene such as BRCA1, for instance – “these are really slow, long-term effects that drive a gradual evolution of cancer over a man’s life before he gets diagnosed.”
Going back to John Dillinger: his most prolific string of bank robberies – 12 banks – was between June 1933 and June 1934, and his estimated loot was about $500,000 ($7 million in today’s money). His crime spree was brief, acute, and violent. But here’s the thing: a dishonest bank clerk who embezzled a little bit here and there over decades could steal that much, too, in sneaky increments. When it comes to prostate cancer, genes in the dark DNA may be much more like that squirrelly clerk – doing damage that can be significant, over the course of many years.
“Hiding in Plain Sight”
How has Boutros been able to identify regions of the dark DNA that are important in prostate cancer? First, there’s timing: if this were 10 years ago, such a quest would have been so time-consuming and labor-intensive that it would have been “completely impractical,” he says. No person would, or could, “simply look at every single thing that’s there.” However, this is a great job for computers! “We can write computer programs, and sequence genomes, and measure in high-throughput types of experiments,” looking at long strings of DNA. Even better: “We can be a little more clever, and factor in other things we know about prostate cancer, and identify regions (of chromosomes known to be involved in prostate cancer) that are high priorities.” By looking at “multiple views of the same region of the genome, identifying dark DNA candidates that have a lot of independent lines of evidence, and using multiple layers of evidence” to highlight likely regions to study, Boutros and colleagues have found areas of genes “that are much more penetrant and much more common” in prostate cancer. What they’re seeing is “something that we could see all the time, but we didn’t know to look at it,” pockets of genes that were “hidden by the huge size of the genome. They were almost hiding in plain sight, but because there’s so much to look at, we didn’t see them.”
Maybe when you were a kid, you looked for “Hidden Pictures” in Highlights magazine. Or you had a special decoder ring – tinted a certain color, perhaps – that revealed an invisible message on a cereal box. “In a way, the genome has so much noise, that until you put on the right 3-D glasses, the picture is blurry,” says Boutros. But once you know where to look, “you can pull out the right pieces of information from that dark genome.”
Understanding Germline Mutations
The genes you’re born with, the germline genes, are with you all your life. “They don’t change,” says Boutros. Thus, “it makes sense to measure those at any time in life,” and this, in turn, “could change how you might interpret other lab results.” Boutros and colleagues have identified about 140 regions of dark DNA that could spell prostate cancer trouble, “if someone inherits exactly the wrong group of these 140 regions, which happens in about 2 percent of people.” Men in this 2 percent “have 10 times the risk of developing prostate cancer. It’s almost a certainty that they’ll get it.”
But other men may be lucky enough to inherit “the exact opposite set” of dark DNA regions. These men may be less likely to develop prostate cancer – or, if they do, to develop a less aggressive form of it. This is news we can use! Wouldn’t it be helpful to know, as a young man, if you need to start getting screened for prostate cancer sooner, and that you need to be checked more regularly – so, if you did eventually develop prostate cancer, you could get curative treatment as soon as possible? These 140 regions of dark DNA, says Boutros, “should be shaping the way we start to look at things like PSA or MRI screening. Men don’t all have the same risk at birth, and we could make screening much more efficient. The magic of these regions is that they put everything else in a better context. There’s pretty good evidence that you could come up with different thresholds for PSA” – highly specific, personalized PSA numbers that could severely curtail unnecessary biopsies. For example: New personalized, dark DNA-based guidelines could say that Bob should get a biopsy if his PSA goes above 1.0, while Frank wouldn’t need a biopsy until his PSA is over 2.5.
“Massive Ethnic Differences”
Smarter risk classification could save many lives, particularly in high-risk groups including African American and Hispanic men. “There are massive ethnic differences in prostate cancer risk,” says Boutros. “In African American men, we understand that there is much more aggressive disease. But in Hispanic populations, it’s almost unknown what makes prostate cancer different” from cancer in Asian or Caucasian men. “There are differences depending on whether the men are from Puerto Rico or from South America, and even local geographic variability among Hispanic men in the U.S.” In contrast, “Asian men in the Han Chinese group have different risks for prostate cancer than men from Southeast Asia.” And here’s the kicker: a biomarker test developed and tested primarily in Caucasian men is “likely to underestimate the risk of cancer in African American men and overestimate the risk in Asians. What the biomarker is measuring is attuned to the aggressiveness of prostate cancer.” But clearly, more specific tests – looking for those suspicious 140 dark DNA regions, for instance – are needed now more than ever. “There are a billion people in India, and a few hundred million others on the subcontinent for whom prostate cancer is going to become an increasingly important health problem,” as screening becomes more common and more men are diagnosed, as the population ages, and as diets become more Western – higher in fat and sugar, and lower in fresh fruits and vegetables.
The Bottom Line
What does all this mean for you? Good things, Boutros says. “Prostate cancer management has often treated everybody the same. We haven’t paid enough attention to individual genetic heritage. That’s on the cusp of changing, and when it does, it’s going to change everything: every aspect of prostate cancer treatment and management. Most of that is going to be because of the dark DNA. We had no previous understanding of what it did.” Now that Boutros and colleagues are tapping into its power to forecast the future, “we want to make this new knowledge impactful,” and get this information into medical practice as soon as possible, “to a test that can be done automatically, with low cost and high accuracy.” For many men, he hopes, “the result of this test would be, ‘You don’t need active treatment. We can monitor a disease that you will never die from.’”
Boutros envisions such a test costing about $200, and being available from “any good quality pathology/molecular diagnostic lab.” The Prostate Cancer Foundation has co-funded much of the initial research into the dark DNA and its translation into medical care. We are very invested in this story and will keep you posted on its progress. Stay tuned!
