Apart from your long-lost evil twin, you’re the only person in the world who has your unique combination of genes.
Genetic variation is a good thing – without it, we’d be the pugs of the primate kingdom.
But when it comes to figuring out how genetics might affect our chance of getting a disease, this bountiful diversity of human uniqueness makes things complicated.
Take pituitary tumours – around 10% of people have a small tumour in the pituitary gland under their brain, but most will never know.
At their best, these tumours are a harmless internal accessory, like a bauble for the brain. At their worst, they’re devastating growths that wreak havoc on hormone levels, leading to life-threatening health issues.
What causes pituitary tumours, and why some remain decorative while others choose violence, has so far eluded researchers. While scientists have long suspected that genetics plays a role, the complex variation among individuals makes it hard to identify the culprits.
“We intuitively know that there are genetic drivers of pituitary tumours,” says Associate Professor Sunita De Sousa, Staff Specialist in Endocrinology and Genetics at the Royal Adelaide Hospital.
“We know that they can occur at a young age and they can run in families – but more often than not, we can’t figure out the culprit genes, despite using the best available genetic tests.”
Humans have about 20,000 genes – fewer than a banana, but still a lot. In the past, scientists would guess which genes they thought might be involved in a disease, based on what they knew of how it worked and what it’s role was. Then, researchers like A/Prof De Sousa would painstakingly analyse the genes one at a time, hoping to find something that connected them to pituitary tumours in particular.
Now, new laboratory technologies and computer software allow researchers to collect the genomes of hundreds of people with tumours and scan them all for gene mutations they might have in common.
“Rather than back in the old days when you had to study one gene at a time and have a very solid mechanistic basis for why you were selecting that gene, we can now scan literally thousands of genes to try and find areas of the genome that are recurrently mutated between affected patients. We can then use that commonality as a clue to the gene playing a role in the disease in question.” says A/Prof De Sousa.
The gene is out of the bottle
With the new tools at their disposal, A/Prof De Sousa and her team began to analyse the genomes of people with pituitary tumours. By comparing these genomes the genomes of people without pituitary tumours, they hoped to find recurring patterns that might point to a genetic culprit. And that’s when they stumbled upon something unexpected.
They found two genes, CHEK2 and PAM, that weren’t previously thought to have anything to do with the pituitary gland. One has been linked to breast cancer but never pituitary tumours, and the other is the blueprint for an enzyme that modifies peptides to help them work better.
“We’ve been able to find that actually these two genes are recurrently mutated in different individuals with pituitary adenomas.” says A/Prof De Sousa. “Now we’re trying to figure out how PAM or CHEK2 actually plays a role in tumour development.”
The fact that these genes were usually mutated in patients with pituitary tumours suggested they might play an important role. But even after finding the smoking gun, the researchers still didn’t have a clue how it all worked. What were these particular genes doing that would cause tumours in the pituitary gland?
Keeping pituitary tumours in CHEK
The mystery deepened as A/Prof De Sousa delved further into the roles of CHEK2 and PAM.
CHEK2’s job is repairing DNA. It actually helps to prevent cancer by fixing up DNA that would result in tumours. But if something happens to make CHEK2 stop working properly, then it can’t do its job as effectively.
PAM, on the other hand, was more enigmatic. This gene is responsible for making an enzyme that puts a finishing touch on peptides. This process is crucial for hormones to function optimally. But how could errors in this gene cause pituitary tumours?
As A/Prof De Sousa explored these genes, she realised the key might lie in whether these genes act as “tumour suppressors.”
“Here you’ve got a loss-of-function variant that reduces the function of the protein product, and so it stops the ability of that gene to have its usual function in protecting the cell from excessive proliferation.”
As the name suggests, tumour suppressors usually suppress tumours. They’re like tiny chemical cats that guard against any cancerous mice that might pop up in your body. But if someone has a mutation that makes those cats bright pink, or lazy, or have no ears – then more mice will be able to slip by them and start a nasty tumour.
Double or quits
It might even be more subtle than that. Genes come in pairs, one from the mother and one from the father. Only one copy might be dodgy. With some genes you need both copies to work perfectly, but other genes run fine with just one.
“With classic tumour-suppressor genes, you have something called the Knudson two-hit hypothesis,” adds A/Prof De Sousa.
This idea proposes that in order for a tumour to develop, both copies of a tumour-suppressor gene need to be mutated. One mutation might be inherited, while the other happens later in life, creating the conditions for tumour formation.
“Say you have a germline genetic variant in the tumour-suppressor gene. That’s throughout all the cells in your body and it might have been inherited from a parent” A/Prof De Sousa explains.
“And then the second hit is the somatic second hit. In the tumour, the other copy of the gene has just by chance developed a mutation and that’s when the tumour has been developed.”
“That explains why children born with these genetic variations don’t develop tumours immediately and may never develop a related tumour – it takes time and chance for that second hit to occur.”
A pituitary mystery
As her research continues, A/Prof De Sousa is still piecing together how PAM and CHEK2 work in the context of pituitary tumours.
While she’s discovered that these genes play a significant role, much is still unknown. The next step will be to piece together the whole chain of events that starts with these genes and ends in a dangerous tumour.
In the meantime, the rest of us don’t have to worry too much.
“If someone has a variant in one of these genes,” A/Prof De Sousa says, “it doesn’t mean that they’re going to develop a tumour necessarily. It’s more about increased risk – it compounds with other risks.”
“When you’ve got a risk allele, like we imagine PAM and CHEK2 variants to be in the pituitary gland, you may have an increased chance of developing a pituitary tumour compared to people without these risk alleles, but that chance is still reasonably low.”
“The most likely outcome, if you have a PAM or CHEK2 variant, is that you will never develop a pituitary tumour.”
The genetics of these tumours are complicated – it’s not like having a PAM or CHEK2 variant means you’re going to die instantly. Most people with these genetic variants will live long lives without ever having to try and spell “pituitary”, while plenty of other people without such variants will still develop a tumour. What A/Prof De Sousa’s research does mean is that if you do have one of these mutations, and you do develop a tumour, there might be targeted treatments especially for you, down the road.
