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Serena Nik-Zainal: "We will never live without cancer, but we will delay its appearance"

2022-04-22T04:23:05.844Z


The British geneticist is one of the world's leading experts in analyzing the millions of mutations caused by cancer and discovered kataegis, a new phenomenon caused by hypermutations in breast tumors


Cambridge University clinical geneticist Serena Nik-Zainal.CRUK CC

Hearing Serena Nik-Zainal talk about cancer fills anyone with hope.

"Right now every cell in my body is accumulating mutations, so if they live long enough it will be inevitable that they will end up developing a tumor," admits this doctor and geneticist from the University of Cambridge (United Kingdom).

"Having said that, let's remember that a human is made of 30 billion cells, all accumulating mutations, and only one of them will start a cancer throughout my life.

This is amazing.

Furthermore, we know that only one in three people develop cancer, which means that there is actually only one cancer cell for every 90 trillion healthy human cells.

This shows us that the body is quite good at avoiding cancer despite accumulating mutations.

In fact, it's amazing how sturdy it is,” she highlights.

The explanation for this wonder is that within each of our cells there are mechanisms that repair DNA damage that occurs by the simple fact of being alive.

The oxygen and water we need to live damage DNA.

Tobacco, alcohol or sunlight that reaches us from outside, too.

Cancer deactivates these repair mechanisms, which allows it to accumulate tens, hundreds, thousands, millions of mutations that are its instruction book to generate an aberrant and unrestrained growth of malignant cells.

We humans understand our instruction book—our genome—much better than that of cancer.

Nik-Zainal, a 45-year-old British woman of Malaysian origin, is trying to understand this aberrant programming.

The researcher has just coordinated the publication of the largest catalog of cancer genomes in the world: the complete sequence of the tumors suffered by more than 18,000 people from various countries, including Spain.

The data—published today in the journal

Science

—is the largest compendium of cancer mutations that science has ever had access to.

In this huge database, Nik-Zainal searches for marks and patterns that can explain why each cancer appeared and, above all, if there is already a drug that could cure it.

In this interview, the scientist explains the implications of her work for our understanding of cancer and the search for new treatments, an issue that she will speak about today at a symposium organized by the Spanish Association of Human Genetics.

Ask.

What is the point of studying all the marks that cancer leaves on our DNA and not just those that we know are useful for something?

Response.

Those marks are like footprints in the sand.

You go to the beach and see a bunch of footprints that seem randomly scattered.

But if you look closely you can distinguish which ones belong to a person and which ones belong to an animal.

You can know which are dog and bird.

In human ones, you can tell if they were left by an adult or a child.

If they walked or ran and where.

By studying those marks, you can find out if a person's tumor has a genetic defect that makes them very vulnerable to a particular drug.

We call all these marks the genetic signature of cancer.

Q.

How many genetic signatures can there be in a tumor and how do you know which ones are important?

A.

Our understanding of this subject is constantly changing because it is a very new field.

We're still learning, but I can tell you that when you look at any cancer you don't see just one pattern of mutations, but several.

Sometimes there are only two and sometimes there are seven or more.

It all depends on the type of tumor and age.

Younger patients tend to have fewer mutations because they have lived less.

Normally a cancer has between four and seven patterns.

That means there is a highly variable number of specific mutations, from 1,000 to a million or more.

But even tumors with fewer mutations sometimes show very clear patterns that tell you: this cancer is vulnerable to this drug.

Q.

How often does that happen?

A.

If you have ovarian cancer, I will tell you that you have a very good chance of getting better if I know the signature of your cancer.

The same goes for breast, colon or uterine cancer.

Then there are others where the signature is not so useful for now, especially tumors in children, because they have fewer mutations.

P.

In breast cancer you discovered the kataegis, what is it?

R.

I was still a doctoral student.

I looked at all the patient data.

At that time we only had 21 people and it was still an atrocious volume of data.

The first thing I understood was that each patient had a unique cancer genome, very different from the next.

However, they all received the same treatment!

There was a patient with an inordinate number of mutations.

They were all crowded into a particular area of ​​his genome: chromosome six.

The mutations were very close to each other.

They were typos of one letter.

DNA has four letters GATC, and here they all followed the same pattern: the letter C, cytosine, became T, thyminine.

That had to mean something because in theory any letter can mutate into any other.

It was as if in this part of the genome there was a huge storm, which in ancient Greek is called kataegis.

Q.

And it turned out to be something important?

A.

When we looked at more patients who had other types of tumor we found the same hypermutation.

We now know that kataegis is common in tumors of several different organs.

It happens because a part of the genome splits.

The cell's repair system tries to put it back together, but in doing so it eats up other adjacent letters and causes more mutations.

Q.

Is it good or bad for a tumor to have this mark?

R.

In HER 2 positive breast cancer, it happens a lot.

And when you have this type of breast tumor you can receive a therapy directed at that protein, which greatly improves the chances of survival.

Probably this storm increases the copies of certain genes against which we can direct a therapy.

But we also see these hypermutations in other parts of the genome, in other tumors, and we don't know what effect they have.

We need to study it more.

Q.

How does all this information about cancer signatures translate to treating patients?

A.

One of the genetic repair mechanisms is related to mutations in the

BRCA1

and

BRCA2

genes , which are hereditary and increase the risk of breast tumors throughout life.

There are specific medications for women who have inherited this marker, such as PARP inhibitors.

In one of our first studies, we discovered that these women have very characteristic patterns of mutations, and then we saw that those patterns are so clear that they predict whether the tumor has

BRCA1

or

BRCA2 mutations .

.

We have developed an artificial intelligence system – an algorithm – that reads cancer genomes and gives a score.

What we saw is that one in five breast tumors have a deficiency in these genes.

This means that there are many patients who have acquired these mutations not by inheritance, but spontaneously throughout their lives.

And it's very likely that their tumors are vulnerable to the same drug.

We have studied this algorithm in two clinical trials with phase one and two patients.

The phase two study showed us that the algorithm can determine which patient will benefit from receiving PARP inhibitors.

We can not only see the patterns, but also predict the evolution of a tumor.

We are now setting up phase three, which is the last before we can use it in clinical practice.

Q.

How does knowing these facts help patients?

R.

Right now everyone receives the same treatment.

If I know it won't work for me, I don't want to take it, because it has a lot of side effects.

On the other hand, you can give the drug to the patient as soon as possible, if he is fit for it, and increase his chances of survival.

And the economic impact is very important, because you can make patients get better sooner with fewer drugs and reduce the cost associated with side effects of a drug that does not work.

Q.

Being alive means accumulating mutations, which increases the risk of cancer.

Will it be possible one day to eliminate this link, to avoid cancer 100%?

A.

Can we get to the point where there is not a single cancer cell?

Probably not.

But I think we can delay the appearance of that cell, of those tumors.

We have a long way to go and I don't have a crystal ball to know when it will arrive, but I think we can do it.

Q.

Will it be possible to prevent cancer before it occurs?

A.

I hope so.

There are familial cancers that show a clear genomic signature before they appear.

Although we still do not know how to prevent the tumor from forming.

On this we have published the largest list of complete cancer genomes from around the world in the journal

Science

.

We have found 58 new genomic signatures of cancer.

We even knew of another 51, so with this work we doubled the sample.

Some are due to genetic defects inherited from parents and others due to external factors.

We don't know how they all originate, but at least now we can see and study them.

The list of signatures continues to grow, so what we have also done is create a computer tool so that other teams can search for new genomic signatures.

P.

Is there any further progress in this new catalog of tumors?

A.

One concerns exposure to aristolochic acid.

It is a carcinogenic substance of plant origin.

In the Balkans, people were exposed to decomposing leaves of some plants that contained this substance, and this caused a high incidence of kidney and liver cancers.

What we have found is that three cancer patients in the UK database had the characteristic genomic signatures of tumors caused by this substance, even though they did not recall being exposed to it.

So we see that these techniques can also reveal that a person has developed cancer from being exposed to carcinogens without being aware of it.

Q.

How many different genomic signatures can there be?

R.

We have no idea.

We have much to do.

When we do science, it seems slow, but discoveries come fast.

Mind you, when you try to translate those findings into treatments, that does take many years of testing and regulatory process.

The genomics revolution has happened so fast that the frontier of knowledge is far, far ahead of the regulatory process.

It can improve?

Maybe yes, changing the way we do clinical trials with patients.

We continue to think of genomics in a binary way: you either have a mutation or you don't.

But the genome is huge, it has 3 billion letters and there are thousands of mutations that we simply ignore at the moment.

We have to change the chip and think about the genome in another way.

When a person is diagnosed with colon cancer, it is likely that they will then do a scan of other organs to see if it is also in them.

Why don't we do the same with the genome?

We cannot look at a single gene or a few, we have to look at everything.

Q.

Do you fear that these new techniques will create inequality between patients who can access this personalized treatment and those who cannot?

A.

It depends on whether the drug in question is protected by patent.

The real challenge has to do with the data.

Right now there are cancer genomic sequencing projects in many countries, including Spain.

There are no limits when it comes to generating data.

The big problem is connecting a genetic profile with the right drug for him.

Many times that drug is no longer protected and is very cheap.

Q.

Do we need an army of bioinformaticians to make those connections?

R.

Bioinformatics is just another tool, like the microscope or X-rays. What we need is to educate young people to think the right questions and for bioinformaticians to pose them to artificial intelligences and databases.

The most important thing is the questions we ask.

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Source: elparis

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