Breast cancer, a deeper understanding: The science behind the story

Uploaded by sangerinstitute on 18.05.2012

We've known for many decades now, that all cancers are due to abnormalities in DNA
Now, although we've known that, it's remarkable how rudimentary our knowledge is
About the processes that cause these abnormalities, these mutations in our DNA are
Now we know about some, for example we know that if you smoke cigarettes
That tobacco smoke contains chemicals that damage DNA in the lungs that damaged DNA
Turns into mutations and those mutations in our lung cause lung cancer
However, for must other cancers we do not know what the underlying mutational processes are
That have been operative over the lifetime of the patient to generate the cancer
So what we have done in this study is to sequence the complete genomes of 21 breast cancers
And from those 21 breast cancers, we have made catalogues of the mutations that are present
And we've looked into those catalogues to see if we can find particular patterns that reflect imprints
That those mutational processes have made on the DNA sometime in the past
In our research we were intending to study the entire genomic sequence, the entire DNA sequence
Of cancer genomes from breast cancers
In the past cancer research has often focused on identifying individual cancer genes
Individual genes that are driving cancer because these become obvious targets for cancer treatments
But the human genome is vast, with 3,000 million building blocks, 3,000 million bases in the human genome
And cancers are the ultimate genetic pathology, we have many, many thousands of mutations in cancers
So we reasoned that if we use the entire compliment of genetic changes in a cancer
That we would understand more about the biology of cancer development
What has changed in science in the last five to ten years has been the improvement in DNA sequencing technology
Where previously we could only sequence small chunks of the genome
Now we can sequence the entire genome in a very short time
The most dramatic finding from this study is that across the 21 breast cancers
there were a number of different processes acting to cause mutations
We kind of imagined going into it that each breast cancer would look pretty similar
To every other breast cancer, but in fact there are at least seven or eight different processes
That are causing mutations and the all operate to different degrees in different people
And trying to tease apart and understand what these processes are
May give us insights into how breast cancers develop in some women but not in other women
We found in the first instance five major processes
Thatt can cause one letter of code to be changed to another letter of code
And of these there is one of those five processes for at the moment we really
Do not know what the underlying biological mechanism is and we have never really seen it before
But this seems to overwhelm about 10% of breast cancers with mutations
So that is one of the interesting things we found
The second thing we have found that is of interest
Is that there are, in some cancers, small parts of the genome which appear
To have been a target of huge numbers of mutations
And we call this process kataegis which is Greek for thunderstorm
Because of the accumulation of the enormous amounts of mutations in these parts of the genome
And what is remarkable is that in each of these cancers
The particular part of the genome which is mutated is different
So at the moment we really do not understand how the mutational process is directing itself
To these different parts of the genome in different cancers
We can also tell the timing of these processes, we can tell which one's have come on early, which one's have come on later
So we can see additional structures in the development of cancers
And that it's far more complex than we ever thought
We think from our analysis that some of those mutations are probably happening in our cells normally
And they are probably happening in the cell before it becomes a cancer
And then some of those processes die off as the cancer becomes more aggressive
There are other processes that come on later during cancer development
And the may contribute to the aggressiveness of the cancer
So there are different mutational processes that come on at different times during cancer developments
and during normal cellular development as well
At this time, we really don't understand what the majority of these processes are
that are causing mutations. We know for maybe two or three of the processes
What's going on at the DNA level to cause them
But for most of them we don't know. What we can say on the basis of this study
Is that most of them are specific to the cancer
They are not the same mutational processes that are going on in the rest of our body
Some of those mutational processes that we identified
Cells were probably accumulating mutations even before they turned into cancers
But at some point, just as the cancer's developing, it can diverge into smaller families, smaller populations
Or clones of cells
At some point, one of those clones becomes the dominant clone, it expands to become the dominant clone
And that is likely to trigger diagnosis
One of the striking findings of the research is
That every patient we looked at showed evidence for a dominant sub-clonal lineage
By which I mean a sub-clonal lineage that contributed more than 50% of the tumour cells
No there's no way of prime or right reason why a breast cancer should have such a dominant sub-clonal lineage
And yet there must be an explanation for why it must be so universal in these cases that we studied
So what we think is that actually the expansion of this dominant sub-clone triggers diagnosis
If you imagine the average breast cancer being 10cm3 when it's diagnosed
Then a dominant sub-clone like this will contribute maybe 50/60% of the mass of that tumour
And may well be the difference between a tumour detectable by say palpational mammography
Or it not being detectable
So these are early studies, they've already yielded a number of new mutational processes
Which we have never encountered before and which we are now going to have to investigate what they're due to
But as the sequencing of cancer genomes accelerates, as thousands, tens of thousands of cancer genomes
Are sequenced, there is no doubt that we are going to find even more mutational processes that have been operative
That'll give us a much more complete idea of what has been causing the mutations
In other words what's been causing our cancers in the first place