Our DNA influences the behavior of our cells.
DNA is found in the nucleus and it provides
the template for the production of proteins.
So a specific DNA sequence makes a specific
protein.
However, the story is a little more complicated
because only 1% of the DNA makes protein!
So what does the other 99% of the DNA do in
our cells, this dark matter as people used
to call it?
Is it just junk DNA?
Well, it turns out that 99% of our DNA is
NOT useless, it controls WHEN and HOW MUCH
proteins are made from the 1% of the DNA that
makes proteins.
And thanks to great technical advances, scientists
have recently started looking at the ENTIRE
DNA sequence of patients.
Not just the 1% that makes proteins but 100%
of the DNA: all 3 BILLION DNA BASE PAIRS.
If you were to read out loud all of the DNA
sequence it would take 9.5 years reading non
stop at a rate of 10 base pairs/second!!
That's a HUGE amount of information!!
Changes in the DNA sequence, which we call
mutations explains the development of one
of the biggest killers in the world: Cancer.
Cancer cells divide uncontrollably to form
tumors.
This is due to mutations in their DNA sequence.
We can visualize the process of cancer development
as a staircase where as cells acquire more
and more mutations, they move up this staircase
to become cancer.
The mutations that allow a cell to move up
the staircase are called "driver mutations".
Because one type of cancer (for example breast
cancer) can take multiple paths and be caused
by different DNA mutations depending on the
patient, it's very important for us to understand
what is the underlying genetic cause in order
to develop targeted therapies.
In other words, what are the driver mutations?
To find these mutations, scientists had previously
been looking mostly for DNA changes in the
1% of the DNA sequence that makes proteins.
But the scientists of this paper wanted to
shed light on this "dark matter" to see if
there were any driver mutations in the rest
of the DNA that doesn't make proteins.
Their findings were published in their article
titled "TERT promoter mutations in familial
and sporadic melanoma" produced by the Schadendorf
and Kumar labs at the German Cancer Research
Center and the University Hospital Essen in
Science Magazine in February 2013.
These scientists studied a large multi-generational
family that had a very high incidence of skin
cancer or melanoma.
Because cancer ran in the family, this suggested
that something in the DNA sequence was causing
these individuals to develop cancer.
So the scientists looked at the ENTIRE DNA
sequence of individuals in the family with
and without cancer.
And what they found was a mutation or a change
in the DNA sequence in a part of the DNA that
doesn't make proteins.
This mutation was found in ALL individuals
that had developed cancer but only present
in one individual that didn't develop cancer,
but instead had many moles (which increase
one's likelihood of developing melanoma).
Considering the size of the family, this provides
strong evidence that this mutation is responsible
for causing cancer in this family.
So how could this mutation be involved in
causing cancer?
Well this mutation is present near a piece
of DNA that encodes a protein which makes
telomerase.
The mutation controls how much telomerase
is produced and causes a 2-4 fold increase
in the levels of telomerase in cells.
To understand what telomerase is and what
happens when you have more telomerase, let's
step back a little bit and go back to the
DNA.
DNA is not one long sequence.
Instead, DNA is organized in 46 chromosomes
which consist of different strands of DNA
twisted on themselves.
At each end of the DNA sequence is a piece
of DNA called a "telomere" here in red which
is similar to the plastic sheath at the end
of shoelaces that prevent shoelaces from getting
too short.
As cells divide, the telomere in red gets
shorter and shorter.
When the telomere gets critically short, the
cell can't divide.
Similarly, if the plastic sheath on a shoelace
is removed, you will eventually no longer
be able to tie your shoes.
What telomerase does is it lengthens this
telomere DNA to allow the cell to keep dividing
essentially forever.
So telomerase is important to extend lifespan
in normal cells.
Before this finding, it was thought that telomerase
in cancer cells simply allowed the cells that
had reached the top of the staircase to keep
dividing but was not important in driving
the cells up the staircase to a cancer state.
So how does this finding contribute to this
view?
As I mentioned, the mutation discovered here
increases telomerase levels in cells and was
found in a family where every person (except
1) that had the mutation developed cancer,
and mostly melanoma.
So this strongly suggests that this mutation
is doing more than just allowing cells that
are cancerous to keep dividing.
Instead, this suggests that this mutation
is actually driving cells one first step up
the staircase.
If these cells acquire more mutations, they
will keep moving up the staircase until they
become cancerous.
So this article makes us rethink the way we
see telomerase in cancer development.
This is one of the first indications that
increasing telomerase alone can drive cells
towards becoming cancer!
But the scientists also found evidence that
this mutation is present in 74% of melanoma
patient cell lines that didn't have a family
history of melanoma.
That's a HUGE percentage.
In those patients, the mutation was caused
by UV light damage from sun exposure!
Another scientific article that was published
at the same time by the Garraway laboratory
at Harvard Medical School also found this
mutation in bladder, liver, kidney, and thyroid
cancers.
So what did this study show?
These scientists identified one of the most
common cancer-causing mutations in melanoma:
a mutation that increases telomerase and drives
cancer development of all sorts of cancers
(melanoma, bladder, liver, kidney, etc.).
although it still remains to be seen exactly
how telomerase drives cancer development.
Cancer patients with the mutation inherited
the mutation from their parents, in the familial
case, or acquired it from sun exposure.
So overall, this study showed that it's very
important to look at 100% of the DNA sequence
because mutations in the 99% of the DNA that
doesn't make proteins can be DRIVING cancer
and it's not just about the 1% that makes
protein!
So what does this mean for you?
- This study identifies a pathway that increases
telomerase and that drives tumor development
so it provides new evidence that developing
a therapy to block telomerase may be very
effective to prevent 75% of melanomas.
- Because this mutation is a simple change
in the DNA sequence, it would be possible
to determine if a specific tumor is caused
by this mutation and how likely a patient
would be to respond to a drug against this
pathway.
It is surprising that mutations in what was
seen as "junk DNA" can be so common and so
important to driving cancer development!
So as you can tell, sequencing 100% of patients'
DNA in a cost-effective way has and will continue
to provide clues as to the cause of many diseases,
in this case melanoma.
This will be very important as we develop
targeted therapies for an individual patient
based on his or her genetic makeup.
This is where the future of medicine is heading,
towards precision medicine.
