While the human genome sequence has transformed our understanding of human biology, it isn’t just the sequence of your DNA that matters, but also how you use it! How are some genes activated and others are silenced? How is this controlled? The answer is epigenetics. Epigenetics has been a hot topic for research over the past decade as it has become clear that aberrant epigenetic control contributes to disease (particularly to cancer). Epigenetic alterations are heritable through cell division, and in some instances are able to behave similarly to mutations in terms of their stability. Importantly, unlike genetic mutations, epigenetic modifications are reversible and therefore have the potential to be manipulated therapeutically. It has also become clear in recent years that epigenetic modifications are sensitive to the environment (for example diet), which has sparked a large amount of public debate and research. This course will give an introduction to the fundamentals of epigenetic control. We will examine epigenetic phenomena that are manifestations of epigenetic control in several organisms, with a focus on mammals. We will examine the interplay between epigenetic control and the environment and finally the role of aberrant epigenetic control in disease. All necessary information will be covered in the lectures, and recommended and required readings will be provided. There are no additional required texts for this course. For those interested, additional information can be obtained in the following textbook. Epigenetics. Allis, Jenuwein, Reinberg and Caparros. Cold Spring Harbour Laboratory Press. ISBN-13: 978-0879697242 | Edition: 1
7.3 Hypermethylation of sets of CpG islands in cancer
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From the course by The University of Melbourne
Epigenetic Control of Gene Expression
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From the lesson
Week 7 - Cancer Epigenetics
This week we’ll bring together much of what we’ve learned in previous weeks of the course, to understand how the epigenome is affected, and can also affect, cancer development and progression. We’ll then go on to discuss the potential therapeutic benefits that can come from using epigenetic biomarkers, and targeting epigenetic modifiers in cancer.
Meet the Instructors
Dr. Marnie BlewittHead, Molecular Medicine Laboratory
Walter and Eliza Hall Institute of Medical Research
So in the last lecture we thought about hypermethylation and how single gene
biomarkers could be used prognostically, diagnostically and/or to
treatment outcome. But now we're going to think about how
you can have hypermethylation and measure hypermethylation of sets of genes or
panels of genes and how these might be useful.
Want to start out by telling you about a particular tumour type called CpG island
methylator phenotype, CIMP, as a way of describing the
hypermethylation of sets of genes and what it might mean.
So these cancers, these have got more than you would expect.
So, higher levels of CpG island hypermethylation than you would see in
general in cancers. And so this methylated phenotype, has
been, has been called CIMP in the literature.
So, this frequent occurrence of hypermethylation has been described for
several different types of cancers. It was first described for colorectal cancer.
Later for glioma, more recently for
neuroblastoma and many more. So in each of these cases we know that
although in, for each of the tumour types you see hypermethylation.
That's very frequent, hypermethalation of CpG islands, that's quite common in them
and perhaps more so than in other tumours.
The actually sets of CpG's that are hypermethylated differ by tumour type.
So colorectal cancer won't necessarily have the same set of CpG islands that a
hypermethylated as you see in glioma, for example.
So why would we care if they're a particular cancers that have this
hypermethylation phenotype, this methylated phenotype or CIMP?
Well, as usual with cancer, the reason that we care is because these types of
tumours are clinically different. They're clinically distinct and
therefore, alter the way that they can be interpreted by the doctors, and therefore
the outcome for the patients. So, if we start out with Colorectal
cancer. And just think about Colorectal CIMP,
because this is where we know them most. It was when it was earliest described for
the first time. We know that in general in these
patients, they tend to be of older patient age, they're mostly females.
They tend to have defective MLH1 function, this mismatch repair gene which
I've told you about with regard to Lynch syndrome.
The tumours tend to be in the ascending colon.
They even have a particular place that they occur in the colon.
And importantly, they have good prognostic outcome.
So, if you can diagnose a person as having CIMP then you can tell them that
they are that you can infer that they are likely to have a good outcome, and this
is really important for patients. But also these clinically distinct
phenotypes, these clinically distinct features of CIMP suggest that perhaps
some particular epigenetic therapy would be useful in these cases.
So just like we spoke about single bio markers in terms of being useful for
diagnosis and prognosis and for monitoring panels of bio markers are also
very useful in this way. So where single genes can be very useful
if they're are a perfect bio marker if you like.
if you have panels of bio markers, each individual bio marker may not be as
strong as say MGMT was for determining whether temozolomide would work, or GSTP1
in the prostate. But each of them can be slightly less
efficient or slightly less sensitive, but as a panel you can have overall they'll
end up giving you a very efficient and very sensitive, read out of where the
situation is occurring. So, they're now becoming more
commonly used, and more commonly these panels of biomarkers are being put
together so that you can still have useful diagnostic information, for example.
So, with these panels of biomarkers, you
might be able to identify a tumour type. Say, for example, be able to determine
that it was a CIMP tumour, because of the level of hypermethylation. How
frequently hypermethylation occurred. So other than just tumour type you may
also be able to look tumour sub type. So because of these genome wide studies
which I mentioned earlier that have occurred for DNA methylation, we now know
it's been fairly recent data where they can lets look genome wide at the where
the CPG islands are hypermethylated. And they find it's not just possible to
say this is a CIMP tumour or not. But rather, you're able to say this is
this particular tumour sub type. And so if you stratify each of the tumours
based on their methylation profile, genome wide,
you can very, very accurately determine which sub type of a tumour is found.
And what's intriguing is that this
definition of which sub-type you have is perhaps more efficient when using DNA
methylation biomarkers than if you use gene expression.
So that's intriguing because you would imagine that the DNA methylation marks
would be just mirrored by gene expression, but indeed perhaps not all of
these methylation markers are mirrored by gene expression and therefore DNA
methylation ends up being a little more powerful.
So, what I think is perhaps one of the most interesting uses of having a panel
of biomarkers, is that in patients where they don't actually know what their
original tumour is, you might be able to work out what their primary tumour was.
So, in to my mind, if you think about it naively,
you think that probably know what their primary tumour was.
But this isn't in fact the case. There are a large number of patients that
present each year in any country around the world where they don't
necessarily know what the primary tumour was.
By the time they've been ill enough to come and present to a doctor they already
have metastasis, so clinically it's very important to work out which was the
primary tumour and which the metastasis. Because it's the primary tumour that will
usually define the type of treatment that will be required.
And the metastases will relate to that primary tumour.
So say for example, if the primary tumour was in a location where you wouldn't
detect a lump. Or you wouldn't necessarily begin to feel
ill quickly, it will often have metasicised before you felt sick enough
to go to the doctor. So in these cases, it's very useful to be
able to work out what that primary tumour was.
We also know that these panels of biomarkers just like detecting which
particular cancer it is, whether its a particular cancer subtype for diagnosis,
can be useful for prognosis. So, while I've mentioned that CIMP has a
favourable prognostic outcome. It tends to have a very good outcome.
The patients respond well to treatment. High methylation in other cancers for
example myelodysplastic syndrome this is found in the blood.
It's of the myeloid cells. Or lung cancer.
High methylation in both of these cases has a poor prognostic outcome.
And this is perhaps what you'd expect based on what I said about how the
methylation progresses over time. And so each of these are important
measures to make. And finally, as I've mentioned before, by
using single biomarkers or indeed panels of biomarkers, you're able to monitor the
tumour burden, or measure whether the tumour is declining or perhaps again
recurring again over time. And this is because of the cell free DNA
or because of tumour cells that can be found in the blood and easily monitored.
And again, as I mentioned just before, if you use panels of biomarkers, you are
more sensitive to be able to take this more accurately as opposed to a
single biomarker. So, while we in general have
hypermethylation of CpG islands associated with tumour suppressors, it is
the most common type of hypermethylation found in tumour cells.
What's been recently discovered is you also have hypermethylation of the regions
surrounding those CpG islands. These are called the CpG island shores.
So, if you imagine that your CpG island is in a certain block and this is, tends
to be unmethylated but in a tumour cell will be methylated.
The regions surrounding the CpG island. The 2 kilobases upstream or downstream.
It's been recently discovered that although they don't have the same density
of CpGs, therefore they're not still considered the island, they are also
hypermethylated in cancer. So, this has also been shown in normal cells.
So in normal cells, the methylation at
the promoter can predict whether or not a gene will be expressed or not.
So if, if a promoter is hypermethylated, its unlikely to be expressed.
It's not necessarily true that a hypomethylated promoter will be
expressed, but if it's hypermethylated, it's highly unlikely to be expressed.
And it's known now that this methylation actually does indeed spread to these
shore regions. This happens both in normal cells and in cancer.
What's interesting again is that if you
correlate the hypermethylation at the shores rather than just at the CpG
island, this perhaps correlates even better with gene expression than CpG island
methylation itself. And so this leads to the
possibility that perhaps although I've told you these biomarkers that are at the
CpG islands are actually really good, maybe in the future we'll be able to do
even better. So the final sort of hypermethylation I
want to mention in the context of cancer is hypermethylation of imprint control regions.
So one of the really common features of
cancer cells is they display loss of imprinting.
So in other words, genes that should be displaying monoallelic
parent-of-origin-specific expression, in other words, they're imprinted, no longer
show this imprint of expression but rather they become either expressed from
both parental alleles or silent from both parental alleles.
And the reason this is found in cancer is probably because lots of genes that are
imprinted are involved in growth - in some way.
Either they're growth promoting or growth suppressing.
So we don't exclusively find hypermethylation of imprint control
regions in cancer. You can also find hypomethylation of
imprint control regions, and this of course depends on the particular imprint
control region you're looking at and the function of the genes that are found
within the controlled region. But in this case I just want to mention
the hypermethylation of imprint control regions with one specific example.
But keep in mind that either can occur in fact, that we can have hypermethylation
in some instances. And hypomethylation in other imprint
control regions. So if you think back to the Igf2H19
cluster that we spoke about in week 4, we know here, here is the imprint control
region shown as the oval. And it's methylated on the paternal
allele, and it's unmethylated on the maternal allele.
When it's unmethylated CTCF will binds this insulator element, and it means that the
enhancers in this case will act on H19. But Igf2 will be silent for the maternal
allele, so we don't see expression. On the paternal allele, because this is
methylated, now the enhancers can act on Igf2, because CTCF is not
binding to inhibit this, and IGF2 is expressed from the pattern allele.
However, with loss of imprinting and what happened is you have hypermethylation
of the imprint control region on the maternal allele as well,
now, on the maternal allele, you also have expression of Igf2.
So now you have a double dose of Igf2 in comparison to what you saw in a normal cell.
And Igf2 is growth promoting, and
this is associated with Wilms’ tumour. This is this particular childhood kidney
tumour that is observed. So, while I'm showing you these for these
one specific example, loss of imprinting is observed in a very wide array of tumour types.
And in fact, occurs as a very early
event, so it's often seen in preneoplastic tissues.
So, before you would actually decide that it really was a frank tumour.
And so this suggests that maybe these events at the imprint control regions,
these hypermethylation, or hypomethylation events
might be very early events in tumourogenesis.
So, we've now covered hypermethlyation in the context of cancer and in the next
lecture we'll think about hypomethylation that's observed so the less methylation
that you'd expect which is found genome wide.
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