Tuesday, February 28, 2006

Epigenetics and Cancer

by Pharma Bawd

“Although individual genes vary in hypomethylation, all tumours examined so far, both benign and malignant, have shown global reduction of DNA methylation33, 34, 35. This is a striking feature of neoplasia.”

Nature Reviews Genetics had a good paper up about epigenetics and cancer in January. I planned to write about it, but..., life gets in the way. Not to mention reading blogs, and lately I’ve been reading Aetiology, specifically the threads about HIV/AIDS and then the new thread about viruses and cancer.

If you haven’t been reading these threads, you should. Tara has been visited by noted AIDS skeptic Harvey Bialy, a former editor of Nature Biotechnology. Although Dr. Bialy’s rhetorical style is offensive in the extreme, and many of his arguments about HIV/AIDS are really bad, he and the subject of his book, Peter Duesberg,

have an interesting point about cancer and aneuploidy.

The majority of cancers exhibit aneuploidy and it is Duesberg’s contention that aneuploidy itself is the proximal cause of cancer. This is very much a chicken and egg argument in my opinion, whether the genetic insults that lead to cancer lead to aneuploidy first and cancer later, or whether only once aneuploidy occurs does cancer arise doesn’t seem to be very clear nor very meaningful to me, especially if you can prevent the initial genetic insult that leads to either cancer, or to aneuploidy and then cancer. But Dr. Bialy has contended that there are two primary theories of how cancer arises:

1. The oncogene theory
2. The aneuploid theory

I “assert” that there is at least one other theory, the epigenetic theory of cancer. Now, Bialy may contend or assert, that epigenetic causes of cancer are just an extension of the oncogene theory of cancer. But in this he would be wrong. And therefore it is worthwhile to discuss exactly what “Epigenetics is and how it relates to cancer.

Nature Reviews Genetics 7, 21-33 (January 2006) | doi:10.1038/nrg1748
The epigenetic progenitor origin of human cancer
Andrew P. Feinberg1, Rolf Ohlsson2 and Steven Henikoff3 About the authors
Top of page
Cancer is widely perceived as a heterogeneous group of disorders with markedly different biological properties, which are caused by a series of clonally selected genetic changes in key tumour-suppressor genes and oncogenes. However, recent data suggest that cancer has a fundamentally common basis that is grounded in a polyclonal epigenetic disruption of stem/progenitor cells, mediated by 'tumour-progenitor genes'. Furthermore, tumour cell heterogeneity is due in part to epigenetic variation in progenitor cells, and epigenetic plasticity together with genetic lesions drives tumour progression. This crucial early role for epigenetic alterations in cancer is in addition to epigenetic alterations that can substitute for genetic variation later in tumour progression. Therefore, non-neoplastic but epigenetically disrupted stem/progenitor cells might be a crucial target for cancer risk assessment and chemoprevention.

So, if you’re like most people, you’re asking “What the heck is epigenetics?”
Epigenetics is a very important subject that most college genetics courses give short shrift, as in, it’s never mentioned. But it is arguably the most important part of gene regulation in development and the proper regulation of gene activity that when disrupted causes cancer to arise.

First, let’s talk about DNA for a moment. The genome of an organism is the string of chemical letters As, Ts, Gs, and Cs that make up its genes. Our genome consists of about 3 billion pairs of such chemical letters divided into 46 (23 pairs) individual molecules called chromosomes. If we were to stretch out this DNA to its full length and line it up end to end it would total about two meters in length, with a width across the DNA molecule of 2 nanometers. A nanometer is 1/1,000,000,000 of a meter. So if the DNA is two meters long it is one billion times longer than it is wide. For perspective, let’s say a human hair is about 50 Micrometers wide A hair that represents the same ratio of length to diameter as DNA would have to be 50,000 meters, that’s over 30 miles long! I know, I know! Rapunzel let down your DNA right?!

Well, that’s an awful long molecule with a heck of a lot of important information encoded on it that has to be available at any time for transcription as well as being available from time to time for DNA replication, so it has to be very well organized in order to fit the whole thing into the nucleus, about 5-10 micrometers in diameter, without the whole thing turning into a tangeled mess. So, for perspective again, imagine all the letters in The Bible, how many do you think that is?
3.5 million.

OK, so there’s 3 billion letters in the human genome so we need 857 Bible equivalents of text written on our 30 miles of hair, basically every hair on the head of a woman with .5 meter long hair. Then, all that hair needs to fit into a sphere something like the size of the woman’s head. And all of it needs to be organized so that any given sentence can be easily accessed and read, and all of the hair needs to be maintained in such a way that it can be replicated into two complete copies that are then able to divide into two daughter cells without any tangles or knots forming. In every single cell in the human body, around 70 trillion cells. It’s a pretty tall order and it requires a lot of organization. That organization is provided by proteins around which the DNA is wrapped in order to compact it so that it will fit into the small space of the nucleus. This complex of DNA and proteins is called chromatin and the major protein components of chromatin are the histone proteins. There are five histone proteins, each with specialized variants, histone H2A, H2B, H3 and H4 all occur in pairs that are bound together in a core particle around which the DNA is wrapped two times. Outside this core, sort of like a clip to keep the DNA in place on the core particle, is the linker histone H1. The whole complex eight core histones linker histone H1 and two loops of DNA wrapped around the histone core particle forms a structure called the nucleosome.

Picture of nucleosome.
As you can see from the figure all of this protein is roughly equivalent in volume to the total volume occupied by the DNA (hair) so the nucleus (head) is getting quite full just with the genome and associated histone proteins.

So that’s how cells cram all that DNA into the relatively small volume of the nucleus in such a way that it is still well organized and accessible. Now, on to the epigenetics. Epigenetics is basically the chemical modifications of chromatin (DNA and histones) that does not alter the nucleotide sequence of the DNA. These chemical modifications are primarily methylation of Cytosine residues in the DNA and acetylation of histones. Histones can also be methylated, phosphorylated, or ubiquitylated. All of these modifications contribute to the transcriptional activation or inactivation of gene sequences in the DNA.
This picture of methylated and nonmethylated DNA shows how a slight modification can alter the binding site for a protein on DNA.

These modifications to both DNA and to the histones are heritable through both mitosis (one cell divides into two) and in some cases meiosis (sperm and egg formation). (If the IDers are really looking for support for Lamarck, this is a much better area to look into than transfer of antibiotic resistance between bacterial species.) So this represents another level to the genome, an "epigenome" as it were, a collection of information present within our cells that is separate from the information contained within the DNA sequence itself. This epigenome is crucial to the regulation of gene expression by regulating which genes are able to be transcribed in certain cell types. In cells where certain genes are not transcribed they can be highly condensed as heterochromatin leaving room for the genes that are necessary in that cell type. And this is where it becomes important in cancer.

Old models of cancer such as the two hit model for knocking out both copies of a tumor suppressor gene suggest that cancer is selected clonally after a series of mutation events that knock out the various control mechanisms that regulate cell division. This process would require numerous sequential mutations to several different genes involved with regulating cell division.

Epigenetic modification of the genome is a much more dynamic and common process than mutation. Cells are constantly modifying the DNA and histones to regulate gene expression and for a variety of reasons they may perform these functions improperly. Epigenetic changes important to carcinogenesis include global hypomethylation across the geneome, site-specific hypomethylation and hypermethylation, and chromatin modification of gene promoters that control expression of oncogenes and/or tumor suppressor genes.

The authors’ model posits that epigenetic modifications of genes in stem cells lead to dysregulation of oncogenes or tumor-suppressor genes which leads to a gatekeeper mutation (basically a mutation in a gene that controls cell division, the gatekeeper mutation allows the precancerous cells to begin dividing, a critical step in cancer progression.), followed by further epigenetic and genetic instability.

This model is attractive in that certain stem/progenitor cells already have many of the features seen in late stage tumors, such as metastasis, and would not require precise genetic mutations in order to acquire these functions. It should also be noted that any of these three models: the genetic theory, the epigentic theory, or Duesberg's aneuploidy theory; would require Darwinian evolution and natural selection in order for tumore progression to occur.

I can see where Bialy or Duesberg may argue that the epigenetic modifications may be involved with the initial aneuploidization event in the cell. But I'm not sure I can buy the idea that it is the aneuploidy that is the cause of the cancer. I am more likely to agree that the upstream genetic and epigenetic events allow a cascade of events to occur, one of which is aneuploidization, that frequently leads to cancer. Their argument seems to be similar to saying: It's the driving that causes the accident when drinking and driving. The drinking may be an important factor in leading up to the driving, but the driving is what causes the accident. This may be true, but I don't think it makes the drinking any less necessary or important in causing the drunk driving accident.

(Will probably modify this when I have more time.)

Comments on "Epigenetics and Cancer"


Anonymous Anonymous said ... (3/01/2006 9:08 PM) : 

Personally I think Bialy is full of it and I agree that epigenetic versus mutation versus some other initiating event is really one big chicken and egg argument that only becomes relevant if it affects treatment options.

Dale (who wandered over here via a link at Aetiology)


Blogger Pharma Bawd said ... (3/02/2006 5:20 AM) : 

Hi Dale,

Yeah I think you and I are of similar mind, from the whole HIV/AIDS discussion to cancers.

The most important thing I can see coming from an aneuploidy model of cancer is the possibility of specifying treatments:


Even then though, I think gene expression patterns measured on microarrays will prove to be even more appropriate in determining treatments that should be applied, and just as importantly, treatments that should not be applied to people they are unlikely to help.



Blogger Abel Pharmboy said ... (3/02/2006 5:28 AM) : 

Pharma Bawd, really enjoyed this post and others, having been directed over here from Grand Rounds.

The epigenetics angle is truly fascinating and serves to reconcile inconsistencies in cancer risk when one considers genetics and environmental/dietary issues independently of one another.

Given the focus of NIEHS on epigenetics, I believe that this field will be a boon to cancer chemoprevention. Perhaps epigenetic interventions will have greater impact on cancer death rates than even the best, molecularly-targeted cancer therapy.

Thanks for such a lucid and detailed description of a rather complicated field. Looking forward to more of your insights.


Blogger Pharma Bawd said ... (3/02/2006 5:51 PM) : 

Thanks abel pharmboy,

I consider that high praise indeed, or at least, praise from a high source indeed.

I used to think that with the advent of genome sequencing and so forth that they would figure everything out about biology during my lifetime. Then they realized how important epigenetics is to gene expression, development, cancer,... and then they found RNAi and PTGS, and now we know that PTGS and epigenetic modifications are connected...

Now I figure there's plenty of new avenues for research just waiting to be discovered.


Blogger Abel Pharmboy said ... (3/06/2006 7:30 AM) : 

All good points. I've also gotten peripherally interested in fatty acids in the liver that underlie drug-induced liver injury, a major anathema for big pharma - can't pick these up by microarrays.

BTW, did I read correctly on Dr Free-Ride's comments that you are pursing an alt career in pharma sales or marketing? I'm sure that with a Ph.D. you must start at some higher mgmt level than the frontliners. Would be curious to learn about your experiences here (or via gmail to me) since I counsel quite a few folks who pursue careers other than bench science - in fact, The Scientist noted recently that we should stop calling these "alternative science careers" since 53% of PhD grads in the biomed sciences work outside the typical academic/industry lab area.


Blogger Pharma Bawd said ... (3/06/2006 7:15 PM) : 

I have a Master's not a Phd. I got the idea that a Phd, rather than giving me a leg up, might make me unemployable in industry without a 2-4 year post-doc. So I got while the gettin' was good.

Geographic limitations precluded an academic career.

By the way, I had a really bad day and a bottle of Chardonnay before I posted that comment. I'm really not that bitter. ;)

I really do think we are encouraging too many people to pursue Phds in biology when there really aren't jobs for them. It may self-correct though, with NIH paying Phd students $30,000 per year (+ tuition & etc.) and encouraging universities and professors to follow suit. Universities and Professors are going to do the math and say: I can get a lot more for my money from a post-doc with experience than I can from a graduate student who has to teach, take classess, ....


Blogger Abel Pharmboy said ... (3/07/2006 10:09 AM) : 

No need to defend your comments because I took them as realistic and constructive, not bitter at all (and a bottle of Chardonnay never hurts anyway!). In fact, the place I ended up going to grad school had the only grad coordinator who told me this was a brutal business and asked me why I really wanted to do it. I appreciated the honesty and went there because I felt they'd give me the tools to succeed. I wish I had more folks like you and him tell me the straight dope early on. I'm staying funded and doing okay, but it hasn't been a walk in the park in the least.

Very insightful how the rising grad stipends may cause a self-correction. I totally agree that we are training more students than necessary; if we continue, we owe it to them to include other tools in the training process that prepare them for non-research careers.

Greatly appreciate your insights.


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