Sunday, January 25, 2009

DNA repair and cancer II

I just wrote about this at some length, here.

It's funny, sometimes, how there are a bunch of results released in a short time period on the same topic. Usually it's because there's a big meeting that covers the topic, or else the editor of some journal wants several papers on the topic.

I've just come across three more papers on the topic and can't recall such a flurry of activity related to it. The papers were all published in different journals, and there doesn't appear to have just been a meeting on the topic, but it's understandably an active area of research.

The issue is whether or not variants of genes for DNA repair proteins make good biomarkers for cancer risk. As I discussed before, the recent meta-analysis suggests that in general this isn't as great a place to look for biomarkers as one might expect.

Compared to the most common allele of a DNA repair gene, less common alleles may correlate with either increased or decreased cancer risk, depending on the type of cancer and type of DNA repair involved.

In neither case can one automatically conclude that the common allele yields protection against cancer. By repairing DNA, the repair enzyme might actually help cancerous cells survive, offsetting any benefit from preventing further genome damage.

As a result, if one finds that a specific allele reduces cancer risk, it could be because the allele is actually less effective at repairing DNA. Conversely, if another allele increases cancer risk, it could be because the allele is too effective at repairing DNA.

Just looking at the situation from an anticancer perspective, when DNA damage is detected, the smart thing to do is to sacrifice the cell via apoptosis. But that's not the way nature looks at things. The type of damage involved may be so common that it's smarter to try to fix it, and then hope for the best cancer-wise. After all, most cancer depends on the presence of other, unrelated and probably very uncommon, kinds of genomic damage.

Research studies in this area really need to try to suss out what is actually happening, and that could be rather difficult. Basically, this is an evolutionary problem, with the outcome depending on what happens, statistically, in millions or billions of cells over a period of time. Which alleles will ultimately win out? The ones trying to fix DNA damage, or the others trying to exploit the damage? All the "players" in this game have different interests at stake.

Progress here may require some heavy-duty computer simulations trying to sort it all out. Cancer research could turn out to be a lot like climate modeling.

What would better understanding mean therapeutically? It could be possible to discover biomarkers – alleles that indicate significant cancer risk. Where serious risk is indicated to exist, then standard interventions like surgery or chemotherapy may be appropriate.

On the other hand, developing drugs that attempt to silence an allele which is found to predict significant cancer risk may not be very rewarding, for all the usual reasons that drugs may fail (e. g. side effects). That's what clinical trials are for – and trials are very expensive.

The first study we'll look at here involves fairly unique circumstances. It does not address many of the issues we'd like to know about, in particular concerning a direct mechanistic relationship between DNA repair and cancer.

But let's look at what it does say, with a view towards where further research could go. The study, first, determines that a specific type of DNA repair ("nucleotide excision repair") rises and falls substantially with the circadian clock. Second, it finds that levels of a specific repair-related protein (xeroderma pigmentosum A, or XPA) also rises and falls with the clock. Third, it shows levels of XPA are directly related to DNA repair activity.

Now, it's well known that certain types of chemotherapy have a circadian dependency. Quoting from the paper, there exists "empirical observation that circadian time of delivery of chemotherapeutic drugs such as cisplatin, whose major DNA lesions are cisplatin-d(GpG) and cisplatin-d(GpXpG) diadducts (6, 7), may be a significant contributing factor to the efficacy of the drug and the severity of its side effects (4, 5)." Thus it's at least plausible that circadian variability of the levels of repair-related proteins could account for this.

However, that hypothesis remains to be checked directly. It will be interesting to see how this develops.

Here's a press release:

Chemotherapy Most Effective At Time Of Day When Particular Enzyme At Lowest Level (1/13/09)
For years, research has hinted that the time of day that cancer patients receive chemotherapy can impact their chances of survival. But the lack of a clear scientific explanation for this finding has kept clinicians from considering timing as a factor in treatment.

Now, a new study from the University of North Carolina at Chapel Hill has suggested that treatment is most effective at certain times of day because that is when a particular enzyme system – one that can reverse the actions of chemotherapeutic drugs – is at its lowest levels in the body. ...

The study, published in the Proceedings of the National Academy of Sciences, provides the first solid evidence that the daily oscillations of the cell's repair machinery can affect the potency of cancer drugs.

Meta-observation: It's apparently difficult to pin down specific mechanisms at work here, so a fair amount of indirect inference is needed to draw conclusions. We'll see the same thing in two other recent studies (below).

Research paper:

Circadian oscillation of nucleotide excision repair in mammalian brain
T.-H. Kang, J. T. Reardon, M. Kemp, A. Sancar (2009). Circadian oscillation of nucleotide excision repair in mammalian brain Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0812638106

Next up is a a case-control study that looked at nine single-nucleotide polymorphisms (SNPs) of seven DNA repair genes. The researchers were looking for correlations with the occurrence of pancreatic cancer. They studied 734 pancreatic cancer patients and 780 individuals without cancer. The strongest association was with a variant allele of one gene (LIG3), where individuals with the allele were 77% less likely than carriers of the normal gene to have cancer. The next strongest association was with a variant allele of another gene (ATM), carriers of which were in excess of 100% more likely to have cancer. (ATM also figures prominently in the third study, discussed below.)

Further investigation considered other cancer risk factors, such as smoking, heavy alcohol consumption, excess body weight, or diabetes – factors which might be responsible for excess DNA damage. The most significant factor turned out to be diabetes. In individuals with diabetes, carriers of an ATM allele were more than 200% likelier to have cancer, while carriers of a LIG4 allele were more than 100% likelier to have cancer.

So here's a study that successfully found several biomarkers, but involving only a few of the DNA genes studied.

Press release:

Abnormal DNA Repair Genes May Predict Pancreatic Cancer Risk (1/15/09)
Abnormalities in genes that repair mistakes in DNA replication may help identify people who are at high risk of developing pancreatic cancer, a research team from The University of Texas M. D. Anderson Cancer Center reports in the Jan. 15 issue of Clinical Cancer Research.

Defects in these critical DNA repair genes may act alone or in combination with traditional risk factors known to increase an individual's likelihood of being diagnosed with this very aggressive type of cancer. ...

With this in mind, [lead author Donghui] Li and her colleagues set out to identify DNA repair genes that could act as susceptibility markers to predict pancreatic cancer risk. In a case-control study of 734 patients with pancreatic cancer and 780 healthy individuals, they examined nine variants of seven DNA repair genes. The repair genes under investigation were: LIG3, LIG4, OGG1, ATM, POLB, RAD54L and RECQL.

The researchers looked for direct effects of the gene variants (also called single nucleotide polymorphisms) on pancreatic cancer risk as well as potential interactions between the gene variants and known risk factors for the disease, including family history of cancer, diabetes, heavy smoking, heavy alcohol consumption and being overweight.

Research abstract:

DNA Repair Gene Polymorphisms and Risk of Pancreatic Cancer
These observations suggest that genetic variations in DNA repair may act alone or in concert with other risk factors on modifying a patient's risk for pancreatic cancer.

The last study we'll consider here is a little more tangential to the issue of DNA repair genes and cancer. It's primarily about how defects in DNA repair genes may be responsible for two related neurological diseases – ataxia telangiectasia-like disease (ATLD) and Nijmegen breakage syndrome (NBS).

The two diseases result from defects in the proteins Mre11 and Nbs1 (respectively), which are part of a protein complex called MRN (Mre11-Rad50-Nbs1). MRN is a part of a mechanism that repairs double-stranded DNA breaks.

The research used mouse models. Mice engineered to have an ATLD-like disease had defective genes for Mre11, while those with the NBS-like disease had defective genes for Nbs1. In both cases, DNA-damage stress was induced either by radiation or by knocking out another DNA repair enzyme. The idea was to trigger disease effects due to inadequate damage repair by MRN.

A further relevant fact is that part of the MRN damage-repair process invokes a protein kinase called ATM. Part of the role of ATM is to trigger apoptosis if the damaged DNA cannot be repaired.

For our purposes here, the relevant finding was that neurons of the ATLD mice were resistant to apoptosis, and consequently DNA-damaged neurons survived longer than they should, in view of their defects. The disease pathology results from the persistence of damaged neurons that cannot perform as required. However, neurons of the NBS mice were not unusually resistant to apoptosis, so the neurons died more rapidly, and pathology results from the excessive cell death.

How Defective DNA Repair Triggers Two Neurological Diseases (1/14/09)
To explore the differences between ATLD and NBS, the researchers used mice engineered to have defects in the causative genes, which produce two proteins that help form a critical component of the DNA repair machinery, called the MRN complex. The MRN complex zeroes in on broken DNA segments and attaches to them. It then recruits another important DNA repair protein, called ATM, to launch the repair process. However, if the damage is too severe, ATM may also trigger programmed cell death called apoptosis.

"It happens that defects in ATM also lead to a disease similar to ATLD, highlighting the connections between diseases resulting from defects in this DNA repair pathway," [senior author Peter] McKinnon said.

The mice engineered to mimic ATLD, like their human counterparts, had defective genes that produce a protein called Mre11; while NBS mice were engineered to have defects in the gene for the protein called Nbs1.

The key point may be this: when Mre11 is defective and ATM is then activated, it does not always trigger apoptosis when it should. But when Nbs1 is defective, ATM is able to do its job properly. In any event, when either Mre11 or Nbs1 is defective, MRN does not repair DNA damage as well as it should (in cells other than neurons). This may raise the risk of cancer due to randomly damaged DNA.
"There is a suspicion that people who carry these mutations may be predisposed to cancer and also more susceptible to chemotherapy agents or even to standard X-rays," McKinnon said. "Those agents induce the type of DNA damage that requires the MRN complex and ATM for repair. More generally, studies of the MRN complex and ATM are fundamental to understanding how to prevent changes to DNA that lead to cancer.

"Understanding more about how these proteins signal and interact, and how different cells in the body transduce the DNA damage signal, is of fundamental biological importance," McKinnon said. "This knowledge is necessary not only for understanding DNA repair diseases but for understanding the broader implications of maintaining of the stability of DNA."

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