Saturday, January 24, 2009

DNA repair genes and cancer

DNA encodes genes needed for the production of essential proteins in a cell, and this DNA is vulnerable to damage in a number of ways. Perhaps the most common way is a consequence of inevitable errors that occur in the copying of all of a cell's DNA during cell division.

But there are a number of other ways that DNA damage can occur, such as damage due to reactive oxygen species or carcinogenic chemicals, ionizing radiation, or retroviruses, which insert their own DNA at random locations in the genome. (Technically, there's a distinction between DNA damage and DNA mutations, but we'll gloss over that for a moment.)

Most DNA damage affects only a single cell, and then, at most, only in the cell's ability to make certain proteins needed for normal cell function. Damage that occurs in DNA regions that don't affect protein production may have no effect at all. If important proteins are afffected, the cell may be unable to do its job properly, such as being a neuron or muscle cell. At worst, the cell dies, but its function is probably duplicated by billions of other cells in the same tissue or organ. Over a long enough period of time, of course, eventually a large percentage of cells will die due to DNA damage – and then the organism dies of "old age", if nothing more traumatic occurs first.

Against the relative improbability of one DNA damage event having serious consequences for a particular cell has to be weighed the frequency with which damage occurs. Most cells divide fewer than 100 times in their whole lifespan, though many errors can occur during each division. External factors like radiation, however, can cause millions of DNA damage events per day in a single cell. (Don't go sitting in front of an X-ray source all day! Or even under a source of UV radiation, like the Sun.) Internal factors, such as reactive oxygen species produced during normal metabolism, can cause many 1000s of mutations per cell per day, so DNA damage isn't something that cells can just ignore.

There are a couple of exceptions, when DNA damage can be an even more serious problem. One is in case the cell is an egg or sperm cell (a gamete), in a multicellular, sexually-reproducing organism, and the cell goes on to generate a new individual, which will inherit the damaged DNA. Since gametes are only a small proportion of all cells, and very few gametes are ever "lucky" enough to become new individuals, this is a fairly rare event. But it is how errors accumulate in genomes, over long periods of time. Such errors, being random events, are seldom beneficial to a species. But rarely they can be helpful and drive species evolution to adapt to a changing environment.

The other exception, which is much more consequential for the individual in which it occurs, is when the DNA damage affects one of the relatively small number of proteins responsible for keeping cell division and proliferation under control. Then you have a circumstance that can lead to cancer, even if only a single cell is affected to begin with. Clearly, it is in the best interest of the individual, and perhaps the whole species, for cells to have good mechanisms for dealing with the problems caused by DNA damage.

Apart from dealing with the original causes of DNA damage, cells have basically two ways of coping with damage after it occurs.

One sort of mechanism involves being able to detect the presence of DNA damage, and to initiate measures that limit or stop the cell's ability to proliferate, or even cause the cell to die. P53 is perhaps the best known protein involved in this type of mechanism. Compromised p53 production is found in more than half of all cancers. If a gene, in the same cell, that codes for a protein needed to implement one of these mechanisms has been damaged previously, the probability of cancerous proliferation will rise. Mechanisms of this kind are complex. There's a lot that can go wrong, and that's one reason cancer is as common as it is.

The other sort of mechanism is actual DNA repair. It's not so draconian. Such mechanisms attempt to actually correct the DNA damage, returning the DNA to its state before the damage occured. That's great. If it actually works, the cell can survive unharmed, and not pose any extra risk of becoming cancerous.

There are a variety of kinds of DNA damage, and hence a variety of repair mechanisms are needed. Individual bases attached to the nucleic acid backbone can be modified or deleted. The base sequence can be altered by faulty copying. The backbone itself can be broken or warped, preventing expression of some genes. Entire chromosomes, which carry DNA in a compact, packaged form, can be broken or improperly duplicated.

It's easier to recognize that damage has occurred than it is to repair it. Here the distinction between DNA mutations and other kinds of damage becomes relevant. A mutation exists when a base pair on the two strands of DNA is replaced with a different but otherwise normal base pair (i. e. adenine-thymine or guanine-cytosine). The resulting DNA is still technically undamaged, although the protein resulting from a gene with a mutation may not work as well as the unmodified version. In such a case, it is difficult or impossible for the problem to be recognized by DNA repair mechanisms. And it the problem can't be recognized, it certainly can't be repaired.

However, with most DNA damage, one or both strands of the DNA molecule is/are either distorted or broken. In that case, the DNA cannot be properly transcribed into RNA, or the DNA cannot be copied during cell division (or both). But for the same reason that these copying problems occur, it is also possible for appropriate enzymes to recognize that things are not right, and to activate a suitable repair mechanism (even if the repair cannot always succeed).

If, on the other hand, the damage is not repairable, other pathways can be activated to cause cell senescence or apoptosis. This more drastic situation may lead to cancer if there is already a problem with the senescence or apoptosis pathways. However, the research we're about to mention doesn't deal with this case. It's about problems in the repair mechanisms, due to DNA damage or mutations affecting those mechanisms, that lead to repair failure and that, consequently, lead to cancerous cell behavior.

The nature of repairable damage is varied, and the details of repair are quite technical, so we won't go into that here. Suffice it to say that there are effective damage repair mechanisms. What's not clear is whether malfunctions in those mechanisms (resulting from previous uncorrected errors or mutations) frequently result in cancer.

Researchers investigated genes that code for proteins involved in DNA repair. After statistical analysis of many relevant studies they found only two with a significant correlation to cancer:

Few DNA Repair Genes Maintain Association With Cancer In Field Synopsis (12/31/08)
Variants of numerous DNA repair genes initially appeared to be statistically significantly associated with cancer risk in epidemiological studies. When the data from individual studies are pooled, however, few DNA repair gene variants appear truly associated with increased cancer risk, according to a new field synopsis. ...

In the current study, John P. Ioannidis, M.D., of the University of Ioannina School of Medicine in Greece, and colleagues identified 241 previously reported associations between gene variants and the risk of cancer. The team pooled the data from 1,087 data sets and reexamined these associations.

Initially 31 of the 241 associations appeared to be statistically significantly associated with cancer risk in the meta-analysis. However, only two remained statistically significant after the researchers adjusted for multiple comparisons. An XRCC1 allele (-77 T>C) and an allele of ERCC2 (codon 751) were associated with lung cancer risk.

The conclusion of the meta-analysis is that either there's a problem with the way in which candidate genes were selected, or else problems in DNA repair mechanisms do not by themselves play a big role in carcinogenesis.
"The lack of many signals with strong credibility that emerged from our analysis, despite an enormous amount of work in this area over the years, needs careful consideration," the authors write. "The ability of the candidate gene approach to identify genetic risk factors may have been overestimated. Alternatively, the importance of the DNA repair pathway may have been exaggerated. However, there is increasing recognition that genetic risks of cancer conferred by single variants are almost always very modest. This means that even if the DNA repair pathway is essential for carcinogenesis, extremely large-scale evidence would be necessary to establish with high confidence the presence of specific associations."

Even though it seems that genomic studies have failed to turn up important oncogenes among genes that are involved in DNA repair, there is practical significance in these research findings.

For one thing, we should not expect to find useful biomarkers of cancer risk among alleles of DNA repair genes. Likewise, it's probably not worth exploring gene therapy approaches to compensating for malfunctioning DNA repair genes. Instead, what's more likely to succeed is a focus on alleles of genes involved in detection of DNA damage or of genes involved in senescence or apoptosis pathways.

Still, DNA repair genes remain very important. In many types of current cancer therapy, such as chemotherapy or radiotherapy, the intent is explicitly to cause DNA damage in order to bring about senescence or apoptosis. A problem with DNA repair in cancer cells cuts both ways. On one hand, faulty DNA repair leaves more errors uncorrected, exposing the cells to senescence or apoptosis as long as those pathways remain intact. That's good. But on the other hand, it can allow new errors to accumulate, making the cells more vulnerable to compromise of the senescence and apoptosis pathways, hence more likely to proliferate. That's bad.

Perhaps this ambivalence of DNA repair in the cancer process explains the apparent lack of strong correlation between faulty DNA repair and cancer.

Here's another way to think about the "right" way for an organism to defend itself from cancer. Cancer is a problem that's of concern only to multicellular organisms – communities of cells. While the integrity of each cell is certainly important, it's even more important to protect the whole community. A suitable analogy might be that it's more important to the community to have a good fire department as the last line of defense, than to rely on effective sprinkler systems to put out small fires in every separate location. If the fire department itself is compromised, and unable to combat a spreading conflagration, the community as a whole is in serious danger.

Here's the research abstract:

A Field Synopsis on Low-Penetrance Variants in DNA Repair Genes and Cancer Susceptibility
We have conducted meta-analyses of 241 associations between variants in DNA repair genes and cancer and have found sparse association signals with strong epidemiological credibility. This synopsis offers a model to survey the current status and gaps in evidence in the field of DNA repair genes and cancer susceptibility, may indicate potential pleiotropic activity of genes and gene pathways, and may offer mechanistic insights in carcinogenesis.

Update, 1/25/09: There's a significant follow-up on all this here.

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