Monday, July 09, 2007

Cancer: Genes, Chromosomes or both

The Gene Sherpa recently posted on the chromosomal instability theory of cancer, which he sees as an emerging paradigm shift, displacing the dominant gene-centric model of cancer. I'd like to point out some recent results that paint a much more complicated picture & suggest that both theories have a lot to contribute.

It's worth reviewing some background on the two-hit model. Knudson described in 1971 a statistical model to explain different patterns of retinoblastoma, including the inherited familial form. The model proved true in retinoblastoma, with the responsible gene (Rb) being cloned and sequenced. Other familial cancer syndromes also appear to fit Knudsen's model.

The key question is how well does this model work in general. This is truly an important question: huge amounts of cancer research in both academia and industry are focused around the oncogene / tumor suppressor model of cancer.

Two competing theories are the cellular disorganization theory and a central role for aneuploidy. Each of these holds that biological disorganization, either at the level of cells or chromosomes.

There are probably few biologists who believe that one of these hypotheses utterly trumps the others; the question is which comes first and which should we focus our efforts on.

A paper in Nature last month (alas, you'll need a Nature subscription) nicely illustrates the interplay, but also would favor single genetic events leading to aneuploidy and not necessarily the other way round.

The authors present a transgenic mouse model of cancer. These mice carry inactivating mutations in three key genes, Atm, Terc and p53. Atm is a protein kinase important for turning on many DNA damage repair genes. Terc encodes the RNA component of the telomeres, the special structures which protect the ends of chromosomes. p53 is another gene critical to DNA repair and the growth arrest of deranged cells. Inactivating mutations in p53 are found in roughly half of all human cancers, and ATM is also often mutated. Mice lacking Atm function develop lymphomas, an effect suppressed if the mouse is also knocked out for Terc.

The triple mutant mice develop tumors much like those mutant only for Atm, suggesting that the tumor suppression in Terc null mice is effected by p53. They also have high levels of aneuploidy, much more pronounced than in Atm null only mice.

So, high levels of aneuploidy can be driven by knockouts in a few key genes, a point for genes before aneuploidy.

Using genomic arrays the precise regions of aneuploidy, meaning those DNA segments amplified or reduced in copy number, can be determined. DNA sequencing can identify point mutants in selected genes. An important point about this paper is that many of the changes observed parallel those seen in human lymphomas. Mutations in Notch, Fbxw7 and the Pten/Akt pathway were all observed as well as many other changes. So the mouse model, driven by three genetic changes, mimics the genetic changes seen in human tumors.

This is not the first paper in this vein. Last year there was a burst of papers showing that transgenic mouse models of cancer could recapitulate genomic alterations seen in human tumors, including breast, liver and melanoma. Many of these models used more traditional oncogenes such as RAS, which are not directly involved in chromosome maintenance. So again, gene changes can beget chromosome changes.

Any model claiming primacy of genetic events will need to incorporate these, and many other observations. However, trying to claim complete primacy of genes would be silly as well. For example, events in a small number of genes might ignite aneuploidy, but it could easily be the case that restoring function to those genes later would be ineffective. Similarly, genetic events might initiate cellular disorganization, but chaos at the tissue level may eventually be self-sustaining.

Paradigm shift? Not from how I read Kuhn. Simple models being replaced by messy models reflecting the chaos of cancer; that's a sure bet.


Steve Murphy MD said...

Nicely said. I agree there will never be a removal of the primacy of genes per se. However, I think we all know that chromosomal alterations play a much larger role in at a minimum haematologic cancer outcomes. I agree with you in thinking both have a role. But I think that is the paradigm shift.

Ping said...

It is an interesting paper anyway, whether or not there would be a paradign shift. In reality the situation may be complicated (or simple?). One of my own papers addressing 3 "absolute discrepancies" in cancer theories is here,
Orders of Magnitude Change in Phenotype Rate Caused by Mutations. P. Ao, Cellular Oncology (2007) 29: 67-69.

It is based on a simple genetic switch study. Perhaps someone else can address all 9 "absolute discrepancies" listed by P. Duesberg based on simple theories.