Aurora2 may be cancer 'susceptibility' gene 24/7/03. By UCSF A common variant of a gene known as Aurora2 may increase susceptibility to cancer development. The finding provides one of the first examples of an elusive type of 'low penetrance' tumour susceptibility gene in humans.

The new research, led by a team from the University of California, San Francisco (UCSF), supports the emerging viewpoint that common variant forms of some genes can contribute to cancer susceptibility, particularly when a number of these variant genes are co-inherited and therefore can act in concert.

Traditionally, advances in understanding cancer predisposition have involved discoveries of rare, inherited, full-fledged genetic mutations that dramatically increase the risk of cancer, such as the Brca1 and Brca2 genes in breast cancer. But scientists have come to recognise that such 'high penetrance' genes account for only 5-10 per cent of cancers.

Evidence from mouse models and human epidemiologic studies suggests that susceptibility to most cancers results from numerous low penetrance polymorphisms acting together to disrupt a cell's regulatory controls. In themselves, these subtle variations are not harmful. A mouse - or human - that inherits a mildly more active form of a certain regulatory gene such as myc or ras won't necessarily have a problem. But the evidence suggests that if either inherits a number of overly active regulatory genes that act synergistically, cancer is more likely to develop.

"It's like the components of a lock – it's the combination of these polymorphisms that makes a substantial difference in susceptibility," says Professor Allan Balmain at UCSF. "We're trying to identify the components of the lock. The Aurora2 story is the first component we've identified."

While much evidence has suggested that cancer susceptibility genes exist in humans, identifying them has proven daunting. In the current study, the researchers used a novel approach involving both mouse models of cancer susceptibility and resistance, and human tumours to systematically move in on the Aurora2 gene, and to identify the culprit variation of the gene, known as Ile31.

Scientists already knew that an abnormal number of copies of the Aurora2 gene, known as a kinase, were found in more than half of colon tumours, indicating the gene’s possible role in destabilising the cell. But they have not known whether it actually contributes to the development of cancer, or is a by-product of cancer.

The new finding, says Balmain, should heighten scientific interest in exploring whether an inhibitor of the gene, already being developed by pharmaceutical companies, helps to prevent the recurrence of colon tumours and to treat existing cancers.

The discovery of the Ile31 variation's apparent impact on cancer susceptibility should also broaden interest in the gene as a potential therapeutic target for many other cancers, including those of the skin, breast and prostate, where the researchers suspect varying degrees of activity.

The Aurora2 gene codes for a protein that plays a key role in ensuring that the correct number of chromosomes - two for each of the 23 pairs - is passed to each daughter cell during cell division. But the Ile31 variation makes the gene slightly more active than normal, causing some daughter cells to inherit extra copies of chromosomes. The abnormal and haphazard increase or decrease in the number of chromosomes, a form of aneuploidy, disrupts the growth control of the cell.

While the impact of genomic instability on cancer development remains hotly debated, Balmain and many others believe that it incites a spiraling chain reaction of unregulated behaviour that can lead to the accumulation of mutations in key regulatory genes. When enough mutations accumulate, the cell moves into replication overdrive, one of the hallmarks of cancer.

The Ile31 genetic variation is likely to be a particularly important factor in cancers in which an environmental stimulus - almost always a contributing factor in cancer - has prompted the cell into a state of rapid cell proliferation, says Balmain, as cell division will be occurring at an increased rate. Given this, he says, colon and skin cancers are particularly likely targets, as a diet high in saturated fat can prompt colon cells to proliferate, and ultraviolet radiation from the sun makes skin cells proliferate.

Notably, almost a quarter of people inherit the Ile31 variant of the Aurora2 gene, but most do not develop cancer. Given this, says Amanda Eward-Toland, "the variant is a classic low penetrance susceptibility gene. This is just the beginning of this field, where we are trying to establish what the networks are that make us susceptible."

The evidence suggests that multiple low penetrance genes can confer a dramatic increase in susceptibility to cancer. In women without a family history of breast cancer, says Balmain, there can be a 40 to 50 fold increase in susceptibility in a woman because of the particular combination of low penetrance genes she inherited from her parents.

Ultimately, he says, "If scientists could identify the network through which the Aurora2 variant works, clinicians potentially could treat patients with drugs that target several of the genes involved. In this way, we could dismantle the network that controls the progressive growth of the cancer cell. That's the critical point we're aiming for in this field. It's network analysis."

Adapted from a news release issued by University of California, San Francisco (UCSF).

Photo credit: Dr David Becker

Links

Ewart-Toland A et al. Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Genet 2003 34: 403-12. Abstract