LONDON  New clues to the genetic mechanisms that cause some types of cancer are emerging from a study of the gene responsible for the rare disorder known as ataxia telangiectasia (A-T).

The ataxia telangiectasia mutated gene, ATM, also is mutated in tumor cells in some people with the common blood disorder chronic lymphocytic leukemia (CLL), researchers in the U.K. have shown.

The finding could lead to new therapeutic approaches for CLL. The scientists postulate that, because loss of the product of ATM in A-T causes increased sensitivity to ionizing radiation, tumor cells in CLL may be more sensitive to radiation  or drugs with a similar effect  than normal body cells.

Tatjana Stankovic, of the Cancer Research Campaign¿s Institute for Cancer Studies at the University of Birmingham in Edgbaston, U.K., together with colleagues from the same institute and the department of hematology at the University of Birmingham, reported their results Jan. 2 in The Lancet, in a paper titled ¿Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukemia.¿

A-T is a recessively inherited disorder affecting between three and 10 people per million. About 150 families are known to be affected by the condition in the U.K. The disease starts to become apparent at about 18 months of age, when the child is learning to walk. It causes abnormal movements and eventually the patient is confined to a wheelchair. Another feature of the disease is abnormally dilated blood vessels in the skin (cutaneous telangiectasia). Although some people with A-T survive to the age of 40, most die by their early 20s.

People with A-T have mutations in both copies of ATM, and these mutations are usually different from each other, although both result in loss or deficiency of the gene¿s protein product. Little is known about the protein which ATM makes, although it is known to be involved in cell cycle ¿checkpoints¿  phases of the cell cycle that normally shut down DNA synthesis if the DNA is damaged.

Malcolm Taylor, senior author of the paper and professor of cancer genetics at the Institute for Cancer Studies, told BioWorld International: ¿Because we knew that about 15 percent of children with A-T die from lymphoid leukemias, we reasoned that possibly ATM may be involved in sporadic forms of leukemia in patients who have not got A-T. We chose to look at CLL because it is the commonest leukemia, and because it is a lymphoid tumor  the kind that children with A-T get.¿

CLL is the most common leukemia in developed countries, affecting mainly elderly people. It causes the accumulation of large numbers of mature B cells, possibly as a result of loss of the signals that normally trigger apoptosis (programmed cell death).

Stankovic and her colleagues examined samples of B cells from 32 people with CLL, and managed to detect mutations in ATM in six of them (19 percent). The team also analyzed 20 samples to find out the level of expression of ATM protein. It was impaired in eight out of the 20 (40 percent), absent in three cases and expressed at lower than usual levels in five.

Taylor added, ¿In two out of the six CLL patients in whom we found mutations, the mutations appeared to be in the germ line. We took DNA from buccal cavity [cheek] cells and found the same mutation there as in the tumor cells. This implies that these people are carriers of a mutated ATM gene.¿

While only 0.5 percent of the general population have a mutation in ATM, the mutated ATM was found in about 6 percent of CLL patients. ¿The implication is,¿ Taylor added, ¿that carriers of a mutated ATM may be at higher risk of this form of leukemia.¿

Taylor described the results as ¿quite exciting.¿ They suggest, he said, that ATM has a wider significance than previously appreciated, especially in CLL.

Commenting on the paper, Colin Arlett, of the Medical Research Council¿s Cell Mutation Unit at the University of Sussex in Brighton, U.K., said Taylor had been working steadily on A-T for many years. ¿These latest observations are going to be very important for our understanding of the genetic mechanisms which may give rise to cancer,¿ he said. Given that this is the second blood cancer associated with mutations in this gene, it will increase the importance of the study of this gene, he added.

One big question raised by the findings is whether the discovery could lead to new therapies for CLL. People with A-T are unusually sensitive to ionizing radiation and there have been instances where patients being treated for their cancer have died following normal radiotherapy. This begs the question of whether tumor cells from people with CLL will turn out to be much more sensitive to radiation. If they were, this could provide a means of targeting treatments  such as radiomimetic drugs  to tumor cells while sparing normal cells.

Taylor concluded: ¿I think ATM is going to be shown to be extremely important, because it is related to the repair of DNA damage in some way. If this gene is lost in cells, this could mean that damage is not repaired and the mutated cells go on to become malignant.¿

This theory fits with other observations. One is that most tumor cells in CLL have a high level of expression of the protein BCL-2, which seems to protect against apoptosis. The other is the finding that up to 30 percent of patients with CLL have mutations in the tumor suppressor gene p53.

In a commentary in the same issue of The Lancet, titled ¿Genetics and B-cell leukemia,¿ Andre Reis, of Humboldt University in Berlin, wrote: ¿These investigators have shown that, among its many functions, ATM is also an important tumor suppressor and its inactivation might result in [CLL]. The exact mechanism is uncertain but, taken together with the mutations in the p53 gene, the finding points to a common pathway by which damaged cells are prevented from dying through apoptosis.¿

Reis added that studies are still in progress examining the increased risk of breast cancer in people who are heterozygous carriers of ATM. n

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