Gene team detects cancer clues

June 9, 1995

Scientists believe that they have traced a hereditary link to breast cancer and can predict which women can tolerate a stronger blast of radiation. Aisling Irwin reports.

The photograph was taken in someone's back garden, green with summer life; there were two women, one sitting, one standing, both lucky to be alive. They survived breast cancer but now they have another problem, which is why they are posing, grim-faced, for the newspapers. They are suffering painfully from the legacy of their cancer treatment. Too much radiotherapy, they argue, has damaged their good tissue as well as obliterating their cancerous tissue: now they endure severe pain, loss of function in their limbs, broken bones and skin damage. In 1995, the centenary of the discovery of X-rays, they are a reminder of the downside of radiation.

But even as the women campaign through their pressure group, Rage, scientists are beginning to realise why it is that some women can cope with big doses of radiotherapy in the attempt to kill their cancer, while others sustain unacceptable damage to their healthy tissue. The insights started with an odd observation about a rare disease, ataxia telangiectasia. Scientists followed those leads and now a British group has unravelled important strands in the tangle of cause and effect that is breast cancer. The group is suggesting that far more breast cancer is hereditary than had previously been thought; and now group members think they can predict which women can tolerate a stronger blast of radiotherapy.

It was a blast of radiation on people with ataxia telangiectasia that puzzled researchers from Birmingham University. The disease leaves sufferers wheelchair-bound due to loss of balance by their early teens and they have a 100-fold increased risk of cancer. Tackling those cancers with modest amounts of radiotherapy made them worse: some patients were killed by their treatment. This was because radiation damaged their cells far more easily than it did cells from healthy counterparts. Researchers turned to the sufferers' parents, because they are carriers of the disease gene, and made the strange discovery that they also suffer from cancer far more frequently than is usual. They widened their search and found that anyone who carries the gene for the disease - about one per cent of the population - is at a higher risk of getting cancer.

It was when they worked out that women carriers of ataxia telangiectasia had a fourfold increased risk of getting breast cancer, that David Scott became interested. "It seemed to most of us unlikely that there would be such a strong relationship between predisposition to cancer and sensitivity to radiation," says Scott, who heads the Cancer Research Campaign department of cancer genetics at the Christie Hospital in Manchester. "There are a lot of people around who carry this gene. It meant that 5 per cent of all women with breast cancer are carriers of it."

With a grant from the United Kingdom Coordinating Committee on Cancer Research, which had received money from the nuclear industry to investigate unexpected mechanisms that might cause cancer, Scott and his colleagues started doing blood tests: on people with the disease, on carriers and on the normal population. They produced the same results. "Then we wanted to see whether we could pick out those 5 per cent of breast cancer sufferers who are carriers of this gene," says Scott. So they tested the blood of 50 women with breast cancer, hoping to find two or three who would have the tell-tale strangely sensitive cells: instead they found 20.

So there are many more women with cells sensitive to radiation than there could be carriers of the gene. The explanation, says Scott, is that there is probably a whole list of genes that cause this sensitivity. His conclusion is startling: 40 per cent of breast cancer is a result of these genetic predispositions. The genes increase the likelihood, probably by about fourfold, that a cancer will be triggered by an insult to a woman's cells, which are not as robust as they should be. One in ten healthy women carries one of these genes (different from the two, single, breast cancer-causing genes isolated with much publicity in the past 12 months, which cause the 3 per cent of breast cancer for which there is an extremely strong family history).

Robust cells cope with a hailstorm of environmental insults every day: smoke, food and chemicals, as well as radiation, produce free radicals in the body, which bombard cells and can damage them. Normal cell machinery chugs along and routinely repairs the damage. Scott says: "The cancer in these women is unlikely to be triggered by radiation. It's more likely that the damage is produced by their normal metabolism, which produces oxygen free radicals."

So there is no neat rule resulting from his research that says that sensitive women should avoid radiation. Instead his conclusions dump us back in that uncertain realm of environmental carcinogens, and rumoured-to-be carcinogens, and internal chemical reactions, armed only with the knowledge that some people are more sensitive to them than others, that we will be able to identify these people with a simple test within two years - and that there is little that they will be able to do with that knowledge.

There is a small hope: Texan researchers think that antioxidants, the darling nutrients of the diet-and-cancer lobby, found in fresh fruit and vegetables, could be given selectively to people with cell sensitivity. Antioxidants neutralise free radicals. The Texans are now trying to prevent people with head and neck cancer from developing a second cancer.

But the more exciting prospect from Scott's research is in treating breast cancer. Ged Adams, director of the Medical Research Council Radiobiology Unit says: "Half of all cancer patients get radiotherapy. The limit is the damage that it does to the normal tissue. It may turn out that a certain proportion of patients are unduly susceptible."

The damage starts with burning and blistering. Then, sometimes years later, come the dreadful symptoms of tissue damage. Scott says: "It could well be that among that pressure group (Rage) are these sensitive women. The whole efficacy of radiation therapy is limited by these women: for quite a lot of women we are not giving enough therapy. If we could test women in advance, the exciting potential is that we can increase the dose to the others."

Now Scott and colleagues are testing 300 breast cancer cases: he is taking a blood sample from each woman before she starts radiotherapy; then he is giving them all the same treatment to see whether those who react badly are the same as those who have sensitive cells. He will have to follow the women over several years to monitor their long-term responses to the radiotherapy. It is a slow process: too late to help the members of Rage and too slow to help cohorts of women following behind. But it could lead to tailor-made radiotherapy, improving the prospects for some women of overcoming breast cancer and reducing the painful after-effects for others.

The Rontgen Centenary Congress, 100 years of X-rays, will be held in Birmingham from June 12-16 .

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