Curiously enough, an obscure, incurable disease of young children is shedding light on the way in which some women become susceptible to breast cancer. Thomas Cottingham, now nearly five years old, suffers from ataxia telangiectasia, or A-T for short.
A-T is rare, with only about 150 known cases in the UK, though there may be many milder forms not yet diagnosed. It is a recessive genetic disease, which means that to develop it you need a pair of defective genes, one from each parent. A recent surprising finding is that carriers are common.
These people, like Thomas's parents, with one defective gene each have a high incidence of malignancy, although the cancer rates in A-T children are higher still. Women with the gene defect may have a breast cancer risk of one in two.
Because there is no direct test for carriers, estimates vary, but experts often quote a figure of 2 per cent of the population. For comparison, this is half the carrier rate of cystic fibrosis, the commonest similarly transmitted autosomal recessive condition.
A-T usually becomes noticeable in toddlers, with clumsiness or unsteadiness. Speech and eye movements often lack co-ordination, though so far Thomas has escaped this.
Unsteadiness gradually worsens, and by the age of six a spidery network of enlarged blood vessels appears in the whites of the eyes. A-T progresses relentlessly and a wheelchair is often needed by 10 or 11. Sufferers also have about a hundredfold greater chance of developing various cancers. At the age of two, Thomas was found to have a rare and advanced lymphoma of his thymus, the gland situated behind the breastbone.
'This is what really confirmed the of A-T,' says his mother, Beverley Hodson. 'We were devastated. Neither of us had heard of A-T and now our son was fighting for his life in intensive care, with less than a 50-50 chance of survival.'
Against the odds, Thomas survived. Last April he finished two years of chemotherapy. But A-T is a multi- system disease and the future is uncertain. Immune defects often cause recurrent chest infections.
Later on other changes resemble premature ageing, such as thinning skin, greying hair, memory defects and the early onset of heart disease. Premature death is usual.
Michael Swift, from New York Medical College, has studied more than 1,500 relatives of A-T patients and estimates that carriers have three to four times the risk of cancer of the general population. Female carriers are worse off, with a five to sevenfold greater risk of breast cancer.
They may also have a higher incidence of diabetes and both sexes seem to have more coronary artery disease. At this stage, however, there is no definite way of knowing who is a carrier - unless they happen to have an A-T child, in which case both parents must be carriers.
Children with A-T are very sensitive to radiation and so, it turns out, are carriers. Professor Swift found that among blood relatives of A-T patients women with breast cancer were more likely to have had extensive diagnostic X-rays than women relatives without cancer.
That finding raises intriguing questions about the genesis of cancer. How important is radiation as a causative factor? Is the increasing use of X-rays the reason why, as a research group in Boston, Massachussetts, suggests, breast cancer appears to have became more common? Or is it to do with chromosome breakages, which are also a feature of A-T? With its relevance to cancer genesis, and possibly to ageing, too, A-T is of enormous scientific interest.
In this country much of the work is funded by the A-T Research Trust, a charity launched in 1990 by Thomas's parents. At the Medical Research Council cell mutation unit at the University of Sussex, Colin Arlett and his team are engaged in, among other things, clarifying the link between the A-T gene and cancer.
Malcolm Taylor, a geneticist at the Cancer Research Campaign laboratory in Birmingham, is working on identifying the gene itself. It is a gene that is totally independent of other cancer-predisposing genes, and, as Dr Taylor puts it: 'The feeling is that A- T has to do with something very fundamental in biology.'
There are many practical aspects, too. A-T carriers tend to develop their breast cancers at a younger age.
When A-T heterozygotes do develop cancer they tolerate radiotherapy badly, and complications tend to occur at lower doses. It has, in fact, long been noticed that younger breast cancer patients have cosmetically poorer results from radiotherapy.
Given their sensitivity to radiation, known carriers should only have X-rays if they are absolutely essential. The astute may well point out that no one should have superfluous X-rays, but it is difficult to avoid pre-employment chest X-rays and the like.
So where does that leave mammography? In general, mammograms deliver low doses of radiation, provided the equipment is up to date and few films are taken. There is little evidence of radiation being harmful beyond middle age, so the over-50s, including A-T relatives, should not be deterred from routine screening.
For younger women, though, the situation is less clear. Mammograms alone can miss cancer in women under 50, according to specialists such as Mike Burke, of Northwick Park Hospital, London. There is therefore a need for clinical breast examination, too. This is especially true of A-T carriers, who, says Professor Swift in New York, should be checking for breast cancer from the age of 30.
To identify carriers, the A-T gene needs desperately to be found. Humans each carry 23 pairs of chromosomes and 'the A-T gene' actually appears to be a cluster of four separate genes on one chromosome.
'All four seem to be together in a very small area of chromosome 11,' says Dr Taylor. Localisation will be complete soon, but it is impossible to say exactly when. Sometimes interim findings lead to rapid progress - and sometimes they don't.
Gene therapy - replacing a defective gene with a new one - may be much in the news, but with A-T that is going to be a very long way off - if it is ever possible. Identifying carriers, however, will soon help the 2 per cent of the population at high risk of cancer. Even if avoiding malignancy is impossible, they will at least have the chance of having abnormalities diagnosed earlier.
There could also be benefits for non-carriers, such as radiotherapy patients generally. Radiotherapy is usually limited to a so-called 'tolerance dose', based on what can be given to the population at large without causing complications.
The general population, however, includes a number of A-T carriers who are excessively sensitive. If these could be excluded, the rest of the patients might be able to receive higher doses of radiation and achieve better cure rates without side-effects.
A-T Medical Research Trust, Angel Cottage, Colston Bassett, Nottinghamshire, NG12 3FD (0949 91222).
Carol Cooper is a London GP.
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