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Barbara Garvey does not yet know whether she carries the so-called ‘breast
cancer gene’. Nor do her three grown-up children, nor her five granddaughters.
But they have always known that cancer of the breast and cancer of the ovary
run in their family. ‘We just thought we were very unlucky,’ she explains
during a quiet moment at the family pub near Barnsley in Yorkshire. ‘If
breast cancer didn’t get you, ovarian cancer would.’

Now the family knows they have had more than bad luck, and that both
diseases can be inherited. For the past five years Garvey and many relatives,
some as distant as Canada, have been participating in a giant project to
hunt down the gene or genes responsible. The study is one of more than a
dozen involving hundreds of affected families all over the world. Recently,
expectations have been riding unusually high.

Slowly but surely, the geneticists and epidemiologists behind the research
have been edging towards a breakthrough. Now they are close to identifying
a gene that plays a major role in the inherited forms of both diseases.
Perhaps even more importantly for public health, the gene, dubbed BRCA1,
is also expected to shed light on the way all breast cancers develop,
whether inherited or not.

Success is likely by the end of the year, and possibly sooner. When
it comes, the discovery will be hailed as a triumph for molecular genetics.
James Watson, co-discoverer of the double helix and former head of the US
government’s human genome programme, has argued that there is ‘no more exciting
story in medical science’. Eventually, researchers hope the knowledge will
lead to radically improved treatments and even prevention of both diseases.

But before that time comes, there will be a period of uncertainty and
confusion when Western societies will be challenged to their limits. The
test for BRCA1, when it is ready, will be the first to identify such large
numbers of people at high risk for a comparatively common disease – long
before their symptoms develop. Worldwide, hundreds of thousands of women
could be affected. Initially, affected families will be the first to take
the test. But within a very short time, other women who have no family history
of the disease are likely to demand it too.

‘One can imagine that all women might eventually want the test,’ says
Francis Collins, one of the key geneticists hunting the gene and head of
the US government’s genome research programme at the National Institutes
of Health in Bethseda, Maryland. ‘This will be the first really widespread
presymptomatic test.’ But who will educate people about the implications
of a positive result? How should they act on the information? Who will control
the potential for commercial exploitation of the test? Some scientists are
worried that governments and the public are unprepared.

‘If the gene is found fairly soon, private labs will get in on the act
and we’ll never get testing together,’ says Bruce Ponder, who leads a team
searching for the gene at the University of Cambridge for the Cancer Research
Campaign. ‘Before we all go charging around saying we can give women a test,
we need a massive public education campaign.’ He is not necessarily being
alarmist: in the US, one company has already been set up to market the test
as soon as it becomes available.

A test for BRCA1 will be different from a test for, say, cystic fibrosis
or Huntington’s disease, for a number of reasons. First, even though most
carriers will develop breast cancer within decades, some will never do
so. Secondly, unlike Huntington’s or CF, breast cancer is not invariably
fatal and survival rates are high in those whose tumours are detected early.
Thirdly, BRCA1 is probably not the only breast cancer gene, so it will
not explain all the families with a history of inherited disease. And fourthly,
no one is suggesting offering general population testing for Huntington’s
or other rare genetic diseases.

But despite the potential complexity of this test for families, employers
and insurers, governments appear to be sitting on their hands until it becomes
available, rather than preparing for it now. Some research groups have set
up local studies, but there have been no widespread programmes to train
GPs in explaining to patients what the test means, nor national attempts
to assess the cost of tests, the demand for extra counselling or medical
care.

Breast cancer is the commonest cancer among women in the industrialised
world and a major killer. In Britain, there are some 28 000 new cases a
year and more than 15 000 deaths. Not only are cases increasing as the population
of the industrialised world ages, but within each age group the incidence
of breast cancer has risen by 25 per cent in 20 years. Ovarian cancer is
rarer but more deadly; in Britain alone every year there are some 5200
new cases and more than 4500 deaths.

Genes of chance

Most breast cancers are not inherited. They are called ‘sporadic’ because
they seem to occur simply by chance. Overall, as many as 1 in 10 women will
develop breast cancer. However, about 5 per cent of cases in younger women,
such as those that have plagued Barbara Garvey’s family, stem from a strong
inherited predisposition to the disease. BRCA1 has been linked to about
half of the families with inherited disease; for the other half, different
genes may be responsible. Estimates by Doug Easton and his colleagues at
the Institute for Cancer Research in Sutton, London, put the risk of developing
either breast cancer or ovarian cancer from BRCA1 at 59 per cent by age
50 and 82 per cent by age 70.

BRCA1 sits on the long arm of chromosome 17. No one knows the frequency
of the altered form, or allele, of the gene in the population and there
is a heated debate about the figure. Estimates put it between 1 in 1000
and 1 in 300. Double this number – as many as 1 in 150 – may carry one copy
of the allele. This means that up to 600 000 women in the US alone could
be carriers – although it may be half that figure.

Ultimately, it is not the raw numbers that matter. In some ways, the
affected families have less to learn than everyone else. As Barbara Garvey
points out, regular mammograms and ovarian scans are already a part of life
for women in her family. BRCA1 is important for all women because it seems
to play a role in noninherited breast cancers as well as inherited ones.

Mary-Claire King, a geneticist at the University of California, Berkeley,
who has spent 18 years studying inherited breast cancer, sees the search
for the gene itself as ‘just the beginning’. The next steps, she says,
will include a thorough investigation of its biology and interaction with
environmental factors known to affect risk, such as the timing of a woman’s
child-bearing, her age when she had her first period and her age at the
onset of menopause.

For breast cells to become cancerous, a chain of events must first transform
them by altering their DNA. A number of genetic changes have been identified
in cells from breast tumours. Strikingly among these, scientists have found
that in both inherited and sporadic breast cancers, the normal copy of the
chromosome region that contains BRCA1 is missing from cells, leaving only
the copy that contains the altered form. So it seems that the gene may play
a role in both forms of the disease.

The difference between them is that in the inherited form, the normal
copy has never been present since conception, while in the sporadic form,
the normal copy is lost as a result of alterations later in life. Women
who inherit BRCA1 are therefore at a strong disadvantage because the first
link in the chain to transforming cells has already been forged. But for
all women, changes in BRCA1 might one day be used as an early warning of
cancerous changes in the breast – a ‘molecular mammogram’, as King puts
it. Current tests cannot identify a tumour until it is visible on an X-ray,
and such a test could give women and their doctors more time to act. Others
warn that this remains a far-off ideal.

Whatever the mechanism by which the gene causes the disease, all eyes
are now firmly fixed on the last lap of the race to find it. Like other
gene hunts, this has involved scattered teams of geneticists and epidemiologists
from California to Iceland in a search that has sometimes been collaborative
and, more recently, intensely competitive. Now, it’s just a matter of luck
who finds the right one first. ‘It’s a bit of a roller coaster,’ says King.

King’s hopes of using the gene for earlier diagnosis and prevention
will have to wait for the long term. In the meantime, the gene’s discovery
will raise as many questions as it answers. No one knows yet whether all
carriers have the same mutation or whether, at the opposite extreme, each
individual case will be caused by a different mutation. ‘If every individual
has a different mutation, then we might wait years before a test becomes
practical,’ warns Collins. It is also possible that different mutations
confer different levels of risk, with some much milder than others.

Assessing the risk

One of the first uncertainties that will have to be resolved is the
true degree of risk attached to the gene. The answer could influence future
attitudes to genetic screening. Until now, scientists have been able to
estimate the probability that a BRCA1 carrier will develop disease only
by studying large, severely affected families who have come to medical attention
and are, by definition, at the extreme end of the spectrum.

Most researchers admit that this may have led to the risk being overestimated.
But once the gene’s identity is known, this will change. ¿ìè¶ÌÊÓƵs will
make more systematic esti-mates by testing all women with breast can-cer
under the age of, say, 50 for the presence of BRCA1. If there are many different
mutations with different levels of risk, each will have to be calculated
separately.

Yet as time goes by and these uncertainties are slowly resolved, individual
women will still be left with difficult choices. For those who learn they
are not carrying BRCA1, there will be welcome reassurance. However, such
women still face a 10 per cent risk of breast cancer. For those who learn
they are carriers, the knowledge may prove burdensome, not only for themselves
but for their mothers, sisters and daughters. Should they, too, have the
test? And what about male relatives who may carry the gene and pass it on
to their female offspring?

A woman carrying the gene faces limited options. She can decide to start
having regular mammograms and ovarian scans at, say, 25 – much younger than
the age of 50 at which all women are encouraged to join Britain’s national
breast screening programme, and younger than the age at which most health
insurance companies will pay for screening in the US. Many young women in
affected families already do this. Cancers in women as young as 27 have
been detected and treated.

But mammograms are no real solution. They work well in women over 50,
but below this age the tissue in the breast tends to be denser and tumours
are often more difficult to detect. Researchers have detected too few tumours
in the population at large to make screening worthwhile in women under 50.
Screening for ovarian cancer, by ultrasound, is even less certain of detecting
a tumour. However, the balance of cost and benefit may be different in
young carriers of BRCA1, particularly for breast screening. Barbara Weber,
senior oncologist on the team searching for BRCA1 at the University of
Michigan, says: ‘We certainly find tumours in these young women.’

The only real alternative at present to this stepped-up surveillance
is what doctors call prophylactic surgery – an anodyne clinical term that
means removal of both breasts and possibly both ovaries. ‘It sounds invasive
and grotesque,’ says Collins. But British women may be astonished to know
that in the exceptional, severely affected families Collins has studied,
the majority of affected women have chosen surgery. He stresses that these
women have mostly already seen several close relatives die. ‘They have a
very strong personal image of what a horrible disease this is.’ In Britain,
only a tiny minority of women have chosen this option so far.

Surgery does dramatically reduce the risk although, since no surgeon
can be certain to have removed all breast tissue, it does not eliminate
it. Weber stresses the need to give women full information so that they
can make informed choices.

In future, doctors hope that there will be less drastic options, such
as the possible use of the drug tamoxifen to prevent breast cancer in those
at high risk. Despite continuing controversy over the drug’s possible side
effects as a long-term treatment for otherwise healthy women, a large trial
is under way in the US and another is beginning in Britain. No one pretends,
however, that the results will be available tomorrow.

In the shorter term, say scientists, there is an urgent need for pilot
programmes to follow up carriers, record their choices and monitor the
outcomes. The effect of the counselling that women receive should also
be assessed. At the Christie Hospital in Manchester, Gareth Evans has studied
the perceptions of women who have a family history of breast cancer. Before
counselling, only 11 per cent estimated their personal risk to within a
few per cent of the correct level. After counselling, 41 per cent estimated
it correctly.

Interestingly, those who learnt and remem-bered the correct estimate
were largely women who had begun by overestimating their risk and who had
been reassured by what they had learnt. Those who had underestimated their
risk continued to do so. Evans thinks this reflects the different ways women
cope with the information.

None of this counselling, screening or treatment will come cheap. Who
will pay for it and will there be enough services to meet demand? Britain’s
Department of Health has so far made no moves to plan or cost services and
scientists in the US know of no national initiatives either. Local studies
suggest that counselling will be the biggest problem. Clinical geneticists
already have waiting lists. If the demand for tests suddenly spirals, women
will either grow impatient and go for tests without counselling, or non-geneticists
in the health service will have to start offering information in place
of counsellors.

These issues will remain open-ended, however, until we know just who
will demand a test for BRCA1 and who will get one. At the University of
Utah, one of the foremost gene hunters, Mark Skolnick, has already set up
a company called Myriad Genetics that will patent and market a test for
the gene if he finds it first. Skolnick declined to talk to ¿ìè¶ÌÊÓƵ,
but other leading geneticists in the US and Britain are seriously concerned
by the implications of marketing a commercial test. Tim Bishop, who heads
the Imperial Cancer Research Fund’s team at the University of Leeds, says
it is clear that Skolnick believes screening will be widespread – ‘and that
it will be profitable’. Another leading scientist who declined to be named
said: ‘If Mark Skolnick clones this gene I worry a little about what will
happen, because there will be a commercial interest attached to seeing as
many people screened as possible.’

If a woman really wants the test, says Collins, it would be unethical
to withhold it. The first principle, says King, is that every woman has
a right to know about her genotype. ‘That’s lovely,’ retorts Hoda Anton-Culver,
a researcher at the University of California, Irvine, who is conducting
a massive population-based survey to learn more about the true risks attached
to the gene. ‘But a woman also has the right to a programme that can handle
those who learn they are at risk.’

Any company that has a test will want to sell as many as possible. But
some people should definitely be strongly discouraged from taking one, say
researchers. Girls under the age of 18, for example, could be pressurised
by their parents into having a test even though they are unlikely to succumb
to disease for years. ‘The idea of young girls living with the fear of drastic
intervention disturbs me,’ says King.

Another potential market is in fetal screening. Most scientists doubt
that there will be much demand. They feel few prospective parents would
want to terminate a pregnancy for the sake of preventing a disease that
might not strike at all, and certainly not for some 25 years or more – by
which time treatments for breast cancer may have improved radically. However,
Garvey points out that some affected families are so loath to risk more
breast cancer that they decide not to have children at all. Fetal screening
might enable them to begin a pregnancy and reassure themselves that the
fetus was not a carrier.

Won’t commercial interests overturn the best intentions of all the ethicists
and scientists? ‘They’d better not,’ says Collins. He believes the human
genome project will be able to wield its ‘moral authority’ over any overenthusiastic
company. Not everyone shares his optimism, and there is still no legislation
in place to prevent the misuse of genetic information.

But the optimists hope they will win in the end. For Garvey, the point
of all the research is not for her, but for her grandchildren and for the
1 in 10 women facing sporadic cancer. For King, the ideal would be to develop
the equivalent of a cervical smear for breast cancer. Her maternal grandmother
died of cervical cancer, and to women only a little older than herself,
the advent of the smear test was one threat lifted. ‘I hope that we collectively
will be able to do the same thing with breast cancer. When another of the
big threats has gone it cannot but help to have an empowering effect on
women.’ Whether she is right, only time will tell.

* * *

1: A family’s burden

‘I don’t think about cancer when I get up every morning,’ says Barbara
Garvey, whose family is affected by the inherited form of the disease. ‘I’ll
probably be knocked down by a bus first.’ At 53, Garvey knows she is unlikely
to need new life insurance or a second mortgage, but she knows that her
daughter, her sons, and her five female grandchildren will all face difficult
dilemmas over whether to be tested and what to do with the information.

The Garvey family has worked with epidemiologists at the Imperial Cancer
Research Fund in Leeds to trace more than 300 relatives over seven generations.
The family had kept a family tree in a bible passed from generation to generation.
Now there is a five-page computer print-out of the seven generations in
it.

Barbara first learnt of the issue when her mother was contacted five
years ago. Doctors decided to investigate after a 28-year-old relative
developed breast cancer and it emerged that both the woman’s mother and
grandmother had had mastectomies. Barbara’s own mother, who is in her seventies,
also had two mastectomies in her forties.

‘When I was first contacted, my initial thought was that it stands to
sense, it must have been hereditary.’ She and her relatives are now discussing
whether to be tested for the presence of the genetic markers linked to the
gene. Not all families with a strong history of the disease can be tested
in this way at present because a considerable number of samples are needed
and these may not be available if most of those affected have died.

Will the future gene test be desirable? ‘Maybe if someone in the family
develops breast cancer, then OK, test them. But I think there’s too much
we can inherit – who wants to know?’ And Barbara dismisses briskly the idea
of preventative mastectomy as ‘like having your head chopped off in case
you get a headache’.

* * *

2: Race for the gene

The hunt for the hereditary ‘breast cancer gene’ has recently evolved
into a fiercely fought race involving dozens of the world’s top geneticists.
Yet just a few years ago, even proving that breast cancer could be caused
by inheriting a single faulty gene – let alone finding that gene – seemed
a formidable task.

This was partly because the vast number of sporadic cases of breast
cancer tends to mask those instances when the disease is passed from generation
to generation. But in 1990, after years of painstaking epidemiological and
statistical analysis, Mary-Claire King and her colleagues at the University
of California at Berkeley made two important discoveries.

Based on studies of DNA prepared from scores of families with numerous
cases of breast cancer, the researchers found a known sequence of DNA, or
‘marker’, on the long arm of chromosome 17 which seemed to follow the inheritance
pattern of the disease. But not in every family – and that led to the second
key discovery.

Concentrating on those families in which breast cancer arises at an
especially young age, the researchers proved that most, though by no means
all, such cases are caused by a gene dubbed BRCA1 – especially those families
in which ovarian cancer is also common. King presented her results for the
first time to a packed house at a genetics conference in Cincinnati, Ohio,
in October 1990.

Having mapped the gene to chromosome 17, the researchers had to decide
how best to leap-frog from the linked DNA marker to the gene itself. Past
experience suggested this would be a tedious and drawn-out process. Researchers
took four years to identify the cystic fibrosis gene. Francis Collins, the
geneticist whose team was crucial to that success and who now heads the
US government’s genome research programme at the National Institutes of
Health, is also involved in the hunt for BRCA1, as are King at Berkeley
and Anne Bowrocks at the University of Texas, Southwestern Medical Center.
Together they have more than 30 scientists picking apart the crucial region
of chromosome 17.

But they are not alone. In Britain, Ellen Solomon at the Imperial Cancer
Research Laboratories in London, Bruce Ponder of the University of Cambridge
and Tim Bishop at the University of Leeds have all turned their attention
towards breast cancer. Other groups in France, Canada and Japan have joined
the race as well.

Since 1990, the researchers have progressively narrowed down the position
of the faulty gene, partly by identifying new DNA markers and partly by
identifying rare families whose chromosomes have undergone so-called ‘recombination
events’. These events happen when the chromosomes within gametes – sex cells
– swap stretches of DNA before fertilisation. In some cases, the swap separates
markers from genes as they are passed from one generation to the next –
and this disruption of the normal inheritance pattern often pro-vides invaluable
clues to the whereabouts of genes. But the closer you move in on the gene,
the rarer recombination becomes.

Today, the researchers have cornered the gene to just 300 thousand bases
of DNA, having started with several million. Accord-ing to King, however,
there are more than 20 different genes in this short fragment, and sifting
through them all will be a formid-able task. ¿ìè¶ÌÊÓƵs have already excluded
all of the known candidate genes known to reside near BRCA1. Most recently,
Steven Narod at McGill University in Montreal ruled out what had hitherto
seemed the likeliest gene of all, one encoding a protein involved in the
hormone oestrogen.

Now the expectation is that BRCA1 will turn out to be a new type of
gene. But researchers are not totally in the dark about its identity. Evidence
from cell biology suggests that the gene’s normal function is to act as
a ‘tumour suppressor’, helping to prevent uncontrolled cell growth. In many,
perhaps most, women with familial breast cancer, the gene is disabled by
inherited mutations. One crucial line of defence against the cancer is thus
lost. Another possibility is that two genes, whose protein products interact
in some way, must become disabled before a breast tumour develops. One of
these could carry an inherited defect, while the other develops a defect
during an indivi-dual’s lifetime.

Kevin Davies is editor of Nature Genetics.