p53 (24 page)

Having finally put the picture together of what was happening in people with LFS, Malkin and Friend hammered out their paper for
Science
at a nearby pizza restaurant, the table
scattered with handwritten pages amid the plates of half-eaten food, and the two preoccupied scientists oblivious to the comings and goings of other diners. This they knew would cause a stir
because, although LFS appeared to be extremely rare, identifying mutant p53 as the root cause of a problem with such diverse manifestations confirmed the gene’s central importance in human
cancer. Not just in lab dishes and genetically engineered mice, but in real people
like us. Here too was a means of identifying people at risk in cancer-prone families who,
with intensified screening, could be treated for lesions before tumours had a chance to develop.

Over the years mutations have been reported in many different sites in the p53 of people with LFS, just as they have in so-called somatic cases (people who have developed a mutation during life
rather than inherited a mutant gene at birth). The most common ones are those that affect p53’s ability to attach itself to DNA in order to switch on other genes (i.e. to act as a
transcription factor). Researchers have discovered too that girls born with LFS have a lifetime risk of developing cancer of more than 90 per cent, while the comparable risk for boys is around 75
per cent, with breast cancer most probably accounting for the higher risk to females. Though most oncologists recognise a typical pattern to LFS, said Fraumeni, ‘One of the things that
I’ve learnt in studying these families is that the susceptibility is not just limited to the so-called classical tumours – brain, adrenal, breast, sarcomas. It really is almost across
the board; almost every tissue, I think, has an increased risk.’

LIVING WITH LFS – LUANA LOCKE CONTINUES HER STORY

These were the odds that Luana Locke faced when she learnt that her family had Li-Fraumeni syndrome, giving her an explanation at last for why lightning kept striking in the
same spot. When Luana’s mother, sister and aunt died of cancer in the early 1970s, LFS was barely recognised outside of academic circles and had certainly not been named. It was not until her
Aunt Rina’s youngest daughter, Jessica Zendri, in Italy developed bilateral breast cancer and an adrenocortical tumour that a geneticist in Milan discovered the germline mutation in p53. He
suggested that Luana be tested for the same genetic defect back home in Canada, and he recommended to her someone with special expertise,
David Malkin, now working again at
Sick Kids Hospital in Toronto.

After all she had been through, Luana was not surprised to receive the news that her test result was positive, she said. But then all of a sudden the focus was shifted away from her. ‘All
I remember hearing was, “You have a 50/50 chance of passing this on to your child.” Now it was all about my son: does he have a mutation, does he not? So it was just about getting him
tested, because I needed that knowledge; I needed to know.’

Subsequently, as she and her husband Paul sat through genetic counselling, and consulted again with Dr Malkin, the implications of her diagnosis and the possibility that Lucas, now four years
old, also carried the mutant gene, were carefully explained. ‘Everybody we spoke with did their due diligence,’ she commented. ‘“These are the things you really need to
consider: the potential for false positives and false negatives; that this is a decision you’re making on behalf of your child, so you’ll need to think about at what stage you tell him.
What if he’s the type of person who, in adulthood, says he wouldn’t have chosen to be tested; he wouldn’t have wanted to know?” All of these things they were telling me . .
. but I had already stopped listening. I sat there and I went, “Aha, yeah, okay, I have to think about that.” And all along an inner voice was just saying, “He’s going to be
tested; I need to know.”’

What did Paul feel? ‘I’ll admit, there wasn’t a choice there, I would have played the mother card, because I’m that type of person. There’s no way somebody’s
going to hold a secret that’s just within my grasp and me not know about it. That would have killed me. And secondly, I’m the eternal optimist. For me it was, “Huh! He’s not
going to have the mutation! Just give me the results so we can close that chapter and move on.”’

After a period meant for reflection, the Lockes took Lucas along for testing. But none of the messages had sunk
in and Luana was not prepared for the result. Sitting
across a small table from me in the corner of a busy restaurant in Toronto 12 years later, she vividly recalled the meeting at the clinic. ‘The genetics counsellor who was working with Dr
Malkin’s programme came with this manila envelope. She sat us down, Lucas was there too, and she started talking
science,
right? She was talking about the gene, and this strand and
that strand, and I was just following along pleasantly. I was like, “Okay . . . she’s just stringing us along and this is going to end with: ‘. . . but there’s nothing
there; clean bill of health!’” And so when she said, “. . . and we did find . . .” Locke’s jaw drops as she recreates her moment of shock. ‘I thought,
“I’m sorry,
what?
” I didn’t say it out loud, but I remember thinking, “Okay, wait a minute, I was not prepared for this. That’s not the way this story
was going to end for me.”

‘I think the poor woman who was telling us this stuff must have been thinking, “When is this woman going to start getting that I’m going somewhere with this story? Because
she’s still smiling along. . . .”’ Only then did all the questions Luana and Paul had been advised to consider in advance flood their minds. ‘I stopped and I thought of
every single one of them. Oh my gosh, what if he doesn’t want to know? How am I going to be the keeper of this information and knowledge? And am I going to treat him differently? Of course I
am . . . We just felt extremely protective.’ That night she and Paul took Lucas into bed with them – a practice they had never indulged before – and held on to him tightly.

With time, the Locke family came to terms with LFS. They fell into a routine of regular three-monthly visits to Sick Kids for Lucas to be screened, and in due course allowed themselves to
consider having another child. Traumatised by the regular tragedies in his extended family, Paul was only ready to go ahead provided they agreed to screen the unborn baby and consider termination
if he or she carried
the mutant gene. But abortion was never really an option, commented Luana. When she got pregnant and began to think of screening, she realised she could
never go through with it. She was haunted particularly by the question: had such a test been available when her mother was starting a family 47 years ago, would she have chosen to abort Luana and
her siblings?

So Lucas’s little sister Juliet was born in 2006. Once again Luana believed she would be okay. ‘After all,’ she said, ‘two kids, 50/50 chance . . . I’d had the 50
per cent already.’ But once again her optimism was misplaced. Paul and she were given the news that Juliet too is a carrier of the mutant gene, and they will need to help their daughter, as
they are helping their son, face up to life in the shadow of cancer.

As John Berkeley has found, coping with LFS can be an isolating experience. Until recently, however, the condition was considered to be mercifully rare. As of 2011, only about 500 families
worldwide had been reported in the literature with germline mutation of p53. But that was before Dr Maria Isabel Achatz revealed what was going on in southern Brazil.

***

São Paulo is a giant sprawl of a city with extremes of wealth and poverty. Rough wooden shacks cluster in hidden spaces at the foot of skyscrapers of glass and steel,
and here and there destitute people huddle in doorways on streets along which their fellow citizens in designer clothes hurry to work or shop or meet up with friends. Everywhere, huge tropical
trees, as if in dogged defiance of the relentless spread of concrete and tarmac, buckle the pavements with their roots, drop their blossoms on passers-by and harbour chattering birds in their leafy
crowns. This is the city where Maria Isabel Achatz lives and where she began to uncover an extraordinary story of familial cancer as she worked at the huge, modern A C Camargo Hospital. And it is
where I visited her in the late summer of 2012 to hear her story.

A C Camargo, the largest specialist cancer centre in Latin America, was purpose built in 1953 on the site of a former Japanese temple a short distance from the busy boulevards of the city
centre. This is the district of Liberdade, a network of narrow, shabby streets lined with small shops, businesses and open-fronted diners arranged on hills that afford sudden views across
São Paulo, out on to green squares and old churches and beetling traffic. Liberdade is home to the biggest community of Japanese people outside Japan. With its complex of modern research
laboratories and training facilities alongside the imposing white building of the hospital itself, A C Camargo dominates the district. Every year some 15,000 new patients seek diagnosis and
treatment here. Around one in 20 of them comes from outside Brazil, attracted by the fact that A C Camargo’s oncologists are specialists in many different aspects of cancer and are highly
skilled.

Achatz is an oncogeneticist, a relatively young specialism in medicine that is concerned with cancer cases in which the faulty genes are inherited rather than occurring by chance during the
course of life. She grew up in a cosmopolitan family in Rio de Janeiro, the daughter of an economist father and housewife mother, and the youngest of six children. On finishing high school she went
to university in Paris to study art and design. But her plans for a career in the arts came unstuck when she joined a bunch of her university friends on a visit to India. The group spent time on
the Kashmir border, camping in a desert area close to the site of a leprosy colony where the people were living as outcasts in caves in a stony hillside. Their plight, and their extraordinary
resourcefulness, made a deep impression on Achatz. But it was a chance meeting with Mother Teresa, whose religious order ran the colony, that made her decide on a career in medicine instead.
‘It was an amazing encounter and I thought, well, I just have to go back and do something more worthwhile.’

Achatz returned to Brazil and eventually to medical school in São Paulo – a training that was interrupted briefly by the birth of two of her children. Family life has always been
important to her and she says, ‘I decided to go into genetics because I wanted to work with families. Mostly I wanted to work with cancer genetics, which was an emerging field.’ A C
Camargo has one of the busiest oncogenetics programmes in the world, and during her first year there, while she was still a trainee, she saw 30 families with what she believed was LFS.

‘It really struck me because this was considered to be a terribly rare syndrome. There were only 280 families described in the world literature at that time – and I had 30. So I
thought, either I’m over-diagnosing or something unique is happening here,’ she told me as we sat talking in her small, windowless office behind the lab in one of the research
buildings. Maria Isabel is tall, slim and effortlessly elegant, with long brown hair which she occasionally ties back into a swinging ponytail. Dressed casually in white shirt and slacks, she sat
behind her desk, always prepared for a phone call from one of her patients or a colleague or student.

There are more than 70 cancer-predisposition syndromes, she told me, but she thinks she has an eye for spotting LFS, having seen her first family with the syndrome while she was still a medical
student at another hospital in São Paulo. ‘This patient came just for clinical follow-up, but after the consultation she said, “Well, actually I am a cancer survivor. I’ve
already had five different cancers.” I said, “You mean metastases?” And she said, “No, no, five different cancers.” Then she listed all the different tumours
she’d had and she said, “This is something really common in my family – we have so many cancers . . . It just happens, and we get better afterwards.”

‘I was so fascinated that I studied and studied, and when I came to this hospital as a trainee, again, the first patient I saw was a Li-Fraumeni patient. They just kept coming and coming,
till I had by the end of the year these 30 families with LFS.’

One of the ways scientists communicate their findings to each other is through the medium of posters – short summaries of their research projects that they are invited to pin up on special
display boards in side rooms of scientific meetings. In spare moments, delegates can wander around reading the posters at their leisure. Achatz’s boss at A C Camargo encouraged her to submit
a poster on her LFS families to a cancer conference scheduled for France in the winter of 2002, and when it was accepted she and he flew together to Paris to attend. Achatz recounted how she found
herself standing before her poster discussing her work with a tall, earnest, bespectacled scientist whose name she didn’t know, when an agitated official came to tell him he was due on stage
any minute as chairman of the next session. As he hurried away, Pierre Hainaut handed her his card, ‘and I realised I had been talking to one of the top scientists of WHO’s centre at
IARC,’ she laughed.

As keeper of the p53 mutation database, Hainaut was well aware of LFS and its supposed rarity, and he was fascinated by Achatz’s story. He invited her to visit him at his lab in Lyon
before flying home from the conference, and after much negotiation the two agreed to collaborate on research into the Brazilian phenomenon. Maria Isabel had never seen herself as a research
scientist – ‘I was very happy being a medical doctor, taking care of my patients and trying to detect their tumours early,’ she told me. Besides, at the time of the Paris
conference, she was pregnant with her fourth child and fully intended to drop back into the carefully constructed routine of family and hospital life she had left. Encouraged by Hainaut, however,
she did a PhD and today she combines research, and the supervision of a bunch of students, with a busy medical practice at A C Camargo.