Yesterday Angelina Jolie shared her experience as a carrier of a BRCA1 genetic mutation that confers a very high lifetime risk of developing invasive breast cancer. New Scientist spoke to breast cancer specialist Allison Kurian, of Stanford University in California who has developed a tool that enables women to determine how different treatment options can reduce their overall risk.

For carriers of a BRCA1 mutation, the lifetime risk for invasive breast cancer is 65 per cent. What is that based on?
It's based on very large studies of thousands of women. When we're counselling people, we give them average numbers because they're the most robust.

Angelina Jolie said her lifetime risk was 87 per cent, where did that figure come from?
That 87 per cent number is from some of the earlier studies. The BRCA1 and BRCA2 genes were discovered in the mid-90s and the earliest research mostly studied very striking families who came to doctors because everybody had cancer. When you look at those families, you're going to make a very high estimate of risk. But then when you do bigger studies, the average risk is lower.

So that 87 per cent figure is probably not a calculation of her personal risk?
I am not involved with her care, but I doubt it's a personal assessment. I see that number often and in general think of it as coming from slightly older, smaller studies. Most of us in this field tend to use the newer numbers from the larger studies.

From that 65 per cent average, what makes an individual carrier of a BRCA1 mutation more or less likely to get breast cancer?
That's the million-dollar question. There's great interest in understanding why one person with a BRCA1 mutation might develop cancer in their 30s whereas another might never get cancer at all.

But if a woman has a BRCA1 mutation and most of her relatives have developed very early breast cancer, I worry about her a little bit more than a woman in a family with a BRCA1 mutation where, for whatever reason, they don't seem to have as many cancers.

Is there a way to accurately calculate someone's individual lifetime risk of developing invasive breast cancer?
I don't think we're quite there yet. The BRCA decision tool we developed makes the average estimate based on large numbers, because that is the safest thing to do.

The tool then compares different options a person might choose. For example, one might choose preventive mastectomy, like Angelina Jolie did; other women might choose a very intensive screening strategy. Our tool helps to compare those different options and what they would provide in terms of survival and quality of life.

Angelina Jolie wrote in The New York Times that her double mastectomy cut her risk of getting breast cancer to 5 per cent. Is that typical of women who undergo this procedure?
That would be about right. Most of the studies estimate that whatever a person's risk might be, the surgery will reduce that risk by 90-95 per cent. If her risk was about 65 per cent you're going to get down to a single digit number.

Not everyone currently has access to – or can afford – BRCA screening tests. Do you think they should be offered to all women?
I'd certainly like to see expanded access to healthcare of all kinds. But I don't think that every woman needs to be tested for BRCA mutations because they're rare. On average, if you pull people in off the street, about one in 400 would carry a BRCA mutation.

But I think when there are red flags – like early breast cancer, multiple breast cancers, ovarian cancer or male breast cancer – all of those families should be offered genetic testing.

As a geneticist specialising in breast cancer, were you glad to see Angelina Jolie share her experience of being someone with a BRCA1 mutation?
Absolutely, I think she was extremely courageous. I think it greatly increases the opportunity that we would diagnose people who are at high risk and offer them life-saving interventions. I'm very impressed; it's a very generous thing to do.

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Brief episodes of stress could be good for us, protecting us from the effects of ageing – as long as we're not too frazzled to begin with. That's the surprise finding of a study measuring stress-related damage inside cells.

Chronic stress causes wear and tear to body tissues, increasing our risk of developing age-related diseases such as cancer, diabetes and dementia.

One reason for this is that the body responds to stress by burning fuel to release energy. While this helps us respond to a threat, it also swamps cells with toxic free radicals produced during metabolism. Switched on long-term, this response damages DNA, RNA and other molecules, ageing us before our time.

Kirstin Aschbacher of the University of California, San Francisco, and her colleagues wanted to test whether a short period of intense stress is more damaging if we are already living through a stressful period. They took a group of women chronically stressed by caring for close relatives with dementia, and made them give a speech in front of a sceptical panel of judges. A group of unstressed women performed the same task to act as a control group.

The researchers asked the women to say how stressful they found the test. They also measured their levels of the stress hormone cortisol, plus biochemical markers of damage inside their cells.

Unexpected effect

For the stressed women, the extra challenge indeed proved particularly harmful: the threat of the test caused more cellular damage than in the non-stressed controls. Perhaps more intriguing, though, was an unexpected effect Aschbacher and her colleagues found within the control group.

Among these normally relaxed women, those who found the task moderately stressful had lower levels of cellular damage than those who did not find it stressful at all. In other words, while chronic stress can have knock-on effects that damage cellular structures, short bursts of stress can reduce such damage and protect our health in some circumstances.

The idea that being under pressure helps to focus attention and makes us better at cognitive tasks has been around for almosta century. But Aschbacher's study is a first step to showing how it can sometimes make us physically healthier as well – although exactly what is going on at the cellular level to explain the result is still unclear.

"It's like weightlifting, where we build muscles over time," says Aschbacher. As long as there is time to recover in between, short bursts of psychological stress "might allow us to become stronger".

Bruce McEwen, who studies the physiology of stress at the Rockefeller University in New York City, describes the research as "provocative", and says it is starting to untangle the mechanisms by which stress can have positive effects. "Mother Nature put these things there to help us adapt and survive," he says.

Journal reference: Psychoneuroendocrinology, doi.org/mb5

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Your article on my research into the environmental and genetic factors that cause high rates of mesothelioma in the Turkish region of Cappadocia was excellent (13 April, p 34).

But contrary to your headline, the Cappadocian villagers are not "the damned". There are reasons for these proud, religious and dignified people to be optimistic.

I hope that in Cappadocia the incidence of mesothelioma caused by the local mineral erionite will decrease and possibly disappear thanks to a new erionite-free village built in response to our findings. We are also identifying new mesothelioma biomarkers and developing more sensitive tests for early diagnosis and better therapies; I anticipate profound positive impacts for those with the condition.

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In the fight against a silent killer, you've got to resort to dirty tactics.

Pancreatic cancer is deadly because it tends to spread, or metastasise, to other parts of the body before symptoms appear. In previous work in mice, Claudia Gravekamp of the Albert Einstein College of Medicine in New York had shown that weakened listeria bacteria colonise tumour tissue but not healthy tissue. What's more, the bacteria seem to home in on the metastatic tumours.

To take advantage of this, her team have now armed the bacteria with a radioactive payload – attaching the isotope rhenium-188 to the listeria using a type of antibody.

They seeded mice with human pancreatic tumours and then injected them daily with the souped-up bacteria for a week, giving them a week off before four more days of injections. A few days later, there were on average 90 per cent fewer metastatic tumours in this group than there were in untreated mice, and the average weights of original pancreatic tumours had decreased by 64 per cent.

A week later, the animals' livers and kidneys had completely cleared the radioactive bacteria from their systems, with no damage to either organ.

Gravekamp thinks the radiation affected metastatic tumours most because cells there were still rapidly multiplying, leaving their chromosomes more open to damage than those in healthy tissues or in the original tumour. The bacteria also play a part by producing reactive oxygen molecules that again damage the tumour's DNA.

If the approach progresses to clinical trials, says Gravekamp, the idea would be to cut out the original tumour, then clear the rest with radioactive listeria. The next step is to test this strategy in mice, as well as other isotopes such as phosphorus-32, which could be incorporated into the cell wall of the bacterium, removing the need for the antibody tether.

"The results from this fascinating approach are encouraging, but we can't tell whether it would be safe or effective until trials are carried out in patients," says Nell Barrie, science communications manager at Cancer Research UK. "But progress is urgently needed, so new approaches like this deserve further investigation."

Journal reference: PNAS, DOI: 10.1073/pnas.1211287110

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WHEN Michele Carbone first visited the Cappadocia region of Turkey, he was struck by the beauty of the volcanic landscape, sculpted by wind and rain into picturesque caverns and rock towers. But the mountains hid a dark secret: some of the villages appeared to be cursed.

The inhabitants are plagued by a particularly nasty form of cancer, called mesothelioma. "When we wake up, we see if we've got a cough, because whoever coughs is considered ready to die," one of the villagers told Carbone. "If we see somebody cough when they're walking in the street, everybody looks at them and thinks they will be next."

People in neighbouring settlements shun those from the "cancer villages" in case their condition is contagious. Some villagers emigrate but not everyone wants to or can afford to – and anyway, some suspect that leaving will not save them from their "fate".

Carbone, ...

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The doctor looks at her patient's test result and sighs – telling a patient he has metastatic melanoma is hard. Chemotherapy probably won't prolong survival. Immunotherapies help in some cases, but make patients sick. Surgery and radiation are mostly used to relieve symptoms. Most patients with this widespread malignant skin cancer will live only six to ten months.

Or at least that was the scenario five years ago. Things have changed. Researchers have discovered that melanoma can be divided into several categories depending on the tumour's genetic makeup. One type with a mutation in a gene called BRAF can be treated with a drug called vemurafenib, which can bring the development of some tumours to a dramatic halt and double some patients' life expectancy.

Innovations in the genetic sequencing of tumours are bringing about a revolution in personalised cancer therapy. To adapt, doctors and researchers are stepping outside their traditional roles. Today's oncologists are informing the research of scientists, while geneticists and bioinformaticians are beginning to shape the treatment of individuals in real-time.

"I'm at the interface of three or four interesting worlds that have previously talked, but not interacted with as much overlap as they do now," says Nikhil Wagle, an oncologist at the Dana-Farber Cancer Institute and the Broad Institute in Boston, Massachusetts. "It's extraordinary."

Wagle may be a cancer doctor, but his role is not limited to patient care. A typical week involves sifting through sequencing data with computational biologists and discussing functional gene studies with lab-based researchers. The result is a better understanding of how cancers differ, he says. "The size of the groups that we are putting people into is getting smaller and smaller."

The role of the cancer researcher is also evolving. Geneticists and bioinformaticians may increasingly be called upon to help make decisions about the best course of treatment for an individual. A handful of institutions have already started to make genetically-informed treatment choices for patients (see "Doctor, doctor", below).

That scenario is still uncommon, though. Even at research centres with access to sequencing equipment and supercomputers to process the information, the medical system is lagging behind advances in genetics. For one thing, there are many unanswered questions. Will insurance companies foot genetic sequencing bills for all individuals with cancer, or only those with advanced disease and few treatment options? What if a person's best treatment option involves an expensive drug that is not yet approved by the US Food and Drug Administration for that particular tumour? And then there's the problem of how to turn genetic sequencing data into a treatment decision. Sequence a tumour and you're likely to find thousands of mutations, many essentially unknown to science. As Wagle and his colleagues put it, the genomics superhighway has met the bike path of medical practice.

In the meantime, a number of new courses are being offered to prepare researchers for this more clinical role, and to tailor their research accordingly. The idea is that doctors can help scientists better understand the cancers they're working with, and choose the best research questions.

Curtis Pickering, a molecular geneticist by training, was granted a TRIUMPH (translational research in multi-disciplinary programme) fellowship at MD Anderson Cancer Center in Houston, Texas. The programme, which exposes postdoctoral fellows to clinical medicine, offered Pickering the chance to shadow clinical doctors, and take a first-hand look at cancer care.

"Working with physicians to understand how patients are treated, and what a tissue sample goes through before it gets into our hands, actually is necessary for us to properly design our research," says Pickering.

Robert Sikes, director of the Center for Translational Cancer Research at theUniversity of Delaware in Newark, thinks these programmes are vital for cancer researchers. "It keeps people focused on the disease rather than the molecule," he says.

Joining the revolution

To be a part of the translational cancer revolution, it's important to get where the action is. "You have to be around not just cancer researchers but oncologists and pathologists," says Marc Ladanyi, a molecular pathologist at the Memorial Sloan-Kettering Cancer Center in New York. "For this kind of work, it's becoming very disadvantageous to be in a university department that's not connected to a cancer hospital."

It's also vital to get a handle on disciplines outside your own area of expertise. "This is team science at its finest," says Elaine Mardis, co-director of the Genome Institute at Washington University in St Louis, Missouri. Beyond cancer genetics, a basic understanding of clinical care, pathology, and pharmacology will be useful. "When you get involved with a group, you learn by osmosis exactly how all this stuff works," she says. "It really takes all of those areas of expertise to work together."

Translational cancer research also involves a host of other players. When a genetic mutation pops up, pharmacologists can alert both researchers and clinicians of new or in-development drugs targeting that mutation that they might try. Materials scientists play an important role in developing tumour-cell scaffolds that enable human tumours to be studied in animal models, which can offer a platform for testing whether or not a drug will work. Genetics counsellors help patients navigate an increasingly complex set of treatment choices.

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James Watson argues that antioxidant supplements might promote rather than deter cancer. He points to the suspected role of the body's own antioxidants in allowing drug-resistant cancers to thrive via their ability to suppress oxidants unleashed by chemo- or radiotherapy. These oxidants usually trigger apoptosis – programmed cell death – in the cancer (16 March, p 28).

However, there is another possible mechanism to consider. He mentions the use of the diabetes drug Metformin for drug-resistant cancers. This is a known inhibitor of a cellular process called the mTOR signalling system. Inhibition of this can cause resistant cancer cells to die by unleashing another form of cell death.

Some of the antioxidants in fruits and vegetables are also inhibitors of mTOR and may have the same effect. So any anti-cancer benefits of these are probably happening in this way, rather than by a direct antioxidant effect.

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One of the world's most prestigious laboratories is frantically trying to resolve a row over its decision to publish the genome of one of the world's most studied human cell lines – a set of cervical cancer cells.

The cells were taken in 1951 from a woman called Henrietta Lacks, without her consent. Her descendants argue that the published genome may reveal genetic traits of family members.

The HeLa cells, as they are dubbed, are exceptionally easy to grow in the lab and have become the cellular equivalent of lab rats. For decades, scientists have worked with these cells to unravel the secrets of cancer and develop new vaccines and treatments.

After publishing the HeLa genome in the online journal G3: Genes, Genomes and Genetics, researchers led by Lars Steinmetz at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, withdrew the data following a barrage of objections.

"It shouldn't have been published without our consent… That is private family information," said Lacks' granddaughter Jeri Lacks-Whye, quoted in The New York Times in a commentary on the dispute by Rebecca Skloot, whose biography of Lacks, The Immortal Life of Henrietta Lacks, appeared in 2011.

EMBL has apologised to the family and is in talks with them to try to resolve the situation.

"As soon as we learned of this we removed our data from the internet out of respect for the family," says EMBL spokeswoman Raeka Aiyar. "We take their concerns very seriously and have reached out to them with our apologies, and to express our determination to work with them towards an appropriate course of action for handling the availability of this data. We are currently awaiting their response."

EMBL also gave the G3 journal a statement on why the researchers withdrew the data.

Chaotic genes

The paper revealed that the genome of HeLa cells is chaotic. That is as might be expected in cancer cells, which undergo abnormal genetic reorganisation.

Steinmetz found numerous regions where chromosomes are arranged in the wrong order, for example, as well as missing genes and surplus copies of others.

The aim of the paper was to show the degree to which the genomes of HeLa cells diverged from those of healthy cells, so researchers could take that into account when designing experiments and analysing results from studies using the HeLa cell line. Having the genome would also allow researchers to check whether new cell lines have been contaminated by HeLa cells, a widespread and under-reported problem.

EMBL acknowledges that the genome of the cancer cells could be used to make predictions about Henrietta Lacks's genome and those of her descendants. But it cautions that there will be significant differences between the genomes of the cancer tissue and Henrietta's healthy cells, therefore limiting what can be deciphered about her and her descendants.

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Thanks to the largest ever study into the genomics of cancer, we now have the data to prevent more cancers than ever before. The work uncovered more than 80 new gene variants, or alleles, that raise the risk of breast, prostate and ovarian cancers.

This knowledge could vastly improve screening to identify and prevent cancers in those most at risk. However, it could be some time before programmes are in place to capitalise on this bumper haul of data.

Worldwide, there are 2.5 million new cases of the three cancers each year, a third of them fatal. Better identification of those at risk could help doctors prevent cancers or catch cancers early before they become incurable.

The gene trawls, coordinated at hundreds of labs by the international Collaborative Oncological Gene-environment Study, double the number of gene variants so far identified that raise the risks of developing the three cancers.

Although each variant raises the risk by only a per cent or so, the effects add up, so the more variants a person has, the greater the likelihood they'll develop cancer, says Doug Easton of the University of Cambridge and lead author of one of a series of key papers reporting the newly identified gene variants.

Reliable screening

The hope is that screening at a younger age for the variants will enable doctors to identify and monitor people with a higher-than-normal risk of developing cancers. People could receive extra scans, for example, to pick up signs of disease while it's treatable, or prophylactic treatments, such as tamoxifen for preventing breast cancer.

Including the new genes in genetic screening could make it more reliable than other forms of screening, such as mammography for detecting breast cancers and the prostate specific antigen (PSA) test for prostate cancer. Both have led to unnecessary and harmful treatments for misdiagnosed cancers.

"Mammary screening has been a sacred cow for many years, but is less so now, so I think there's more appetite to make use of genetic information," says Easton.

But setting up screening systems to apply the findings won't be easy. "The big science and the databases get all the publicity, but what we found is that this knowledge gets very difficult to apply," says Hilary Burton of the Foundation for Genomics and Population Health in Cambridge, UK.

Burton and her colleagues used computer programs to model how a refined screening system for breast cancer would work, if all the new gene variant data was included.

Their model investigated the scope for stratifying everyone in the population according to the combined risks posed by their genes and age. The aim would be to target monitoring and preventative measures at those at highest risk at a young age, and give less unnecessary attention to low-risk individuals.

Complex issues

"We found that we would pick up just as many cancers, but undertake 25 per cent less screening," says Burton. So potentially, this would save money and avoid the harm caused by treating false positives.

At present, women in the UK start being called for mammograms at age 47, when their risk of developing breast cancer over the following 10 years is rated at 2.5 per cent. Then they go on receiving the scans every three years until they are 73.

Despite the potential gains of pre-assessing people at a younger age, say 35 or 40, Burton says that introducing the system would be "complex", not least because a system is already in place for breast screening. What's more, there would be ethical, social and procedural issues to confront, such as how much genetic information to store, how much should be fed back to those screened and what conditions of consent to apply.

Easton agrees that switching to a genetic model of screening will be a challenge, adding that the new gene data itself also needs to be validated through further studies to make sure the reported risk variations hold true.

In the US, genetic screening at present is restricted only to very "high-risk" genes – such as the BRCA1 and BRCA2 genes that increase the risk of breast cancer by 80 per cent. "Regardless of stratification, we need better screening assays for detecting cancer early in average and high-risk populations," says Ken Kinzler of the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. "So anything that focuses our attention on those who need extra screening is worthwhile, as currently this is applied to high-risk patients who represent only a small fraction of cancer cases."

Journal reference: Nature Genetics doi.org/kxx

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WITHIN just eight days of starting a novel gene therapy, David Aponte's "incurable" leukaemia had vanished. For four other patients, the same happened within eight weeks, although one later died from a blood clot unrelated to the treatment, and another after relapsing.

The cured trio, who were all previously diagnosed with usually fatal relapses of acute lymphoblastic leukaemia, have now been in remission for between 5 months and 2 years. Michel Sadelain of the Memorial Sloan-Kettering Cancer Center in New York, co-leader of the group that designed the trial, says that a second trial of 50 patients is being readied, and the team is looking into using the technique to treat other cancers.

The key to the new therapy is identifying a molecule unique to the surface of cancer cells, then genetically engineering a patient's immune cells to attack it.

In acute lymphoblastic leukaemia, immune cells called B-cells become malignant. The team were able to target a surface molecule known as CD19 that is only present on B-cells. Doctors extracted other immune cells called T-cells from the patients. These were treated with a harmless virus, which installed a new gene redirecting them to attack all cells bearing CD19. When the engineered T-cells were reinfused into the patients, they rapidly killed all B-cells, cancerous or otherwise.

"The stunning finding was that in all five patients, tumours were undetectable after the treatment," says Sadelain.

He reckons that the body should replenish the immune system with regular T-cells and healthy B-cells after a couple of months. However, the patients received donated bone marrow to ensure they could regrow a healthy immune system (Science Translational Medicine, doi.org/kwz).

The treatment is not the first to re-engineer T-cells to attack a form of leukaemia. Last year, an international company called Adaptimmune used the approach to treat 13 people with multiple myeloma – it left 10 in remission.

"Although it's early days for these trials, the approach of modifying a patient's T-cells to attack their cancer is looking increasingly like one that will, in time, have a place alongside more traditional treatments," says Paul Moss of Cancer Research UK.

Sadelain's team is now investigating the scope for attacking other cancers. Where no single surface molecule is unique to a cancer, he is seeking to target pairs of molecules that only occur together on cancer cells. In January, he demonstrated this approach by wiping out human prostate tumours implanted in mice, using T-cells engineered to target two surface molecules (Nature Biotechnology, doi.org/kw2).

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