Nearly a third of cancer cases linked to inherited genes: study

A large twin study has found that in some families, there is a shared increased risk of any type of cancer.

Led by researchers at the Harvard T.H. Chan School of Public Health, the University of Southern Denmark, and the University of Helsinki, the study is the first to look at family risk estimates of common and rarer cancers.

The study, published in JAMA, looked at 23 different types of cancer and familial risk was seen for almost all cancers.

Co-lead author of the study Lorelei Mucci, associate professor of epidemiology at Harvard Chan School said: “Prior studies had provided familial risk and heritability estimates for the common cancers—breast, prostate, and colon—but, for rarer cancers, the studies were too small, or the follow-up time too short, to be able to pinpoint either heritability or family risk.”

Investigators looked at more than 200,000 identical and fraternal twins in Denmark, Finland, Norway, and Sweden, who were part of the Nordic Twin Study of Cancer. The twins were followed over an average of 32 years between 1943 and 2010.

One in three developed cancer in their lifetimes. Cancer was diagnosed in both twins for 3,316 pairs, 38% of identical twins had the same cancer compared to 25% of fraternal twins.

The researchers found that when one twin had been diagnosed with cancer, the fraternal twin’s risk of developing any cancer was 37%. Among identical twins, the risk jumped to 46%.

As fraternal twins are similarly genetically to other non-twin siblings, the study found that there is an increased cancer risk for families when one sibling contracts cancer.

Overall, the heritability of cancer was estimated at 33%. The cancers with the highest heritability were: skin melanoma (58%), prostate cancer (57%), non-melanoma skin cancer (43%), ovarian cancer (39%), kidney cancer (38%), breast cancer (31%), and uterine cancer (27%).

Co-author Jacob Hjelmborg, from the University of Southern Denmark said: “Because of this study’s size and long follow-up, we can now see key genetic effects for many cancers.

“Findings from this prospective study may be helpful in patient education and cancer risk counselling.”

Read the full study in JAMA.

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Why we can trust scientists with the power of new gene-editing technology

A summit of experts from around the world is meeting in Washington to consider the scientific, ethical and governance issues linked to research into gene editing. Convened in response to recent advances in the field, the summit includes experts from the US National Academy of Science, the UK’s Royal Society and the Chinese Academy of Science.

Gene editing is a new technique that allows one to change chosen genes at will. It has been applied to many organisms but a recent report from China showing the modification of human embryos using a technology known as CRISPR/Cas9 mediated editing set alarm bells ringing.

Here’s the main fear: if you modify an embryo (and therefore also its germline), you change not only the person that embryo will become but also its future sons, daughters, grandsons and granddaughters.

Since we don’t know much about this technology, it’s right to stop and think about it. But personally I’m not overly concerned: we’ve been here – or somewhere quite like it – before.

Learning from history

In 1975, scientists met at Asilomar on the Californian coast to discuss a moratorium on recombinant DNA (that’s DNA formed from combining constituents from different organisms).

Alarm bells had started ringing when scientists realised they could combine the DNA from a monkey virus with a circle of DNA called a plasmid, carrying an antibiotic resistance gene purified from the human gut bacteria, Escherichia coli (E. coli).

This cocktail sounded dangerous and scientists discussed a voluntary moratorium on certain experiments, as well as sensible guidelines for containing recombinant material within laboratories.

Why we can trust scientists with the power of new gene-editing technology - Featured Image

Horizontal gene transfer occurs in nature when DNA is carried between species by viruses and related carriers.
Jer Thorp/Flickr, CC BY

Regulations and guidelines are still in place and after 40 years few, if anyone, has been harmed by recombinant DNA. And there have been no reported outbreaks of recombinant material that have significantly affected human health or the environment.

All technologies, including different agricultural practices, have upsides and downsides, and most medicines and treatments have side effects. But recombinant DNA would now have to be classed among the least dangerous of scientific developments.

Understanding science

One reason the technology has proven so safe may be that genetic recombination has been going on for millions of years. In most cases, genes are simply passed on from parent to child. But horizontal gene transfer also occurs in nature when DNA is carried between organisms or even species by viruses.

Over time, DNA is naturally swapped around and moved. Though you may have eaten transgenic plant products, I very much doubt you’ve noticed.

There was a fear “mad scientists” would invent dangerous new superbugs and killer viruses. Perhaps this could have happened, but sadly there are enough pre-existing dangerous substances and naturally occurring diseases, which have been perfected by evolution, out there already. So germ warfare scientists are more likely to just use them.

Another fear was that researchers would modify humans. Most countries quickly outlawed the modification of human germ cells and, to my knowledge, it has never occurred. In general, scientists seem to have obeyed the regulations.

But another reason is that it has proved difficult to introduce new genes into mammalian cells. It’s legal to modify human cells, such as blood stem cells, to cure genetic diseases. But human cells are among the hardest to modify. Human “anti-viral” software seems so powerful that it inhibits the stable insertion and expression of new DNA.

The promise of gene editing

I’m sure you’ve met people who’ve had their teeth straightened or undergone cosmetic surgery. But you’ve probably never met anyone who’s had gene therapy or ever seen a transgenic animal.

Could that change with gene editing? Gene editing is so precise that one doesn’t just lob in a new gene and hope it works; what one does is edit the existing gene to eliminate any misspellings, introduce beneficial natural variants, or perhaps cut out or insert new genes into chosen locations.

Our anti-viral software may not even detect what’s happened. And provided there aren’t any “off-target’” effects, where we hit the wrong gene, there may be no or minimal side effects.

Now that it’s so easy to meddle in human genes, why shouldn’t we worry?

The new technology is a game-changer – but it’s not a runaway phenomenon, like releasing cane toads, blackberries or rabbits into Australia. After 40 years, there have been few, if any problems, with genetically modified organisms. And the experiments – though much easier now – are still so elaborate and expensive that the technology will spread slowly.

We’ll likely remain cautious about modifying human embryos and about any modification that may be passed on to the next generation. To date, consent is required for all treatments. And while patients may opt for experimental cancer therapy or surgery, we always try to think carefully when others, who cannot consent, will be affected.

Some people will even ask why it’s wrong to correct a defect that could haunt future generations. Or, if we could introduce a gene variant that protects people from cancer – such as creating a duplication of the tumour suppressor gene p53 – why wouldn’t we want that for our children?

Genetics is a branch of science that’s ripe for discussions, and conversations on recombinant DNA, gene therapy, cloning and stem cells have all gone well. Guidelines have been sensible and researchers have largely complied with them.

The very fact that people from across the world are gathering to discuss the issues surrounding the latest breakthroughs in gene technology is a very strong sign that the science will be used responsibly. One hopes that the concurrent meeting on climate change in Paris is also a victory for science.

Merlin Crossley, Dean of Science and Professor of Molecular Biology, UNSW Australia. This article was originally published on The Conversation. Read the original article. Main photo: Libertas Academica/Flickr

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No sugar tax in sight

The Federal Government has signalled it is unlikely to implement a sugar tax or other financial incentives to influence eating habits.

Convening the first meeting of its Healthy Food Partnership, Rural Health Minister Fiona Nash – who also has oversight of food policy – indicated that although the Federal Government wanted to encourage consumers to make healthier food choices, it would not seek to “force feed” them.

“Government can’t force feed healthy food to its citizens,” Senator Nash said. “It is up to individuals to take responsibility for what they eat. Government’s role is to educate and provide tools to help people make healthy choices.”

The Partnership includes representatives from food manufacturers and producers, industry groups, the Public Health Association and the Heart Foundation.

Senator Nash said it had been formed to come up with strategies to increase the consumption of fresh fruit and vegetables, as well as to reformulate food to make it healthier, and to “deal with” issues of portion and serve sizes.

Organ donations on the rise

There was a 10 per cent increase in the number of deceased organ donors in the first nine months of the year.

Australian and New Zealand Organ Donation Registry figure show there were 320 deceased donors between January and September, and there were 907 transplant recipients – including 48 who received multiple organs.

AMA President Professor Brian Owler said the increase was encouraging but, with about 1600 people waiting for a transplant at any one time, many more donors were needed.

Professor Owler encouraged people to think about becoming a donor, and urged families to respect the wishes of those who chose to become a donor.

Rural health talks

Rural Health Minister Fiona Nash has convened a meeting of 17 organisations representing rural health professionals, students and instructors as part of an effort to boost health services in the bush.

Senator Nash said a key focus of discussions was ways to increase the number of doctors and other health professionals working in rural and regional areas.

The Minister said that it was not just more doctors who were needed in rural areas, but the whole gamut of other health professionals, including nurses, physiotherapists and dentists.

Fmr NSW Health Minster joins Medical Deans

Former New South Wales Deputy Premier and Health Minister, Carmel Tebbutt, has become head of the peak body representing the nation’s Medical Deans.

Ms Tebbutt, who entered NSW Parliament in 1998 and served in a variety of ministerial portfolios while in government, did not contest the 2015 State election.

She is married to Federal Labor frontbencher Anthony Albanese.

Online credential check for overseas doctors

Overseas medical graduates looking to work in Australia will now have their qualifications verified through a web-based system that will also allow them to keep electronic records of education, training and licensing credential following an agreement struck by the Australian Medical Council and the US-based Educational Commission for Foreign Medical Graduates.

Under the deal the AMC, which provides a centralised service for specialist medical colleges and other organisations to check the credentials of international applicants, requires overseas medical graduates (OMGs) to have their qualifications and experience verified by the Commission from primary sources through its Electronic Portfolio of International Credential (EPIC) program.

The AMC said the EPIC program provided it with a secure, web-based platform for authenticating the credentials of applicants, and enabled paperless processing and record-keeping.

The Commission said OMGs could use EPIC to build a “digital portfolio” of verified credentials accessible anywhere, and could be used to satisfy the requirements of regulators, potential employers and other organisations.

Put cancer drugs on fast track

The Federal Government should speed up approval processes for new cancer drugs and look at developing a national medicines register, a Senate inquiry has recommended.

An investigation into the availability of specialist cancer drugs said that the current trend toward a larger range of treatments that are targeted at small populations of patients is likely to continue, putting increasing pressure on the medicines approval process.

Senator Catryna Bilyk, who was a member of the inquiry, told Parliament that there was increasingly a personalised medicine approach in which the genetics of tumours are established and high-throughput screening of existing medications is undertaken to determine which drugs that show activity against the tumour. This is used by oncologists to inform their treatment.

“More targeted medicines and therapies have the ability to increase the range of treatment options for cancer patients, resulting in improved quality of life and survival for many patients,” Senator Bilyk said.

But such treatments can be very expensive, and often patients face a lengthy wait before they can get subsidised access while regulators, medical experts and ministers assess them for efficacy and cost effectiveness.

The inquiry recommended a comprehensive review of the system, including looking at fast-track processes used overseas, and suggested the Government consider setting up a national register of cancer medicines.

National registration for paramedics

The Federal Government has opposed a move to establish a single national registration scheme for paramedics.

A majority of the nation’s health ministers agreed to include paramedics in the National Registration Accreditation Scheme at a meeting in Adelaide last month, overriding the objections of Federal Health Minister Sussan Ley.

The move is seen as consistent with a push to establish nationally-recognised qualifications across a range of occupations.

But New South Wales has reserved its right to opt out of the process, and, according to a communique from the meeting, Ms Ley argued it was “not consistent with the principles of the NRAS as a national regulatory reform”.

Adrian Rollins

How cancer doctors use personalised medicine to target variations unique to each tumour

The Children’s Cancer Institute in Sydney recently launched an ambitious program. From early next year, scientists will analyse the unique cancer cells of 12 children diagnosed with the most aggressive forms of the disease to find the best treatment for each child.

By 2020, they aim to have these individualised treatment options available to all children diagnosed with cancers that have a less than 30% survival rate. This way of tailoring treatment to each person is known as personalised medicine, and advances in DNA sequencing have paved the way for a new era in cancer management.

Tailoring treatments

The modern use of the term “personalised medicine” is based on the idea that by understanding the specific molecular code of a person’s disease, and particularly its genetic makeup, we can more accurately tailor treatment to them. This approach is also referred to as precision medicine.

Cancer is fundamentally a disease of altered genomics – genetic material making up the structure of cells. Because these alterations are different in each person, every tumour is programmed differently with genes made up of varying sequences of DNA.

How cancer doctors use personalised medicine to target variations unique to each tumour - Featured Image

Cancer cells are programmed with a unique code. From shutterstock.com

This is why not everyone will respond the same way to a given treatment. Determining the DNA sequence that makes up the genome of each tumour (genomic sequencing) helps doctors understand how the tumour may be effectively targeted.

Traditionally, identifying effective cancer treatments relied on large clinical trials involving thousands of patients. This approach successfully identifies drugs effective for general cancer features, but these may miss the unique Achilles heel in some people’s cancers.

Because personalised medicine is customised treatment for individuals, clinical trial designs are moving from population-based to one-person trials. Here, a person with a specific genomic makeup is given targeted therapies and the responses are tracked over time.

Genomic framework

While the Sydney children’s program has been described as the first of its kind in Australia, the concept of personalised medicine is not new. Cancer doctors have always managed each person’s cancer by using all the available information about the tumour and other pre-existing medical conditions.

But there are important differences in the development of personalised medicine today.

Breast cancer treatment is one example. For the last 40 years, a large factor dictating the clinician’s choice for breast cancer therapy was the presence or absence of oestrogen receptors in the tumour. Oestrogen receptors receive signals from the hormone oestrogen, which then generates a reaction. Without them, oestrogen wouldn’t have any affect.

If a woman’s tumour didn’t have these receptors, then doctors wouldn’t give them drugs that affected oestrogen as there would be no point.

But now it has become apparent that having oestrogen receptors is not the only criteria for the use of these drugs, as not all women who have oestrogen receptors will benefit from them.

A personalised approach to treatment can prevent having to undergo a therapy that isn’t working. From shutterstock.com

So researchers have gone deeper to see that this is due to the different way oestrogen receptors function in cancer cells.

Understanding the genomic framework of the tumour can determine this function and thus predict the types of women who, despite having the receptor, would likely not benefit from such hormonal therapy.

Different classifications

This understanding of a tumour’s genomic makeup has also led scientists to expand the way cancer is classified. Where previously we categorised cancers by their organ of origin (breast, pancreas etc), findings like the above mean we can now also use a genomic definition.

This has positive implications for optimising cancer treatment.

For instance, one of the most aggressive forms of breast cancer is HER2-positive cancer (human epidermal growth factor receptor 2). The subtype accounts for about 15% of breast cancers, and occurs when the tumour has extra copies of the HER2 receptor gene that promotes cancer cell growth.

Drugs targeting the HER2 protein have shown dramatic success in improving outcomes for people with this subtype. They have become standard treatment.

But it has recently been discovered that excessive HER2 is also present in about 8% of gastric cancers and 3% of pancreatic cancers. This means a therapy successful in one location has the potential to work in another, because the tumour types are similar.

Clinical trials are currently assessing whether HER2-targeted drugs can then also be effective against these pancreatic tumour types.

Cost and benefit

Most major cancer hospitals in Australia have trials investigating personalised medicine at some level. But genomic analyses aren’t widely performed on an individual patient basis.

It is likely examining each tumour in this way will become routine treatment in the near future. There are already international providers who will (for a fee) sequence tumours and suggest treatments based on this information.

For instance, the Foundation Medicine test profiles some 400 known cancer driver genes and can be purchased for $US5,800 (approximately $A8,000). This type of test is not routine in Australia, but internet-savvy patients who have the financial means can arrange to have their tumour analysed with the help of their doctor.

Further to that cost of sequencing is the actual treatment, which may sometimes be an expensive drug not listed on the Australian Pharmaceutical Benefits Scheme for this particular use.

But there are advantages to the personalised approach that transcend cost.

Besides the potential of finding the right treatment, it can lead to stopping a therapy that isn’t working. Or result in a therapy not being undertaken at all; therapies that in many cases are themselves expensive and often have the added burden of side effects.

Elizabeth Williams, Associate Professor, School of Biomedical Sciences, Queensland University of Technology and Rik Thompson, Professor of Breast Cancer Research, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology. If you work in healthcare and have a blog topic you would like to write for doctorportal, please get in touch.

This article was originally published on The Conversation. Read the original article.

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Testing zero-gravity genomics in “vomit comet”

Nature reports that geneticists from Johns Hopkins University have successfully performed genetics experiments onboard NASA’s reduced-gravity aircraft — known as the “vomit comet” — to see whether astronauts will be able to sequence their own DNA during future long-term spaceflights. “The researchers tested two key tools in zero-gravity: one might aid long-term storage of genetic material; another is a small, transportable genetic sequencer”, known as a MinION. They also tried three pipetting methods on their flights — best results came when they used a small plunger inside the pipette, which touches the sample directly, ensuring that no air gets in. “And the pipette’s tip is small enough to avoid ruining the surface tension, which would let fluid escape up the tube.” One of the researchers, Andrew Feinberg said: “I really have to give NASA huge credit in allowing us to do this”, he says. “They’re very curious people. They really want to know.”

Taking off protective clothing spreads germs

A new study in JAMA Internal Medicine shows 46% of carefully removed protective clothing still showed contamination with a fluorescent lotion used to simulate germs or other dangerous matter, The Washington Post reports. “Researchers set up a simulation that involved asking doctors, nurses and other health-care personnel at four hospitals to put on their standard gowns, gloves and masks and smear themselves with [the lotion]. After the participants carefully removed the protective equipment as they usually would the researchers searched their bodies with a black light to see whether any lotion was transferred. Both participants and researchers were surprised to find contamination in a high number — 46% — of the 435 simulations.” The researchers recommended that “educational interventions that include practice with immediate visual feedback on skin and clothing contamination can significantly reduce the risk of contamination”.

Mexico’s soda tax produces drop in sales

Two years after it was passed into law, Mexico’s so-called “soda tax” is showing solid signs of reducing sales of sweetened drinks, reports The New York Times. “Preliminary data from the Mexican government and public health researchers in the United States finds that the tax prompted a substantial increase in prices and a resulting drop in the sales of drinks sweetened with sugar, particularly among the country’s poorest consumers. The long-term effects of the policy remain uncertain, but the tax is being heralded by advocates, who say it could translate [to other countries] … It cost bottlers a peso for every litre of sugar-sweetened drinks, which amounts to about a 10% price increase, a substantial jump. Because it was applied to distributors, any resulting increase would show up on list prices.”

Patient tweets give insights into hospital experiences

A study published in The BMJ collected more than 400 000 public tweets directed at the Twitter handles of nearly 2400 hospitals in the US between 2012 and 2013, FierceHealthcare reports. “They then tagged 34 735 patient experience tweets directed at 1726 hospital-owned Twitter accounts, and broke them down by sentiment (positive, neutral, negative) and then put them into topical categories, such as time, communication and pain.” Lead researcher Jared Hawkins from Boston Children’s Hospital said: “We were able to capture what people were happy or mad about, in an unsolicited way. No-one else is looking at patient experience this way because surveys ask very targeted questions. Unsurprisingly, you get back very targeted, narrow answers.” The data are “suggestive and highlight Twitter’s possible use as a way to supplement … surveys to improve quality.”

Mysteries of cancer-slowing gene revealed

Researchers have uncovered the role played by a gene which suppresses the development of cancer.

Discovered by scientists at the University of Adelaide in South Australia, the findings on the activity of the gene WWOX open new opportunities for scientists to find treatments for cancer.

Professor Rob Richards, Head of Genetics and Evolution in the University’s School of Biological Sciences said his team worked on the knowledge that in certain types of cancer people with low levels of WWOX protein are more likely to develop cancer and that cancers with low levels of WWOX tend to be more aggressive and less responsive to treatment.

“So a higher level of WWOX activity is definitely a good thing to have but, until now, the role that WWOX plays in cancer suppression has been a mystery,” he said.

Professor Richards and his team of researchers, Dr Louise O’Keefe and PhD students Amanda Choo and Cheng Shoou Lee, studied the impact of lower levels of WWOX on cells using a genetic model ─ the small laboratory fly, Drosophila.

“Our research has shown that cancer cells with lower levels of WWOX had a competitive advantage over those cells with normal WWOX levels, and could outgrow them,” says Professor Richards. “This could lead to a more aggressive cancer and worse outcomes for cancer patients ─ poorer survival rates.”

Further research showed that the WWOX gene plays a role in the altered metabolism of cancer cells which are known to use glucose differently to normal cells. Cancer cells tend to use glucose to make more cell ‘building blocks’ than energy, and this is thought to help them to divide and grow.

“Another set of Drosophila experiments revealed that the WWOX gene helps keep the balance of glucose use in favour of producing energy rather than helping cancer cells multiply,” says Professor Richards.

“This difference in metabolism is a key part of how cancer cells have a competitive advantage over normal cells. Low WWOX levels will allow more glucose to be used for these cancer cell ‘building blocks’.”

The good news is that WWOX belongs to a family of proteins that have enzyme activity – this means WWOX activity can be altered by targeting the enzyme.

“We now have a good idea of what WWOX does in cancer cells and how it acts to help suppress cancer. And we have a potential target to be able to influence that activity to change the properties of cancer cells,” says Professor Richards.

The research has been supported by the National Health and Medical Research Council and The Cancer Council of Australia and published in the journal PLOS One.

This story is supplied by The Lead South Australia.

The Cardiac Genetics Clinic: a model for multidisciplinary genomic medicine

Inherited heart disease can be well managed by preventive strategies if detected early. Building on an expanding body of literature on the contribution of hereditary heart disease to sudden cardiac death (SCD)1–3 and the well-validated principles of predictive gene testing in other single-gene disorders, the Cardiac Genetics Clinic (CGC) was formally established at the Royal Melbourne Hospital in 2007. Published data have supported the benefit of clinical screening in such clinics.4 However, detection of a causative mutation, where possible, also allows identification of individuals who are currently clinically unaffected.

The CGC embodies a multidisciplinary model for translating research into international best-practice care.5 This model exemplifies the translation of genetics to genomics in practice, and also aims to educate and inform individuals, allowing them to assume responsibility for their own ongoing care and health.

The CGC is a joint undertaking by the clinical genetics and cardiology units at the Royal Melbourne Hospital. It is managed by a cardiac trained nurse who performs telephone intake on all referrals, and as well as coordinating screening tests and collating relevant clinical information on individuals and their family members before the clinical appointment.6 On average, patients wait 4 to 5 months between referral and appointment. Cardiologists, clinical geneticists and genetic counsellors, as well as fellows and trainees in each field, attend the clinic. Patients may attend individually or with family members; families of deceased patients generally attend as a family unit. Clinics are preceded by a multidisciplinary planning meeting, allowing discussion and decision-making as a group — a particularly important step in making equitable and consistent decisions regarding access to clinic-funded genetic testing and evidence-based medical advice.

The referral base includes general practitioners, physicians and cardiologists; self-referrals are also possible. Relatives of individuals who have died unexpectedly or with autopsy findings suggestive of a genetic cardiac condition are referred by the forensic pathologists at the Victorian Institute of Forensic Medicine (VIFM).

As a consultative service, the patient is discharged back to the referring clinician once the genetic component has been resolved, or an appropriate management plan is drawn up for the referral of at-risk individuals.

Data are maintained in a customised relational database that links individuals from the same family. In recognition of the complexity of genetics and current knowledge limitations in cases where a genetic contribution is suspected but unconfirmed, a plan for periodic file review is prepared, with an electronic reminder system associated with the database. Further, when the clinical implications of a detected genetic variation are unclear, the results are added to the database for future review and reclassification should their interpretation change.

This article presents details of our clinic’s processes and patient population as we move from disease-specific gene testing to next generation sequencing (NGS).

Clinic structure

Our clinic employs a standard operating procedure (Box 1). We have formalised the process of patient review across the departments of genetics and cardiology in our hospital. As many patients travel long distances to visit us, we attempt to provide same-day cardiac testing, before the clinical review. Additional specialised cardiac testing, such as a flecainide test or adrenaline challenge, are provided after the clinical review.

Methods

We extracted data on all patients (n = 1170) who had a first appointment at the CGC between July 2007 and July 2013. This data set included both the proband (the person who triggered the referral to the CGC) and their at-risk relatives. In families where referral followed a death, we describe only the outcomes of the at-risk relatives reviewed.

We extracted the following details for each patient from the CGC database: referral phenotype; number of probands referred (all individuals within this time period were identified as either a proband or an at-risk relative); age at referral; sex and number of at-risk relatives who were screened. Clinical phenotypes are presented in broad diagnostic groups for the purposes of this article.

Approval for the data analysis was provided by the Melbourne Health Human Research Ethics Committee (QA2014096).

Results

Of the individuals seen, 359 (30.7%) were probands, 331 (28.3%) were at-risk family members, and 480 (41.0%) were at-risk family members referred to the CGC following the death of a family member.

Referral diagnosis for individuals seen at the Cardiac Genetics clinic

The distribution of diagnostic categories at referral is presented in Box 2. Inherited cardiac disease in our clinic is categorised into four broad groups: cardiomyopathies, aortopathies, arrhythmias and survivors of cardiac arrest together with families of an SCD individual. In this study:

Cardiomyopathy (n = 315) included dilated, hypertrophic, restrictive and arrhythmogenic ventricular cardiomyopathies.
Aortopathy (n = 303) included Marfan syndrome, Loeys–Dietz syndrome, familial aortic aneurysm and dissection syndrome, and connective tissue disorders.
Arrhythmia disorders (n = 203) included the long-QT, short-QT, Brugada, catecholaminergic polymorphic ventricular tachycardia, mitral valve prolapse, atrial fibrillation, Wolf–Parkinson–White, and sick sinus syndromes.
We grouped individuals and families seen after a resuscitated cardiac arrest or SCD (n = 341).

A small number of patients with other diagnoses (n = 8) were seen at the CGC during the study period.

Number of visits

The number of visits per individual during the study period ranged from one to five. Most patients (57.5%) were seen only once. A very small number of individuals (six) were seen on five occasions (Box 3).

Sex

Slightly more women (603) were seen at the CGC than men (565), but the difference was not statistically significant (χ² test; P = 0.28).

Age

The median age of the study population at the time of patient review was 39 years (range, 13–93 years). Although we operate an adult service, 51 teenagers between 13 and 17 years of age (median age, 16 years) were seen while accompanying family members for a family appointment. Younger teenagers had been offered appointments at a paediatric service, but chose to come to the Royal Melbourne Hospital to avoid being separated from their families. The distribution according to sex and age in each broad diagnostic category is presented in Box 4. There was no statistically significant difference in age between the genders for each diagnostic category (Mann–Whitney) or in the gender spread within each disease category (χ² test).

Genetic testing

Genetic testing was undertaken in 381 individuals (32.6% of population; median age, 38 years; range, 14–93 years). Of these, five individuals had undergone a total of eight previous genetic tests at another service; the results of these tests were available to us and are included in our summary below. The 788 patients not tested were of similar age (median, 39 years; range, 13–82 years). In 11 individuals (median age, 31 years; range, 15–61 years), a karyotype or microarray test was also ordered, but the results of these tests are not included in this article. Only eight of those who underwent genetic testing were 70 years of age or older (< 0.1% of those tested). The genetic tests undertaken were of two types: mutation detection (in 170 individuals, 44.6%) and predictive genetic tests (in 211 individuals, 55.4%). In total, 47.4% of probands and 26.0% of at-risk family members were offered genetic testing. The apparently low number of at-risk family members offered testing highlights the fact that it has not been the usual practice of the clinic to undertake genetic testing in the absence of a clinical phenotype. For this reason, genetic testing was not undertaken in at-risk relatives when genetic testing of a proband was either inconclusive or uninformative, or when no clinical phenotype had been established for a deceased proband or in an at-risk relative. Of the 211 at-risk family members who underwent genetic testing, this resulted in a new diagnosis for 58 otherwise healthy individuals (27.5% of those tested).

The frequency and type of genetic testing performed in each of the broad diagnostic categories is presented in Box 5. It is notable that our current clinical practice has not expanded to routinely include molecular autopsy in all cases of unexplained death, but is restricted to situations when a diagnosis is suggested by the results of clinical screening in relatives.

The 376 individuals who underwent genetic testing initiated by our service may have had a single gene or a number of genes screened during a single genetic testing episode. In 93.0% of patients, only one genetic testing episode occurred. In 22 individuals, two genetic testing episodes were undertaken; three individuals had three episodes, and one individual had four. A total of 407 genetic testing episodes were undertaken by the clinic during the 6-year period. Pathogenic mutations were detected in 179 individuals (47.6% of those tested), or 15.3% of all patients reviewed by the clinic. These figures underestimate the total number of genetic tests ordered by the clinic, as testing of subsequently deceased probands was not captured in the current data, as previously described.7

Discussion

The CGC aims to confirm or negate a suspected diagnosis of an inherited cardiac condition to allow implementation of a personalised management plan for the affected individuals and their family members. Attending individuals undergo appropriate screening investigations and examination, and genetic testing is offered when indicated, always accompanied by counselling and education. This allows for a targeted risk management strategy or release from screening, as appropriate. For mutation carriers, counselling includes discussion of reproductive options, including both prenatal diagnosis and pre-implantation genetic diagnosis. Clinic staff liaise widely with other specialists, particularly with paediatric cardiologists who provide the clinical care for younger members of identified at-risk families. Translational research is also a focus, and the clinic has been involved with patient groups in education and advocacy, when invited.

The effectiveness of the clinic is facilitated by a formal relationship with the VIFM, whose staff refer at-risk families after potentially genetic cardiac deaths. This includes communication regarding the likely need for genetic testing, which allows the timely storage of biological material.5 To foster robust discussion about the relevance and interpretation of both post mortem findings and family evaluation, the CGC and VIFM meet on a quarterly basis to discuss cases of particular interest or clinical difficulty. This has proved to be critical in allowing detailed discussion of borderline pathological findings where the significance may not be fully appreciated or which could be incorrectly understood to suggest a particular diagnosis.8

The clinical benefit achieved by the simultaneous review of patients by a cardiologist and a clinical geneticist includes the identification of rare diseases and accurate assessment of the utility of genetic testing. This is borne out by the high yield of mutation detection by genetic testing, which highlights the importance of a multidisciplinary clinic and the usefulness of the whole-family approach.9

Published data on genetic testing as part of standard clinical practice of cardiovascular disease in large cohorts is limited, in contrast to genetic testing in a research setting. A Dutch analysis of the results of genetic testing in 6944 individuals identified potential disease-causing mutations in a third of the families seen. The greatest yield was in families with long-QT syndrome (47%) and hypertrophic cardiomyopathy (46%),10 similar to our clinical testing results.

The ultimate intention of the CGC is to prevent adverse cardiac events through early identification and optimal management advice to at-risk individuals. There are currently no long-term data that show improved outcomes are achieved by this approach, and providing these data remains a long-term aspiration of our service. Similarly, although it is anticipated that cost-effectiveness can be achieved, largely by excluding from screening genotype-negative individuals from high-risk families, this remains to be confirmed.

Access to and the application of genetic testing in the CGC has evolved over time. Initially, an iterative approach was adopted, but this was subsequently replaced by small testing panels and, more recently, by a large gene panel (currently including up to 101 known cardiac disease genes). The use of broad panel testing commenced in the clinic during 2013, and the full impact of NGS technologies, in comparison with single mutation detection, has yet to become apparent. With increasing access to large gene panels comes the burden of interpreting multiple genetic abnormalities.11,12 This involves significantly increased time commitment for both the molecular genetics laboratory and for the clinical geneticists and genetic counsellors who inform the patients and their families. These challenges were discussed in a recent review that highlighted the importance of the relationship between the laboratory and clinicians in the delivery of genetic services.13 It is possible that the current targeted panel approach to testing is a transitionary phase before more comprehensive approaches, such as full exome sequencing, are introduced in the clinic. The current methodology has the advantage that, while it generates an increased volume of results that must be managed in the clinic, the risk of completely unanticipated results is minimised.

We anticipate that the use of genetic testing at the CGC will increase in the future, reflecting both its potentially decreasing cost as well as the increased utility of multiple gene testing that is now routine. The currently recommended care model for genetic medicine,9 achieved by a multidisciplinary team working together with the genetics laboratory, provides an effective means for translating advances in genomic medicine into clinical practice.

Box 1 –
Standard operating procedure of the Cardiac Genetics Clinic

Referral

Referral received

Discussion with relevant members of the team, as needed

Preparation

Telephone intake appointment by genetic nurse

Consent(s) gathered for release of information about individuals and family members

Planning file review (usually by genetic nurse; opportunity to discuss and plan with other staff, if necessary)

Appointments made for clinic and baseline investigations

Clinic appointment day

In absence of previous screening and wherever possible: same-day resting 12-lead electrocardiogram and/or echocardiogram

Pre-clinic meeting of whole team (allocation of patients, multidisciplinary decisions about investigation, management planning and genetic testing)

Consultation with cardiologist/electrophysiologist and clinical geneticist and/or genetic counsellor

Post-clinic review of plan; data entry by genetic nurse

After the appointment

Follow-up correspondence with referring doctors

Follow-up correspondence with patient and family

Coordination of additional special investigations and collation of results

Follow-up as required (return to clinic if genetic testing ordered; review of individual in cases of clinical uncertainty; discharge back to referring doctor, or assist with referral to appropriate service; discharge from need for care)

Database notation if future file review is planned, including responsible person and interval

Box 2 –
Reason for referral of the 1170 individuals seen at the Cardiac Genetics Clinic over a 6-year period

Box 3 –
The number of Cardiac Genetics Clinic visits per patient

Box 4 –
Number of individuals in each diagnostic category, according to sex and age at time of first clinical review

Diagnosis

Women

Men

Number

Median age, years (range)

Number

Median age, years (range)

Cardiomyopathy

165

40 (14–93)

150

40 (14–76)

Aortopathy

143

38 (14–73)

160

35 (15–71)

Arrhythmia disorders

105

40 (15–72)

38 (14–85)

SCD or resuscitated cardiac arrest

188

40 (13–82)

153

36 (14–82)

Other

44 (41–56)

40 (21–56)

SCD = sudden cardiac death.

Box 5 –
The number and percentage of individuals in each family diagnosis category who underwent genetic testing (mutation detection or predictive testing)

	Cardiomyopathy	Aortopathy	Arrhythmia disorders	SCD or resuscitated cardiac death

Total number of patients	315	303	203	341
Genetic tests (% of diagnostic category)	154 (48.9%)	101 (33.3%)^*	97 (47.8%)^†	29 (8.5%)
Median age of tested patients, years (range)	40 (15–93)	30 (14–67)	42 (18–85)	40 (18–62)
Mutation detection tests (% of all tests)	51 (33%)	65 (64.4%)	38 (39%)	16 (55%)
Number of positive results (% of tests)	32 (63%)	33 (51%)	20 (53%)	3 (19%)
Predictive tests (% of all tests)	103 (66.9%)	36 (35.6%)	59 (61%)	13 (45%)
Number of positive results (% of tests)	48 (46.6%)	10 (28%)	27 (46%)	6 (45%)
Overall positive results (% of all tests)	80 (51.9%)	43 (42.6%)	47 (48%)	9 (31%)

SCD = sudden cardiac death. *Four patients had been tested before their appointment with the Cardiac Genetics Clinic. †One patient had been tested before their appointment with the Cardiac Genetics Clinic. No genetic testing was undertaken in the eight patients with diagnoses outside the four broad categories.

Precision medicine: are we there?

Implementation of precision medicine requires a multidisciplinary and systematic approach

In his State of the Union address on 20 January 2015, United States President Barack Obama announced a new initiative in precision medicine, which aims to give “access to the personalised information we need to keep ourselves and our families healthier”.1 So, what is precision medicine? Previously referred to as personalised medicine, it can be defined as the correlation of innate and external factors at an individual level, to better understand the pattern of disease and its impact on the individual, and thus to tailor prevention, intervention and treatment. Precision medicine thus combines genomic and epigenomic data with environmental exposure and lifestyle factors. It has the potential not only to improve health outcomes but to save money by better targeting health interventions to those individuals most likely to benefit.

This research initiative in the US will provide funding through the National Institutes of Health and other partners, initially to cancer medicine. The longer term hope is to create better understanding of genomics, molecular biology and bioinformatics in a bid to improve health for all, not only people suffering with cancer.2

Genetics, the study of heredity, investigates the structure and function of a single gene. We are currently in transition from genetics to genomics, the study of all of an individual’s genes, their molecular structure and function, and their interrelationships and architecture. We are thus refocusing from the utility of single genes in monogenic disorders to the potential of genomics in many complex disorders.

Sequencing of the whole human genome, all 3.3 billion base pairs, has become cheaper, quicker and easier. In the 100 000 Genomes Project, Genomics England is sequencing the whole genome of 100 000 individuals with common cancers or rare inherited diseases, to facilitate the incorporation of genomic medicine into the National Health Service (http://www.genomicsengland.co.uk/the-100 000-genomes-project). Similarly, in the Melbourne Genomics Health Alliance, seven health and research organisations are working in partnership to incorporate genomics into health care and assess the health economics argument for genomics (http://www.melbournegenomics.org.au). This has been initiated with pilot projects in areas such as epilepsy, rare childhood diseases and colon cancer.

While genomics might underpin precision medicine, it is only part of the picture. The bioinformatic capacity to analyse the data will allow interpretation of the pinpoint accuracy of current genetic technology. The impetus needs to shift from technology to informatics in clinical practice and improving health outcomes. Benefits to patients will only occur when their clinical details can be linked to their specific genomic data and their treatment altered accordingly.

Implementation of precision medicine will require convergence of disciplines, involving not only clinicians and scientists, but also mathematicians, engineers and philosophers — rather than the siloed approach of previous decades. Governments internationally are now recognising the importance of this convergence.1,3 In Australia, we have much preliminary data already. The University of Melbourne and Cancer Council Victoria host PEDIGREE (Pathology, Epidemiology, DNA, Informatics & Genetics: a Research Enabling Enterprise) (http://www.cancervic.org.au/research/epidemiology/pedigree). PEDIGREE is a resource of 100 000 people, 20 000 families with cancer, 1 million biospecimens, data, researchers and community representatives, evolving through collaboration over two decades to enable studies of the genetic and environmental factors associated with the risk and prognosis of some of the common cancers that affect Australians. The aim is to develop risk management strategies which can be applied at a population level to those who have a genetic predisposition to these cancers and ultimately prevent the cancers from developing.

It is intuitive that a precise therapy, based on the biology of disease, would lead to more effective treatment. And it is intuitive that even if the precise therapy is expensive, the elimination of waste will lead to longer-term cost savings. But to ensure that this is the case, clinical trials must occur in parallel with economic modelling and a robust economic argument must be made to justify the use of precision medicine. Initial support for precision medicine has come through a few effective targeted treatments for cancer. The best known of these are trastuzumab, a monoclonal antibody therapy for HER2-positive breast cancer, and imatinib, a tyrosine kinase inhibitor, for the treatment of chronic myeloid leukaemia. Ward has cautioned that, apart from a few well known exemplars, little has changed in the treatment of cancer and that the “[s]ubstantive benefits of personalised medicine continue to elude us”.3 In the short term, it is the primary objective of the Obama initiative to tackle this problem.1

As a practical example of precision medicine, pharmacogenomics — the use of an individual’s genome to optimise medication prescribing — has promising early outcomes. The dictum to reduce medication errors and harm using the six “rights” — the right drug and right dose for the right person via the right route at the right time with the right documentation — should now expand to include a seventh, the right genotype. An integrated electronic medical record and a pre-emptive pharmacogenomic approach will facilitate this knowledge in advance of the need to use the medication. For example, in individuals of Han Chinese descent, the HLA-B*1502 genotype will predispose an individual taking the antiepileptic drug carbamazepine to severe, life-threatening Stevens–Johnson syndrome.4 It is simple and inexpensive to test individuals of this ethnicity for this allele before commencing carbamazepine. Pharmacogenomics will become more important over time, particularly in areas such as aged mental health, where polypharmacy in frail people complicates a number of comorbidities. Pharmacogenomics will assist in optimising drug selection for an individual, reducing adverse events and also the time lost when drugs are not effective.

To bring precision medicine into practice through genomics, we need a systematic approach. Australia will need to develop genomic literacy in the workforce through a combination of dedicated specialists (clinical geneticists and genetic counsellors), while upskilling all health professionals. In parallel, we require a workforce of genomic diagnosticians and clinical bioinformaticians to receive and translate genomic research discoveries for clinical use.

Precision medicine will be built on a foundation of evidence ranging from population studies to individualised approaches such as single-patient studies, where clinical trials are targeted to the disease process and the individual genotype.

Precision medicine initiatives raise a range of new ethical issues. Until now, most genetic tests have focused on the single gene under investigation, with recent expansion to small gene panels, specific for the clinical question. However, the genome can be sequenced in its entirety once, and then reinterrogated at multiple occasions over an individual’s lifetime. The large amount of data thus generated can be stored and used indefinitely. The issue of unintended findings has been debated for some time. Genomic data may inform individuals about susceptibility to one or many medical conditions which had not been anticipated by their personal or family history. The American College of Medical Genetics has issued a list of actionable genes, defined as genes for which information about mutations, even if found inadvertently, should be returned to the individuals who carry them.5 In the Australian context, in 2014, the National Health and Medical Research Council released a discussion document on the principles for the translation of “omics”-based tests from discovery to health care.6

While uncertainty is not a new concept in health care, the scale of the current uncertainty associated with the interpretation of genomic data is unprecedented. Without correct interpretation, clinical action based on a DNA sequence variation of uncertain significance is potentially harmful. Unless a sequence variation is classified as pathogenic, no clinical utility can be afforded to such a change. This relates to care of the patient, as well as implications for predictive testing and risk management in family members, and the facilitation of reproductive options, all of which need genetic and genomic certainty. Human research ethics and clinical ethics committees will need to be informed and equipped to deal with these issues as more findings from genomic studies are applied to clinical practice. Informed consent for participation warrants consideration in all quarters. It is imperative to gain and retain public trust.

Precision medicine offers a new dimension in prevention, diagnosis and treatment of human disease, one to be embraced and encouraged. In Australia, we have the potential to contribute to the worldwide knowledge base through our genomic capacity and mature research cohorts. The collection of robust, accessible and linked genotype–phenotype datasets, along with lifestyle and environmental data, will help us to realise the potential of precision medicine for the benefit of our communities.

First use of creatine hydrochloride in premanifest Huntington disease

Huntington disease is a devastating autosomal dominant neurodegenerative disorder that typically manifests between ages 30 and 50 years. Promising high-dose creatine monophosphate trials have been limited by patient tolerance. This is the first report of use of creatine hydrochloride in two premanifest Huntington disease patients, with excellent tolerability over more than 2 years of use.

Clinical record

A 33-year-old patient in our general practice carried the autosomal dominant gene for Huntington disease (HD). The abnormal number of cytosine-adenine-guanine triplet repeats in the huntingtin gene she carried meant she would eventually become symptomatic for this dreadful disease.

The patient requested information regarding potential treatments, as she had become aware of clinical trials for HD and of compounds used by patients with HD. A neurologist had previously recommended a healthy diet, exercise, avoiding excessive toxins (such as alcohol), social enrichment and cognitive stimulation, which together may modestly slow clinical disease progression and improve quality of life.1 She had used preimplantation genetic diagnosis during her pregnancies but preferred otherwise not to focus on her condition. She understood that there were no proven therapies for this incurable condition and did not want to attend HD clinics. She was asymptomatic.

At her request, I searched the PubMed database for possible treatment options. There were some that were unproven in HD but had been used safely in humans for other indications, had a reasonable rationale regarding known HD pathophysiology, and had positive results in animal models of HD and/or early-phase human HD trials.2

In January 2012, I sought advice on using these options (eg, high-dose creatine, melatonin, coenzyme Q10, trehalose, ultra-low-dose lithium with valproate) from a specialist HD clinic but was advised against this approach. Instead, it was suggested that the patient might be able to sign up for clinical trials including high-dose creatine. The patient chose subsequently to participate in an observational trial (PREDICT-HD) which did not limit her options. However, she declined consideration for the Creatine Safety, Tolerability, and Efficacy in Huntington’s Disease (CREST-E) study,3 an international Phase III placebo-controlled trial of creatine monophosphate (CM) in early symptomatic HD. It is also very unlikely she would have been accepted for this trial as she was asymptomatic.

In February 2014, the Creatine Safety and Tolerability in Premanifest HD trial (PRECREST),4 a Phase II trial, showed significant slowing of brain atrophy in CM-treated premanifest HD patients. If convincingly replicated, this would be a major advance.

The main practical problem with high-dose CM (20–30 g daily) is tolerability. Adverse effects are common, especially nausea, diarrhoea and bloating. In people who have normal renal function before commencing creatine supplementation, creatine does not appear to adversely affect renal function.5

In PRECREST, about two-thirds of patients tolerated the maximum dose (30 g daily) and 13% of those on placebo were unable to tolerate CM when they switched to it. Moderate intolerance appears to be common. A high dropout rate affected the HD gene carriers in this study despite assumed high motivation.6 Recommended additional water intake for patients on CM therapy is 70–100 mL per gram of creatine per day, which is problematic at high doses of CM.

The patient again requested assistance as she wanted to seek the best available potential treatment to face her condition with equanimity.7 I decided that, provided safety was paramount, I would assist her on an informed consent basis as part of my duty of care, respecting her informed autonomy.

A case presentation and treatment plan was prepared and an expert team of relevant medical specialists was assembled. Comprehensive informed written consent, including consent from the patient’s partner for additional medicolegal protection, was obtained. The New South Wales off-label prescribing protocol8 was followed, actions were consistent with article 37 of the Declaration of Helsinki,9 and medical defence coverage for the proposed treatment was specifically confirmed by my indemnity insurer.

After baseline assessment, including renal function and careful attention to hydration, the patient commenced oral CM therapy at 2 g/day. This was slowly increased to 12 g/day but she was unable to maintain this dosage due to gastrointestinal adverse effects.

Creatine hydrochloride (CHCl), a creatine salt that has greater oral absorption and bioavailability than CM, and requires less water and a lower dose, offered a possible solution.10 The reduced dose also reduces intake of contaminants, which is very important for extended use. Use of CHCl has been confined to the bodybuilding industry and, to the best of my knowledge after a careful search of PubMed, nothing has previously been published in the context of neurodegenerative disorders.

After review by a pharmacologist and consultation with the co-inventor of the available formulation of CHCl,10 a daily dose of 12 g (equivalent to about 19 g CM) with 100 mL water per 4 g of CHCl was proposed. The manufacturer (AtroCon Vireo Systems) provided 1 g capsules of pharmaceutical grade CHCl at reduced cost. The patient decided to commence CHCl therapy after ceasing CM therapy. The dose of CHCl was slowly increased to 4 g three times a day (12 g daily) with a minimum of 100 mL additional fluid per 4 g dose.

The patient has been taking this dosage since January 2013 without any significant adverse effects and is keen to continue. Her serum creatinine levels are stable. Her serum creatine levels before and after doses have also been measured, and this confirmed that the CHCl is being absorbed.

Shortly after this patient began CHCl therapy, a second related premanifest HD patient requested access to CHCl. After a similar informed consent process, the second patient commenced the same dose of CHCl and has also not developed significant adverse effects. Clinically, both patients remain well.

Discussion

This is the first report of CHCl use in HD, with excellent tolerability for more than 2 years by two patients. If replication of the PRECREST findings confirms high-dose creatine as the first potentially disease-modifying treatment for HD, CHCl may represent an important option for patients, warranting further studies.

In this context, it is disappointing that CREST-E was closed in late 2014 after interim analysis showed it was unlikely to show that creatine was effective in slowing loss of function in early symptomatic HD based on clinical rating assessment to date. There were no safety concerns.11

It will be interesting to see, when eventually analysed and published, whether the magnetic resonance imaging (MRI) data from CREST-E showed any benefit in any subgroup and whether the trial cohort as a whole were in fact all in early-stage disease, and to consider whether the clinical rating scales were sensitive enough in this specific trial context.

Although others disagree, I argue that it remains unclear based on PRECREST findings whether the lack of benefit of creatine for early symptomatic disease in CREST-E is strictly relevant to the much earlier presymptomatic stage of the disease, especially when patients are far from onset.

HD symptoms take 30–50 years to develop, and the disease generally progresses to early dementia and death. Progressive MRI abnormalities accumulate for 20 or more years before onset. It appears that by the time the disease becomes symptomatic after 30–50 years, a multiplicity of interacting pathogenic mechanisms have become active (eg, excitotoxicity, mitochondrial energy deficit, transcriptional dysregulation, loss of melatonin receptor type 1, protein misfolding, microglial activation, early loss of cannabinoid receptors, loss of medium spiny striatal neurones, oxidative stress), and early and late events have occurred. The authors of a study of postmortem HD brain tissue refer to these mechanisms as a “pathogenetic cascade”,12 while others refer to them as multiple interacting molecular-level disease processes.13 “Early” downregulation of type 1 cannabinoid receptors has been identified as a key pathogenic factor in HD.14 In a recent review on the pathophysiology of HD, the authors described “a complex series of alterations that are region-specific and time-dependent” and noted that “many changes are bidirectional depending on the degree of disease progression, i.e., early versus late”.15 These and other findings suggest that HD has a complex temporal and mechanistic evolution that has not been fully elucidated. For this reason, we should think carefully before abandoning an agent when it fails at the relatively late symptomatic stage of this devastating and incurable disease.

As creatine is thought to have a useful potential for action in relation to only one of the many relevant disease mechanisms — mitochondrial energy deficit — was it too much to expect creatine to have a significant impact on symptomatic-stage disease in CREST-E? It seems possible, based on the references cited above, that there are fewer (or less intense) pathogenic mechanisms operating at much earlier presymptomatic stages of the disease, when the brain is more intact and plastic. If so, treatment trials in presymptomatic patients assessed using MRI or other biomarkers might offer better prospects for benefit.

I believe that sophisticated replication of PRECREST (or at least clarification as to whether the slowed rate of atrophy on MRI in premanifest patients was genuine or artefactual) is an ethical obligation that we owe to the HD community who contributed so much to CREST-E.

There are significant ethical and sociomedical issues associated with HD research. In reviewing the literature, it was obvious that early-phase research contains multiple examples of existing, out-of-patent or non-patentable potential therapies that appear to warrant modern clinical trials and, I argue, at an appropriate early stage of the disease.2,16,17 Early-phase studies of combination therapies with existing agents appear frequently to receive little, if any, follow-up.2,18

Currently, any drug for which US Food and Drug Administration or European Medicines Agency approval is sought for presymptomatic HD must achieve a clinical end point first in symptomatic HD, then requalify in presymptomatic HD, meeting combined clinical and biomarker end points. Does this arbitrarily overprivilege the clinically observable stage of a disease, which is now understood (based on relatively recent MRI studies) to have a course of 20 or more years before symptoms begin?

Because of the enormous costs associated with drug development, and the uncertainty of such research, I believe that it is time for a renewed focus on small, targeted clinical trials, especially in premanifest HD, using existing and novel agents. Recent advances in MRI and additional biomarkers that are under development19 open the possibility of meaningful small trials that aim to slow HD progression until gene therapy arrives.

None of this, however, will achieve its full potential unless we address the barriers to genetic testing. The true incidence of many genetic conditions, including HD, in Australia is unknown. If a treatment becomes available, more people will want to be tested. The decision to have genetic testing is complex, controversial and uniquely personal. Respecting this, I believe that we need to urgently follow the lead of the United States, Germany, Sweden, France, Denmark and other countries in legislating to end genetic discrimination in health, insurance, employment and services.20 I urge policymakers to replicate and clarify PRECREST and, in full collaboration with the HD community, trial existing and available medications alongside novel agents.

Disclosing genetic information to at-risk relatives: new Australian privacy principles, but uniformity still elusive

Recent reforms to the Privacy Act 1988 (Cwlth)1 have led to a single set of Australian Privacy Principles (APPs), replacing the former National Privacy Principles (NPPs) and Information Privacy Principles (IPPs). Although a key objective of the reforms was to ensure greater consistency on privacy regulation in Australia,2 the law surrounding disclosure of genetic information to at-risk genetic relatives varies across Australia.

Brief legislative history

While patient autonomy features strongly in health law, a legislative exception to a patient’s right to privacy was introduced in 2006 as an amendment to the Privacy Act.2–4

Former NPP 2.1(ea) authorised the disclosure by health practitioners of genetic information to a genetic relative without the patient’s consent if the health practitioner reasonably believed that disclosure was necessary to lessen or prevent a serious threat to the life, health or safety of an individual who is a genetic relative. The amended Privacy Act enabled the National Health and Medical Research Council to publish guidelines (approved by the Privacy Commissioner) on the use and disclosure of genetic information to a patient’s genetic relatives under s 95AA of the Privacy Act in 2009.5 The substance of this approach is similar to that adopted in the United Kingdom.6

In 2014, the original guidelines were revised to comply with the Privacy Act reforms, but the substantive aspects remain unchanged.7

Onerous requirements are imposed on health practitioners who disclose genetic information to a genetic relative notwithstanding the patient’s refusal to provide consent. Guideline 1 reflects the wording of s 95AA — that use or disclosure of genetic information without consent may proceed only when the authorising medical practitioner has a reasonable belief that this is necessary to lessen or prevent a serious threat to the life, health or safety of a genetic relative. The guidelines strongly urge the practitioner faced with this dilemma to strive to win patient consent for disclosure. The guidelines do not have the power of law, but practitioners can avoid actionable complaint by following them closely.

Experience in practice

The importance of the disclosure guidelines is best illustrated through an example. In families where there is a strong history of breast cancer, genetic testing is likely to be recommended to establish whether female genetic relatives of a patient affected carry the BRCA1 or BRCA2 mutation. Drawing on scenario 2 in the revised guidelines,7 a woman whose maternal grandmother had died of breast cancer at a young age and had tested positive for a mutation in the BRCA2 gene may be advised to undertake genetic testing for this mutation. In the event that the test proves positive, this information would be relevant for her genetic relatives (females and males, who can also be affected by breast cancer), and these relatives should be advised to make contact with a genetics service. In some instances, the patient may not wish to share this information. For example, as in the guidelines scenario, the patient may be willing to advise her own daughters but not other relevant family members (eg, sisters). In the event that there was a sustained refusal to allow any of the relevant genetic relatives to be contacted, the guidelines could be used to allow the patient’s health practitioner to make disclosure to those relatives without the consent of the patient, as the threshold requirement of disclosure being “necessary to lessen or prevent a serious threat to the life, health or safety of his or her genetic relatives” would be satisfied.7

The actual use by Australian health practitioners of the disclosure exception in the legislation and accompanying guidelines is unclear. There appears to be some uncertainty regarding the operation of aspects of the legislation. Bonython8 and Arnold9 have suggested that some misunderstandings could arise. For example, doctors may think that if a patient declines to consent to notify their relatives, disclosure by the doctor may then occur. However, the preconditions for disclosure as set out in the guidelines require that the doctor counsels the patient to ensure that they have made an informed decision. In particular, guideline 3 states that “Reasonable steps must be taken to obtain the consent of the patient or his or her authorised representative to use or disclose genetic information” and gives guidance on appropriate processes when consent is withheld by, for example, respecting the patient’s decision by allowing time for review of the decision and considering referral of the patient to a genetics service. It has also been suggested that there is insufficient differentiation between genetic and familial information, with the result that genetic information which cannot pose a risk to genetic relatives may be disclosed.8 This suggestion ignores the preconditions that must be met before disclosure without consent can be made, including guideline 1 noted above, which clearly confines disclosure to heritable information that is actionable.

Further, the guidelines seek to minimise the risks to the privacy of the genetic relative, specifying that disclosure should be limited to such information as necessary to communicate the increased risk. The sample letter, included in the guidelines, suggests that a general indication of genetic risk in the family will be given (where possible avoiding identification of the patient), thereby giving the genetic relative the opportunity to follow up and obtain further information if they wish. The guidelines (at 3.4) and the Privacy Act (s 16A) allow an APP entity to collect personal information (including contact details for genetic relatives) if it is unreasonable or impracticable to obtain the individual’s consent to that collection, including circumstances where a person refuses to give consent to disclosure, and where that collection is necessary to give effect to disclosure to a genetic relative under the Privacy Act and guidelines.

The initial amendments allowing disclosure were limited to health practitioners in the private sector; there was no equivalent provision applying to health practitioners working for Commonwealth government agencies. Further, as the Commonwealth does not have the power to regulate state and territory authorities, which include public hospitals, it was always clear that to achieve comprehensive national coverage, parallel state and territory legislation would also be required.2

2014 Privacy Act amendments

More recently, privacy reforms have been introduced under the Privacy Amendment (Enhancing Privacy Protection) Act 2012 (Cwlth), commencing March 2014. This was the first stage of implementation of the 2008 recommendations of the Australian Law Reform Commission.10 The amending legislation has led to the introduction of the APPs, which consolidate and replace the IPPs and NPPs, and cover the use and disclosure of health information under s 16B(4) of the Privacy Act. Revisions to the enabling s 95AA guidelines were also required; the 2009 version was rescinded and replaced with new guidelines in 2014,7 which replace all references to the NPPs with references to the new APPs. The recent privacy amendments have extended the exemption in relation to disclosure to health practitioners working for Commonwealth government agencies. However, there is still no uniformity because the exemption does not cover state and territory authorities, which include public hospitals.

A call for uniformity

A uniform approach to this issue is surely desirable. Data from the Australian Institute of Health and Welfare indicate that, of the employed medical practitioners in Australia in 2012, 29 834 worked in the public sector, 31 555 in the private sector and 16 497 in both.11 Currently, there is potential for health practitioners working across institutions and jurisdictions to be subject to conflicting regulations whereby they are legally able to disclose genetic information to genetic relatives in their capacity as health practitioners in the private sector but not if employed by a state or territory public health entity. Further, families may be spread across a number of states and it would be desirable if health practitioners only had to comply with a single uniform system. To ensure uniformity across Australia, proactivity is required from the states and territories to allow for disclosure to genetic relatives by health practitioners working for public hospitals. There are two options for securing a more consistent, national approach. States and territories could legislate to adopt s 16B(4) and s 95AA of the Privacy Act and the guidelines for their use or, alternatively, make their own provision through state and territory privacy legislation and guidelines.

The only states to currently make provision for disclosure of health information are South Australia (s 93(3)(c) and (e) of the Health Care Act 2008) and Victoria (Health Privacy Principle [HPP] 2.2(h)(i) of the Health Records Act 2001). However, the South Australian provision is cast in general terms and is not specific to genetic information, while the Victorian provision has limited applicability to genetic information as it requires the risk to be both serious and imminent before disclosure is permitted.

New South Wales passed an amending Act to the Health Records and Information Privacy Act 2002 (the Health Legislation Amendment Act 2012), which specifically covers the disclosure of genetic information. This amends the NSW HPPs in the Health Records and Information Privacy Act, making them consistent with the Commonwealth s 95AA guidelines.12 This will allow disclosure of genetic information to genetic relatives when there is a reasonable belief that this is necessary to lessen or prevent a serious threat to life, health or safety of genetic relatives (HPP 11(1)(c1)).

Conclusion

It is now incumbent on other states and territories to follow, by legislatively adopting the Commonwealth legislation and guidelines or enacting their own legislation and guidelines to allow for disclosure in appropriate circumstances. It is nonsensical that the capacity for a health practitioner to disclose genetic information to genetic relatives without the patient’s consent depends on whether they work in the private or public sector. Clearly, a more uniform approach should be the goal, consistent with the thrust of the Australian Law Reform Commission recommendations,10 but it requires a cooperative approach to be taken on this important issue.